3. A 65-year-old man was admitted with a fever (38 °C) and non-productive cough 4 months after cadaveric transplantation. CMV positive to CMV negative recipient Oxygen saturation on air was reported at 82%. CXR is shown below:
The patient presented with fever and non productive cough, hypoxia and bilateral interstitial infiltrate
Differential diagnosis
PCP
CMV
TB
How manage
Full investigations
FBC, LFT, KFT,blood culture and sputum culture, TB culture, drug level , urine analysis and culture, CMV DNA by PCR
Bronchoscopy, BAL, chest CT
ICU admission
O2 therapy
Good hydration and broad spectrum antibiotics
If PCP give TMP-SMX in high dose
If CMV give IV Ganciclovir followed by oral Valganciclovir
The probable differential diagnosis is mainly PCP vs CMV pneumonia or ARDS.
PCP main characteristic is being early post-transplant especially after heavy induction and high doses of immunosuppression initially, and the presence of dry cough signifies this.
In cases of CMV positive donor serology against CMV negative recipient per worldwide protocols adopt prophylactic measures in the form of antivirals for at least 6 months to 1 year,besides monthly screening for CMV serology making CMV disease diagnosis unlikely.
Confirmation of diagnosis is done by negative CMV serology , BAL is positive for PCP as well as tissue biopsy.
Management of this case primarily needs reduction of immunosuppression, oxygen supply by mechanical ventilation, treatment by TMP using to renally adjusted doses.
CxR showing Bilateral interstitial hilar extending from hilum.
What is your differential diagnosis?
PCP infection
Cytomegalovirus infection
Viral Pnemonia
ARDS
Tuberculosis
Mycoplasma infection
Managment
Diagnosis-The diagnosis of PCP should be considered in patients with risk factors for PCP who present with pneumonia and suggestive radiographic findings. Microbiologic identification of the organism when possible . Detection of the organism in respiratory specimens is most commonly achieved by microscopy with staining of an induced sputum specimen or BAL fluid .The serum beta-D-glucan assay can be used as an adjunct to the diagnosis of PCP.
Treatment–
The dose of TMP-SMX for patients with normal renal function is 15 to 20 mg/kg (dosing is based upon the TMP component intravenously or orally daily in three or four divided doses. Dose may need to be adjusted if creatinine clearance changes during therapy. Patients should receive intravenous therapy until they are clinically stable (eg, PaO2 ≥60 mmHg, respiratory rate <25) and have a functioning gastrointestinal tract. For renal dose adjustment recommendations, refer to TMP-SMX drug information.
Duration-21 days
The differential diagnosis include:
1-CMV pneumonitis
2- TB
3-PCP
4- Malignancy
Management :
full investigations including CT scan of the chest and bronchoscopy +/- tissue biopsy
Give IV valganciclovir
Pneumocystis PneumoniaTMP-SMX is the drug of choice for therapy; drug allergy should be documented before resorting to alternative therapies. Adjunctive corticosteroids may be useful early. Routine PJP prophylaxis is recommended for at least 6-12 months post-transplant, preferably with TMP-SMX.
What is your differential diagnosis? 1. PJP: Immunocompromized patient presenting with desaturation, dry cough and fever. 2. CMV pneumonitis: D+/R- 3. Covid 19 4. Atypical pneumonia 5. Influenza or Para influenza 6. Herpes simplex virus 7. Pulmonary TB 8. Fungal infection 9. ARDS How would you manage this case? o MDT approach involving pulmonologist, ICU and Nephrologist o ITU admission and O2 support o Detailed history and full physical examination o Supportive treatment with IV fluids and Nutritional support o Initial investigations including FBC,ESR, CRP, RFTs. LFTs, and blood culture including TB cultures. Check for Tacrolinus trough level transplant graft US. o Viral throat swab to diagnose viral infections including COVID 19, Influenza and para-influenza and Mycoplasma pneumonia o Urine sample for Legionella urinary antigen o CMV-DNA by PCR test(D+/R-) o Bronchoscopy & BAL ( including CMV PCR on the BAL) o Immunosuppression modification: stop anti-metabolites and continue on CNIs and steroids. o Broad spectrum antibiotics including cover for atypical pneumonia o Definitive treatment: o In case of CMV: IV gancycolvir 5mg/kg BD for 5 days followed by oral valgancyclovir 900 mg od until 2 X PCR are negative.If no response in 2 weeks, assess for ganciclovir resistance and shift to Foscarnet and additional CMV IVIG. o In case of PJP: TMP-SMT given initially IV at a high dose of 15 to 20 mg/kg IV then switching to oral treatment after clinical improvement. Second-line therapy is pentamide 4 mg/kg IV OD with comparable efficacy but worse safety profile .Primaquine plus Clindamycin for severe cases. Increasing steroid dose can be useful in severe hypoxia(Sat <70%) o Monitor graft function during treatment
References: 1) Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. 2) Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587 3. Dominykas Varnas and Augustina Jankauskienė.Pneumocystis Jirovecii Pneumonia in a Kidney Transplant Recipient 13 Months after Transplantation: A Case Report and Literature Review.Acta Med Litu. 2021; 28(1): 136–144.
4 month after cadaveric transplantation
fever (38 °C) and non-productive cough CMV D+/R-
Saturation on air was 82%.
CXR shows diffuse interstitial infiltrates
● What is your differential diagnosis?
Immunocompromised patient with pneumonia and dry cough associated with
Hypoxia and infiltrates in the CXR would make one suspect PCP
Other differential diagnosis include:
CMV pneumonia
Baterial pneumonia
TB
Other viral pneumonia as covid 19
● How do you manage this case?
Laboratory evaluation
CBC,CRP, ABG, TST, IGRA, PCR for CMV , PCJ, and covid 19 , liver tests and renal function.
Chest CT scan
Supportive management as hydration and oxygen.
In PCP pneumonia:
TMP-SMX IV with high doses in case of PCP and pentamide in case that doesn’t response to TMP-SMX
Steroid can be useful in severe hypoxia
In CMV pneumonia:
IV GCV switching to oral GCV when there is improvement
65-year-old man transplanted patient was admitted with a fever (38 °C) dry cough and Oxygen saturation on air was reported at 89%.
CMV positive to CMV negative recipient CXR was done showing fine bilateral interstitial infiltrates with ground-glass opacities more central sparing subpleural space. Dry cough with hypoxia early on presentation with the x ray findings in transplant recipient suggests PCP infection. *Differential diagnosis PCP. CMV. COVID- 19. Bacterial pneumonia. TB *Investigation -Cbc, CRP -ABG -Kidney function test – Tuberculin skin test (TST) and Interferon-gamma release assay. -PCR tests for SARS-CoV-2. -PCR for PCP,CMV,EBV. -sputum and blood cultures -Chest CT scan. *Management -oxygen supply to increase saturation . -adjust immunosuppression. – In case of PCP, treatment with TMP-SMX is the first-line therapy with 15 to 20 mg/kg IV, switching to oral after clinical improvement. -Second-line therapy for severe cases would be pentamide 4 mg/kg IV o.d., though with comparable efficacy but worse safety profile . – Primaquine plus Clindamycin for severe cases. -Atovaquone or Dapsone/TMP for mild to moderate cases are third-line options that can be considered for patients who do not tolerate the above treatments or show no clinical improvement. – Prednisone if oxygen saturation declined to < 70 mmhg on room air. *Reference Dominykas Varnas and Augustina Jankauskienė.Pneumocystis Jirovecii Pneumonia in a Kidney Transplant Recipient 13 Months after Transplantation: A Case Report and Literature Review.Acta Med Litu. 2021; 28(1): 136–144.
65-year-old male, 4 months post-renal-transplant, CMV D/R -ve/+ve, presented with Fever (38), low oxygen saturation at 89% associated with dry cough.
Chest x-ray: bilateral prominent broncho-vascular markings and perihilar infiltrates, few pneumatoceles are seen.
Differential diagnosis includes: 1- Fungal infection like PJP is the first possible DD because of clinical manifestations mainly fever, dry cough and low oxygen saturation associated with minimal chest X-ray finidings. 2- Aspergillosis. 3- Viral infection: CMV, EBV, Covid-19. 4- Bacterial infection. 5- TB pneumonia.
How do you manage this case?
General Non-specific measures: 1- Hypoxia: Oxygen, serial ABG, escalation to non-invasive ventilation (CPAP or BIPAP) 2- Keep ITU in the loop in case of deterioration. 3- Fever: anti-pyretic.
Septic work up: 1- CRP, Blood culture, urine culture, induced sputum culture. 2- CMV PCR, PJP PCR 3- Serum beta D-glucan: is non-specific but if positive it supports diagnosis of fungal infection. 4- Metagenomic next generation sequencing. 5- CT-Chest 6- Bronchoscopy and broncho-alveolar lavage: PJP can be detected using stains like Giemsa, modified Grocott, Weigert-Gram, or methenamic silver.
Modification of immunosuppression medications: 1- Consider stopping MMF or Azathioprine. 2- Monitor level of CNIs, aiming at lower target level. 3- Consider increasing steroids especially if hypoxic.
Specific treatment for PJP: 1- PJP lines of treatment includes TMP/SMX (either IV or orally 15-20mg/Kg/day divided on 12 hours, course for 2-3 weeks), using steroids if ABG shows hypoxaemia PaO2 below 70mmHg. 2- If patient is allergic to TMP/SMX, alternatives include Atovaquone, Dapson, or Primaquine, or IV pentamidine.
Treatment of other pathogens according to results of septic work up.
□Differential diagnosis
1 – CMV Pneumonia
2- Bacterial cause of pneumonia
3- Other viral causes of pneumonia (covid19)
4- fungal pneumonia
5- TB
6- pcp
□Management
● the patient should be admitted to ICU.
● monitoring the vital signs (RR- sat-…)
● O2 supply
● laboratory tests: CBC – CRP- CREA- LFT-
● Sputum samples for staining and culture
●BAL test for (PCP- CMV and other viral herpes and influenza )PCR and culture
●CMV PCR blood test
●HIV status study
●Antibiotics (empirical treatment)
●intravenous ganciclovir until the minimum 2 weeks then it will be changed by oral valganciclovir until the clinical manifestations are improved and the . If there is no response after 2 weeks of treatment, we should assess for ganciclovir resistance CMV and shift to an other type of drugs We should remember that a prophylaxis treatment with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse. ●Immunosuppression reduction is necessary. MMF should be stopped, and adjust the tacrolimus treatment by monitoring the level of CNI and the renal function ●PCP treatment should be started , then , after the laboratory test results become available, it can be withholded
CXR show multiple tiny cysts all over lungs
PCP- caused alveolar infection and sparing of other bronchi
so there is minimal or sputum
DRY COUGH is difficult to diagnose microbiologically as sputum samples are not available;
sputum can be induced with hypertonic saline
invasive test like ET samples or BAL can establish the diagnosis
This recipient renal transplant patient is suffering from a 4 monty history of symptoms and signs suggestive of pneumonia in the form of fever, dry cough, desaturation as well as Chest Xray findings reticulo nodular shadows.
On top of DD is CMV pneumonitis based on the history that CMV positive donor donated his kidney to a CMV negative recipient so high possibility of CMV transmission.
Differential Diagnosis
Viral : CMV, influenza, para influenza, Herpes
Bacteria : streptococcus
Parasites : PCP
Management of this case :
1st step is to transfer the patient to an ICU due to desaturation and critical condition and start resuscitation with O2 and Iv fluids
1. Full detailed history and full general examination.
4 sputum examination for gram stain, cytology, TB C&S may be a bronchoalveolar lavage is required
Regarding Empirical treatment
We shall start empirical antibiotics to cover for Bacterial infections
Based on symptoms and signs and history of transplantation and desaturation we shall start PCP empirical treatment in the form of cotrimoxazole and steroids if o2 saturation drops below 70%
As well as oseltamivir for influenza virus
If CMV is confirmed
Start ganciclovir 5mg/kg IV every 12 hours with dose modifications according to Creatinine clearance continued for 2 weeks then may be shifted to vanganciclovir for 1 to 2 months
If resistance to ganciclovir shift to Foscarnet or IVIG
Secondary prophylaxis with vanganciclovir for 1 to 2 months in high risk patients for recurrence
Admission to ICU with MDT management . may need immunsupresive drug manipulation (stop cellcept and azathioprine ), adequate hydration and monitoring .
A- History and medical record :
– Past medical history
– Viral serology state before transplantation for example CMV serology .
– Crossmatch result , DSA , and immune supresant used for induction ( depleting agent or not )
– Prophylaxis used or not – what and for how long ( methprim, valagancyclovir , nystatin drops….)
– Associated symptoms .
B- Examination :
– General examination ( any skin rash, lymph adenopathy )
– Vital signs ( PR, BP, RR , TEMPRETURE, SPO2 ..)
– Systemic examination ( organomegally )
c- investigation :
– CBC
– CRP
– BIOCHEMISTRY ( B urea , S creatinine , TSB , SGPT, SGOT, Alkaline phosphatase, )
– Q NAT for CMV ,
– Sputum , induced sputum ,bronch alveolar lavage , LDH , β-D-Glucan (BDG), and even lung biopsy to diagnose Pneumocystis jirvocii pneumonia .
– Sputum for AFB , culture and sensitivity, tuberculin skin test, PPD skin test , skin anergy test – for tuberculosis .
d- treatment
should be according to underlying diagnosis .
1- Anti-viral therapy in case of confirmed CMV:
IV gancycolvir 5mg/kg bid for 5 days followed by oral valgancyclovir 900 mg od until 2 X PCR
negative
Adjust the drug doses according to the renal function
2- Anti PCP if confirmed
Trimethoprim-sulfamethoxazole (TMP-SMX): 15-20 mg/kg/day of the TMP component given IV in divided doses every 6-8 h; lower doses may be sufficient. In milder disease, two double-strength tablets can be given po tid 21 days is preferred to avoid disease progression and relapse
Adjunctive steroids: in patients with hypoxemia (pAO2 < 70 mm Hg on room air) Corticosteroid therapy should be considered early for maximum benefit, ideally within 72 hours of initiating antimicrobial therapy. The optimal dose of corticosteroids would be 40-60 mg of prednisone (or equivalent) for 5-7 days before gradual tapering over 7-14 days is recommended to avoid rebound pneumonitis.
REFFERENCE: Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TM, Campos SV, Ramos JF, Latif AZ, Litvinov N, Maluf NZ, Caiaffa Filho HH, Pannuti CS, Lopes MH, Santos VA, Linardi Cda C, Yasuda MA, Marques HH. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015 Jul;70(7):515-23. doi: 10.6061/clinics/2015(07)09. Epub 2015 Jul 1. PMID: 26222822; PMCID: PMC4496754.
Differential diagnosis: CMV Pneumonitis PCP Pneumonia Management: 1. MDT approach 2. ICU admission 3. Reduction of immunosuppression: stop MMF/AZA, continue CNI and steroids, and discuss the risk of rejection. 4. CNI levels measurement 5. Broad spectrum antibiotics and IV ganciclovir if CMV PCR positive 6. BAL for PCP 7. Septic workup: blood and urine cultures 8. Optimizing volume status and preventing AKI. PCP should be excluded because the patient is immunocompromised, timeline is fist six months of transplant and patient has dry cough with hypoxia.
-Oxygen inhalatiion to maintain adequate SpO2 >95%.
-ABC assesment and associated supportive treatment.
Investigations:
– CBC, CRP, ABG
– HRCT of chest
– Broncoscopy
– BAL- for CMV PCR, PCP PCR & gene Xpert for TB.
Quantiferon TB gold test
Treatment:
Definitive treatment according to cause
CMV pneumonitis
a) RIS
– Stop/ reduce (by 50%) azathioprine/ MMF/ myofortic
– Continue corticosteroid
– CNI can be continue unlesd life threatening infection.
b) Anti CMV therapy
– I/V gancyclovir – 5 mg/ kg bd for 5 days followed by oral valgancyclovir for 2-3 weeks or until 2× CMV DNA by PCR are negative.
– If there is reduced absorption e.g- diarrhoea I/V GCV for 14- 21 days.
– Dose adjustment acvording to renal function
Given the clinical picture and radiographical picture, it seems to be more of
“PCP induced pneumonia”
Management of the case:
Lab investigations needed would be
serum LDH level,
serum (1 → 3) β-d-glucan assay
BAL SOS transbronchial biopsy
Trimethoprim-sulfamethoxazole (TMP-SMX):
15-20 mg/kg/day of the TMP component given IV in divided doses every 6-8 h; lower doses may be sufficient. In milder disease, two double-strength tablets can be given po tid
21 days is preferred to avoid disease progression and relapse
Adjunctive steroids:
in patients with hypoxemia (pAO2 < 70 mm Hg on room air)
Corticosteroid therapy should be considered early for maximum benefit, ideally within 72 hours of initiating antimicrobial therapy.
The optimal dose of corticosteroids would be 40-60 mg of prednisone (or equivalent) in adults given two to three times daily and 1 mg/kg twice daily in children for 5-7 days before gradual tapering over 7-14 days is recommended to avoid rebound pneumonitis.
Refrences:
Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation
Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587. doi: 10.1111/ctr.13587. Epub 2019 Jul 1. PMID: 31077616.
Viral(CMV , Covid 19, adenovirus)
bacterial like miliary TB
apportunistic infection like PCP and aspergillosis.
How do you manage this case?
Sputum (either induced or BAL) examination for PCP cyst or trophozoit and for AFB and PCR.
CMV PCR
HRCT
complete investigation
improve oxygenation, hydration, AB , specific treatment accordingly.
This is an 65 year old , S/P renal transplantation , from D+ CMV to R – CMV presented with fever , dry couph , hypoxia and bilateral interstitial infiltration .
D/D
1- CMV pneumonitis
2- PCP
3- TB
4- A typical bacterial infection
5- Less likely fungal infection
nt
How do you manage this case?
This patient needs admission to ICU , with MDT involvements
detailed history should be taken including , type of induction therapy , maintenance immunosupression , is he on PCP prophylaxis or not ? , is he toke CMV prophylaxis post transplantation or not ??
Full work up including , CBC , LDH ( high in PCP ) , Kidney function test , liver function test , CRP , ESR , blood urine and urine culture , sputum culture looking for bacterial viral fungal infection and TB , IF no sputum can be produced consider BAL , serum (1 → 3) β-d-glucan assay ( for PCP ) , ABGs , CMV PCR
HRCT scan
Stop MMF and decrease the dose of CNI , continue steroid
Management of PCP
1- Trimethoprim-sulfamethoxazole (TMP-SMZ) given in a high dose, combined with corticosteroids in patients with moderate to severe infections. 2- If there is allergy or side effects to trimethoprim-sulfamethoxazole, alternative drugs can be used including; Dapsone, Inhaled pentamidine , Atovaquone , Primaquine combined with clindamycin , Combined dapsone and trimethoprim , Pyrimethamine and sulphadiazine. 3- Prophylaxis is highly efficacious in preventing PJP in transplant patients. 4- Overall, with prompt treatment, survival is good (50-95%), relapses are common.
Management of PCP
GCV 5 mg / Kg x 2 for 14 – 21 day or IV GCV for 5 days followed by oral vGCV for 2 – 3 weeks
References :
1) Up to date
2) Prof Ahmad Halwah Lecture
the given patient is a post transplant patient 4 months ago… The details of induction agent is not mentioned…He has now presented with fever cough which is non productive and desaturation on room air…He is also a recipient of CMV Positive to CMV negative cadaveric transplant….
Chest X ray shows bilateral diffuse reticulo nodular opacities
The differential diagnosis are
Respiratory viral pathogens like Swine flu, RSV, Covid 19 infection..These infections are more common and they should be kept in mind with changing epidemiological patterns
CMV pneumonitis – given the picture of the above scenario and transfer from CMV Positive to CMV negative recipient..
Pneumocystis jiroveci pneumonia – they would also present with fever, cough which is non productive and hypoxia
Miliary tuberculosis in a transplant patient can have a fulminant presentation with fever, cough and hypoxia
Fungal infections like cryptococcus and hisotplasmosis
The management includes investigation and treatment
renal function, CBC< LDH, LFT needs to be monitored…LDH levels are known to bee increased with PCP… It is important to assess and monitor renal function while on therapy for renal transplant…It is important to rule out concomittant bacterial sepsis in a renal transplant patient and I will keep them on empirical antibiotics…Throat swab could be done for infuenza, covid… Induced sputum can be tested for AFB, gram stain and culture.. CT chest can confirm the above changes…
Bronchoscopy will be ideal to diagnose…. but in view of hypoxia it would not be possible to perform the same ….
Patient needs to be stopped with antimetabolite, Tacrolimus level needs to be checked and dose needs to be monitored….
Empirical steroids should be given in IV form…
cotrimoxazole 160/800mg 2 tablets twice a day or in the intravenous preparation twice a day should be given….once the clinical resolution is better oral tablets maybe switched over to…..
CMV can be confirmed only by doing BAL and tissue diagnosis by lung biopsy demonstrating invasive lung disease with owl eye inclusion bodies…Mere presence of CMV DNA PCR is not diagnostic of CMV related lung disease… Patient needs to be started on IV Ganciclovir 5mg/kg IV twice a day for 5 days and later switch over to oral valganciclovir 900mg twice a day…Oral CMV prophylaxsis with Tab valgan 900mg once a dya is then recommended
In this patient i would start both IV Cotrimoxazole and IV ganciclovir initially and later decide on the clinical response based on therapy and clinical signs…
Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587.
Kang EY, Patz EF Jr, Müller NL. Cytomegalovirus pneumonia in transplant patients: CT findings. J Comput Assist Tomogr. 1996 Mar-Apr;20(2):295-9
.
PCP is associated with thick sputum which cannot be expectorated ..And as it is not able to diagnose we need BAL with special stains to diagnose PCP
Mx: ICU support, O2 saturation maintain, after stabilised the pt, do BAL fluid for Staining or PCR for PJP, do blood PCR for CMV, HRCT, LDH, RFT, LFT.
Immunosuppressant modification ( stop MMF, continue CNI, steroid), intimate both TMP/SMX & oral Valganciclovir, adjunctive steroid…
Back ground 65years male; Cadaver transplant recipient (organ?) ?? received induction with T cell depleting agent (ATG / Campath) CMV sero-status – D+/R-: ?? received prophylaxis for CMV and PJP 4 months post-transplant Low grade Fever, dry cough and respiratory distress with hypoxia CXR – bilateral diffuse small nodules, milliary mottling, ground glass opacities
1. Clinical and radiological features suggestive of Pneumocystis Jiroveci pneumonia
– dry cough, yet severe hypoxia is the hallmark.
– Cotrimoxazole resistance likely, if the patient is already on prophylaxis
2. CMV pneumonitis – second likely diagnosis
– D+/R- serostatus with high immunosuppression; typical clinical picture, although hypoxia is less severe compared to PJP.
– malaise, weakness, systemic illness, leukopenia & thrombocytopenia are common
3. Milliary Tuberculosis – low grade fever, dry cough, CXR – diffuse milliary mottling; Tb is common in many parts of world – 30-40% people have dormant infection and risk of reactivation following severe immunosuppression and old age
4. ARDS – symptoms pertaining primary source of infection are not mentioned. ARDS secondary to sever Pneumonia would have high grade fever, productive cough, full blown sepsis, hypotension and multi-organ dysfunction
5. Covid-19 – pandemic, high disease prevalence in IS patients
Other viral / atypical bacterial / Mycoplasma / Fungal pneumonia
How do you manage this case? – admission to ICU / HDU – MDT involvement – Pulmonologist, Intensivist, infectious disease specialist and Microbiologist – Oxygen supplement on mask 2-5 litres to maintain adequate PaO2 v Nebulisation with Saline and N-acetyl cystine – liquify sputum for drainage, can be used for diagnostic tests
Ø HRCT Chest is the gold-standard imaging modality
central and diffuse distribution and ground-glass pattern with septal thickening with a “crazy paving pattern”. The hallmark finding of PCP on HRCT scans is diffuse ground-glass opacity, which reflects accumulation of intra-alveolar fibrin, debris, and organisms–“ground-glass” refers to parenchymal opacification, which does not obscure the underlying pulmonary architecture – in bilateral, symmetric, predominantly perihilar distribution and may be geographic or mosaic pattern. consolidation, halo signs, and nodules (all P< 0.05) were significantly more frequent in patients with cytomegalovirus pneumonia than in those with pneumocystis.
Small nodules (32.5% in cytomegalovirus pneumonia, 6.41% in pneumocystis pneumonia; P< 0.001) without peri-lymphatic distribution were particularly common in patients with cytomegalovirus pneumonia.
Ground-glass opacity, reticulation, and bronchial wall thickening (all P > 0.05) were common in both groups. Diffuse, fine, reticular opacification, pneumatocele, pneumothorax are typical pictures of PJP Blood Investigations
· ABG, CBC (leukopenia, thrombocytopenia), RFT, LFT, LDH, Tac C0 level
· CMV pp65 antigen – can detect within few hours, high false negative
· CMV-DNA quantitative PCR à Genotype analysis for UL54, UL97 mutation
· HIV serology
· Covid rt-PCR – from nasal and oropharyngeal swab
· Sepsis markers – CRP, Procalcitonin
· LDH – may be elevated in patients with PJP
· Plasma level of 1-3-beta-D-glucan (cell wall component of P. jirovecii) is elevated in patients with PJP – assay can support the diagnosis of PCP in sick patients not fit to undergo BAL or lung biopsy. (In 282 patients with HIV, diagnosed with PCP, had significantly higher median beta-D-glucan levels than patients without the disease). Starting empirical treatment covering bacterial, PJP and CMV disease is important in seriously ill patients, before reaching the diagnosis by invasive tests.
– Broad spectrum IV antibiotics (Piperacillin-Tazobactam), IV Gancyclovir and IV/ oral Cotrimoxazole should be started immediately – shall help stabilize the patient.
– IV Hydration – oral intake may not be adequate,
After stabilisation with prompt intravenous therapy, invasive tests can be planned to make the diagnosis and tailor further definitive treatment specific to the disease.
– BAL: Fluid PCR to look for PJP, CMV inclusion body (Owl’s eye)
o Gram stain, AFB and culture (Bactec media)
o Special stain – Crystal violet, Giemsa, Diff-Quik, and Wright stain are used to detect both the trophozoite and cyst forms of PJP
– Trans-brochial Lung Biopsy – yield 100% because of more tissue available; indicated if BAL sample fail to detect organism
Treatment: Reduction of Immunosuppression: to Stop MMF, may resume at low dose after complete recovery from PJP / CMV disease. Treatment of PJP depends on the degree of illness determined on the basis of alveolar-arterial gradient: mild (< 35 mm Hg), moderate/severe (35-45 mm Hg), or severe (>45 mm Hg).
Severe disease is also indicated by PaO2 <70mm Hg on room air
Cotromoxazole160/800mg PO daily x 14-21days, till symptoms resolve. Initial IV TMP-SMX indicated in sick patients (on ventilator), poor oral intake (ill, CNS involvement), not tolerating orally (vomiting, gastritis) or poor absorption due to diarrhoea.
Oral TMP-SMX has been shown to be as effective as intravenous pentamidine and more effective than other alternative treatment regimens.The parenteral route may be considered in patients who present with serious illness or in those with gastrointestinal side effects.
Response to treatment should begin within 4-5 days, may take longer time (up to 8days) to respond in HIV patients. If no response occurs within the expected time, an appropriate alternative regimen should be used.
If symptoms still persist beyond 8days – dose adequacy should be checked and a second-line agents pentamidine, dapsone (with pyrimethamine), or atovaquone may be tried. Secondary prophylaxis shall be required for at least 6months.
For CMV Pneumonia – second possibility Intravenous Gancyclovir for 7days – then change to oral Valgancyclovir 900mg twice daily 14-21 days. If patient improve clinically, check CMV viremia (DNA- PCR or QNAT) after 14days, then every 7days till symptoms resolve. Frequent monitoring of CBC every week during treatment to look for pancytopenia, which may need GCSF supplement. Completion of therapy shall be guided by complete resolution of symptoms + clearing of viremia (CMV not detectable in 2 consecutive assays).
Secondary prophylaxis shall be required for at least 6months. If symptoms do not resolve, increased CMV viremia (PCR / QNAT) to be assessed early (7days) and Gancyclovir resistant infection should be suspected. Treatment options for GCV-R CMV disease are IV Foscarnet / IV Cidofovir – high risk of Nephrotoxicity, electrolyte disturbances, seizure. Other treatment options include CMV hyperimmune globulin with or without Leflunomide.
Reduction in immunosuppression – stop MMF; conversion of CNI à to mTOR-I
Reference:
1. Ali Nawaz Khan. Pneumocystis jirovecii (carinii) Pneumonia Imaging: Practice Essentials. Medscap Updated: Jun 29, 2022
2. Shelley A Gilroy. Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia. Medscap. Nov 04, 2022
3. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. bts.org.uk/uk-guideline-on-prevention-and-management-of-cytomegalovirus-cmv-infection-and-disease-followingsolid-organ-transplantation. 05 July 2022
4. nders Åsberg1, Atul Humar2, Halvor Rollag3, et al. Lessons Learned From a Randomized Study of Oral Valganciclovir Versus Parenteral Ganciclovir Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR Trial. Clin Infect Dis. 2016 May 1;62(9):1154-60. doi: 10.1093/cid/ciw084. Epub 2016 Feb 16.
5. Klompas. Treatment of Ganciclovir Resistant Cytomegalovirus Infection Michael
6. Robin K Avery, Sophie Alain, Barbara D Alexander, et al. Maribavir for Refractory Cytomegalovirus Infections with or without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clinical Infectious Diseases 2022; 75 (4)-15 Aug: 690–701. A correction has been published: Clinical Infectious Diseases, Volume 76, Issue 3, 1 February 2023, Page 560, https://doi.org/10.1093/cid/ciac970
Given the clinical picture and radiographical picture, it seems to be more of PCP induced pneumonia
Management of the case:
Lab investigations needed would be
serum LDH level,
serum (1 → 3) β-d-glucan assay
BAL SOS transbronchial biopsy
Trimethoprim-sulfamethoxazole (TMP-SMX): 15-20 mg/kg/day of the TMP component given IV in divided doses every 6-8 h; lower doses may be sufficient. In milder disease, two double-strength tablets can be given po tid
21 days is preferred to avoid disease progression and relapse
Adjunctive steroids: in patients with hypoxemia (pAO2 < 70 mm Hg on room air)
Corticosteroid therapy should be considered early for maximum benefit, ideally within 72 hours of initiating antimicrobial therapy.
The optimal dose of corticosteroids would be 40-60 mg of prednisone (or equivalent) in adults given two to three times daily and 1 mg/kg twice daily in children for 5-7 days before gradual tapering over 7-14 days is recommended to avoid rebound pneumonitis.
Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587. doi: 10.1111/ctr.13587. Epub 2019 Jul 1. PMID: 31077616.
· What is your differential diagnosis? · This is very fresh transplantation, although the possibility of CMV is very high in first 12 months post transplantation. And also on the bases of history the patient is immunocompromised, donor was positive for CMV and recipient was negative for CMV, the probability of CMV infection is high so the clinical findings and X ray chest findings, . . The initial finding, clinical features, radiological findings (consolidation, ground glass appearance, cystic lesions) the initial provisional diagnosis would be PCP. suggest CVD disease, other DDs are, · PCP, · COVID-19 infection, · Atypical lower respiratory infection, · Other viral and bacterial infections. · How do you manage this case? · Need further investigation like BAL and biopsy (giemsa stains, immunofluescent assay, PCR HRCT, CULTURE, GRAM STAIN, , COVID-19 RT-PCR, galactomannon. · Decide the need of intensive care requirements. · Need other specialty opinion like infectious disease specialist, pulmonologist. · Supportive care like IV fluid, antipyretics, · Immunosuppression medication modification, · And specific to underlying cause, if PCP the drug of choice would be Co-trimoxazole 120mg/kg/day, steroids to decrease inflammatory cascade, if not responding then can be switched to IV pentamidine 4mg/kg OD. · If CMV then IV genciclovire 5mg/kg BID dose for minimum of 21 days, · Antibiotic to cover the super impose infection, atypical coverage. References ;
Good history and physical examination .
send full investigation [CBC,RFT,S.electrolytic,CMV PCR,]
send ABG , HRCT, COVID 19 PCR,CRP,blood culture and sensitivity.
treatment:
O2,if patient vitaly stable if not ICU admission
Trimethoprim-sulfamethoxazole in high dose , increase dose of steroid ,stop cell cept and CNI in high risk patients .
in low risk patients no need to stop immunosuppression and increase dose of steroid .
in moderate risk patients stop cell cept continues CNI and increase dose of steroid .
1-What is your differential diagnosis? -Pneumocystis jirovecii (formerly P. carinii) pneumonia) (most likely). -CMV Pneumonitis. -Pulmonary aspergillosis. -Respiratory viruses; Respiratory syncytial virus, adenoviruses, and human metapneumovirus COVID-19 – ARDS. -Idiopathic Pneumonia Syndrome. -Tuberculous pneumonia (M. haemophilum and M. avium complex) -Drug-induced interstitial pneumonitis( mTOR) 2-How do you manage this case? -Maintain the O2 above 94% by giving High flow O2 (BIPAP CPAP) & Request ABG, -Check Vital signs, to evaluate the need for ICU or high dependency unit. -Multidisciplinary Teams (Nephrology / ICU / Pulmonology / ID). -Further Investigations; CBC (search for leukopenia and thrombocytopenia) CRP (often normal) – LDH Liver function tests, and Renal function tests. BAL staining for PCP (Gomori methenamine silver (GMS) staining)& serum beta-D-glucan assay . BAL and send for respiratory panel (Influenza type A,B, Adenovirus ,covid-19 , etc). (CMV PCR) – As the patient is at high risk for CMV. Full septic screen (including sputum C/S). -Management; Treatment of PJP; -Trimethoprim-sulfamethoxazole (TMP-SMZ) given in a high dose, combined with corticosteroids in patients with moderate to severe infections. -If there is allergy or side effects to trimethoprim-sulfamethoxazole, alternative drugs can be used including; –Dapsone, Inhaled pentamidine , Atovaquone , Primaquine combined with clindamycin , Combined dapsone and trimethoprim , Pyrimethamine and sulphadiazine. -Prophylaxis is highly efficacious in preventing PJP in transplant patients. -Overall, with prompt treatment, survival is good (50-95%), relapses are common. Treatment of CMV tissue invasive disease (cmv pneumonitis);
-Consider decreasing the IS; (stop the antiproliferative medication, and decrease the CNI by 50%, with monitoring Graft Functions.
-IVganciclovir(5 mg/kg every 12 hours) for 2-3 weeks; should be used in place of valganciclovir. (after ID recommendations)
-IV ganciclovir can be transitioned to oral valganciclovir once the patient has demonstrated clear clinical improvement, viral loads are down-trending, and the patient can tolerate/absorb oral medications.
-While treating with either ganciclovir or valganciclovir, we monitor the serum creatinine at regular intervals in case dose adjustment is needed.
-Monitoring on therapy;RFTS / LFTS / Blood cell counts / LDH. -References;
Up To Date; diagnosis of Pneumocystis pneumonia in patients without HIV:Aug 02, 2022.
Differential diagnosis: (i) Most likely this is a case of pneumocystis jirovecii pneumonia (ii) CMV pneumonia (iii) Pulmonary Tuberculosis (iv) Covid 19 pneumonia (v) ARDS Management: Need to confirm the diagnosis prior to specific treatment Investigation:
CBC with PBF
Sputum for Gram staining, fungus, AFB and Culture sensitivity
BAL for pneumocystis jirovecii pneumonia.
CMV PCR
covid-19 PCR
Sputum for GeneXpert TB test
HRCT scan of the chest
Treatment: General: Oxygen, Broad spectrum antibiotic, Nutrition Specific: According to confirm diagnosis
Reference: 1. Zuhair M, Smit S, Wallis G, Jabbar F, Smith C, B, Griffiths P Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Reviews in Medical Virology 2019; 29: 2034 2. Wentworth BB, Alexander ER. Sero epidemiology of infections due to members of the herpes virus group. Am J Epidemiol 1971; 94: 496-507. 3. Shelley A Gilroy. Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia.Medscap. Nov 04, 2022
Recipient with fever ,non-productive cough 4 months and desaturation after cadaveric transplantation. CMV positive to CMV negative recipient
With bilateral diffuse infiltrate on cxr
What is your differential diagnosis?
At top of list Pneumocystis carinii pneumonia (PCP)
Viral infection : CMV pneumonia ,Covid 19 , influenza a,b …
Miliary Tb
Bacterial infection
How do you manage this case?
Full history and physical examination
CBC , KFT, LFT ,urine analysis,LDH ,serum electrolytes,Blood culture,induced sputum for culture ,PCR for viral infections
HR chest CT
Trimethoprim-sulfamethoxazole — We recommend trimethoprim-sulfamethoxazole (TMP-SMX) as the treatment of choice for PCP of any severity in patients without HIV .
The dose of TMP-SMX for patients with normal renal function is 15 to 20 mg/kg (dosing is based upon the TMP component and expressed as mg/kg per day of TMP) intravenously or orally daily in three or four divided doses. Dose may need to be adjusted if creatinine clearance changes during therapy. Patients should receive intravenous therapy until they are clinically stable (eg, PaO2 ≥60 mmHg, respiratory rate <25) and have a functioning gastrointestinal tract.
For patients with allergy to TMP-SMX, desensitization should ideally be performed since TMP-SMX is the most effective regimen. However, if the patient has a history of a severe allergy (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis), TMP-SMX should be avoided and desensitization should not be performed.
Unfortunately I am late in replying so now I know that it is PCP pneumonia hinted by dry cough and marked hypoxia.We can consider CMV pneumonia is in such a scenario as well.
The fact that sputum is sticky and think and difficult to expectorate makes cough as dry. BAL can confirm the diagnosis.
High dose septran is first line therapy.
In view of hypoxia and non-productive cough, probability of PCP will be my main suspicion. In D+/R- CMV status, CMV pneumonia is also consideration
How do you manage this case?
Investigations
A detailed history and clinical examination to avoid missing clinical clue for other diagnosis. Exertional drop in SpO2 will highly suggestive of PCP
Full blood count, renal function tests, liver function tests, C reactive protein, blood culture, chest X ray, respiratory virus panel
sputum for cytology, gram stain and acid-fast bacilli stain, and culture
HRCT of chest if patient stable
CMV QNET testing
Treatment
With oxygen therapy to maintain SpO2
Bronchoscopy with bronchoalveolar lavage and biopsy if indicated
co-trimoxazole and steroids (should be started.
Antimetabolites to be stopped, CNI doses to be continued unless severe septic and level maintain to avoid graft loss
Supportive care: Intravenous fluids, nutrition as per needed
Roux A, Gonzalez F, Roux M, Mehrad M, Menotti J, Zahar JR, et al. Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Medecine et maladies infectieuses. 2014 May;44(5):185-98. PubMed PMID: 24630595. Epub 2014/03/19. eng.
Diffuse, bilateral infiltrates point out to a range of etiologies including CMV, PJP, respiratory viruses, Mycoplasma and Legionella,
Ground glass or mixed ground glass/micronodular infiltrate raises concern for PJP and CMV
complete blood count with differential, electrolyte chemistries, and liver function testing to assess the toxicity risk of empirical antimicrobials
Blood cultures
Testing of urine for Legionella antigens
gram stain and bacterial culture if sputum production is triggered
Bronchoscopy and bronchoalveolar lavage
PJP, CMV PCR
HRCT
Treatment
Oxygen therapy,
if critically ill reduction of immunosuppression is recommended high dose spectrin for PJP
for CMV IV Ganciclovir for five days followed d by oral valganciclovir
_The index case has fever, dry cough and severe hypoxemia together with just bilateral interstitial infiltrates in the CXR that most probably goes with the diagnosis of pneumocystis jirovecii pneumonia. _Other differential diagnoses includes:
1. Viral pneumonia as COVID 19, CMV pneumonitis (as high risk for CMV infection , D+/R_).
2_ Bacterial pneumonia as staph and stept pneumonia (unlikely, as the fever is low grade and no typical lobar infiltration characteristic of bacterial infection).
3_ TB (unlikely with dry cough )
_ The clinical criteria are highly suggestive of PCP. However, dry cough and absent sputum makes it difficult in diagnosis and Bronchoscopy with BAL is the standard for diagnosis _Management of the case: 1.MDT is essential (transplant team, pulmonologist, infectious disease specialist, and ICU team).
2_ General supportive care as oxygen, IV fluids.
3_ Reduction of immunosupression (stop anti proliferative as MMF or AzA, reduce dose of CNI as guided by target trough level)
4_ keep on steroids.
5_ ttt of PCP by sulphamethoxazole _trimethoprime (shift from supressive dose to therapeutic dose).
_Required additional investigations:.
_CBC, ESR and CRP.
_blood and sputum culture
_HRCT chest .
_liver and kidney function.
_PCR for CMV and BAL for PCP PCR.
_Close monitoring of graft function.
# What is your differential diagnosis?
Pneumocystis jirovecii pneumonia
Viral pneumonitis (CMV pneumonitis), and other viral infection
Bacterial pneumonitis
Covid 19
Miliay tuberculosis
ARDS
# How do you manage this case?
CBC, ESR,RFT, LFT, ABG, CRP, (MCV and covid 19 PCR)
Blood and sputum culture
C X Ray
CT chest
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection diagnosed in immunocompromized patients. After solid organ transplantation, early infection has decreased as a result of effective prophylaxis, but late infections and even outbreaks caused by interpatient transmission of pneumocystis by air are present in the SOT community. Different risk factors for PJP have been described and several indications for PJP prophylaxis have to be considered by clinicians in patients even years after transplantation. Diagnosis of PJP is confirmed by microscopy and immunofluorescence staining of bronchial fluid but PCR as well as serum ß-D-Glucan analysis have become increasingly valuable diagnostic tools. Treatment of choice is Trimethoprim/sulfamethoxazole and early treatment improves prognosis. However, mortality of PJP in solid organ transplant patients is still high and many aspects including the optimal management of immunosuppression during PJP treatment require further investigations.
Brakemeier S, Pfau A, Zukunft B, Budde K, Nickel P. Prophylaxis and treatment of Pneumocystis Jirovecii pneumonia after solid organ transplantation. Pharmacol Res. 2018 Aug;134:61-67. doi: 10.1016/j.phrs.2018.06.010. Epub 2018 Jun 8. PMID: 29890253.
1-pneumocystis pneumoniafavor
favour by presence of oxygen desaturation, and dry cough in the immunocompromised recipient 2-CMV disease of end-organ disease
this post renal transplant recipient CMV negative from CMV positive donor 3-pulmonary TB needs to be role out 4- atypical pneumonia 5- typical pneumonia (bacterial infection). 6-fungal infection 7- covid-19 infection
How do you manage this case?
first to confirm the diagnosis
CBC with differential
peripheral blood film and inflammatory marker(ESR,CRP)
full chemistry LFT,KFT,
SPUTUM culture and fo AFB if available
if no sputum BAL for PCP,fungal and inflammatory cells(diagnostic 90 to 100%)
CMV PCR
Gamma interferon for TB
septic screening,culture for blood,urine, and sputum
covid-19 PCR
HRCT scan of the chest
ABG
o2 to maintain the o2 sat
assess if the patient needs intravenous fluid
specific management
FOR CMV INFECTION:i.v ganciclovir 5 mg per kg for 2 to 3 weeks after negative PCR of CMV continues more 2 weeks.
for PCP pneumonia trimethoprim and sulphasalazine 80/400 for 3 months.
antibacterial broad-spectrum antibiotics till reach the final diagnosis
REFERENCES
1- prof/AHMED Halwa lecture
2-Zuhair M, Smit S, Wallis G, Jabbar F, Smith C, B, Griffiths P Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Reviews in Medical Virology 2019; 29: 2034
Wentworth BB, Alexander ER. Sero epidemiology of infections due to members of the herpes virus group. Am J Epidemiol 1971; 94: 496-507.
DD
PCP is most probable due to dry cough and associated hypoxia.
Others: CMV,ARDS,TB .
Management:
Reduction of immunosuppression ; D/C MPA &AZA, using CNI and steroids with O2 support.
Suitable dose of co-trimoxazole till diagnosis confirmed.
-Investigations: routine work up in addition to:
HRCT chest, BAL examination; CMV PCR.
In case of confirmed CMV:IV Gancycolvir 5mg/kg bid for 5 days followed by oral Valgancyclovir 900 mg once daily until negative PCR.
Discussion of risk of acute rejection with reduction of immunosuppression.
PCP should thought of considering: immune compromszed patient, time of occurrence(1-6 months),dry cough with hypoxemia; due to thick sticky sputum and CXR findings of bilateral interstitial infiltration.
Dry cough is a typical symptom for PCP specially associated with fever in immune compromised patient.
What is your differential diagnosis?
-The diagnosis is the most likely P jiroveci pneumonia
-CMV pneumonia
-Acute Respiratory Distress Syndrom
-Tuberculosis
How do you manage this case? Investigations:
-A lactic dehydrogenase (LDH) study is performed as part of the initial workup. LDH levels are usually elevated (>220 U/L) in patients with P jiroveci pneumonia .
-PCR of respiratory fluid, in particular bronchoalveolar lavage (BAL).
-High-resolution computed tomography (HRCT) scanning of chest Treatment:
The treatment of choice is TMP-SMX, with second-line agents including pentamidine, dapsone (often in combination with pyrimethamine), or atovaquone. Reference:
Shelley A Gilroy. Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia.Medscap. Nov 04, 2022
What is your differential diagnosis? This will include: · Viral pneumonitis , like CMV · ARDS · Bacterial pneumoonitis · Fungal infection like Pneumocystis jirovecii Pneumonia · Tuberculosis · Cryptococcal infection · Covid 19 Investigations These will include- · Full blood count/ESR, Renal and liver functions · ABGs · HRCT Chest · CMV PCR · Blood culture · Sputum Culture · Covid 19 PCR How do you manage this case?
For CMV pneumonitis– start IV gancilovir 5 mg/kg for 2-3 weeks Monitoring by CMV PCR Continue treatment for 2 week after achieving negative PCR
For PCP pneumonitis Start Trimethoprim and sulphamethoxazole 80/400 mg oral for three months. In case of bacteria pneumonitis – brad spectrum antibiotics according to cultures Review by pulmonologist and Infections disease team CMV in kidney transplant- Lecture By Prof Halawa
I like your comprehensive approach, but references need to be properly cited. As much as I adore my academic elder brother Ahmed Halawa ,referring to his lecture is not a reference.
What is your differential diagnosis?
KTR, with fever and respiratory symptoms beside mottling appearance on CXR. The serostatus of CMV pre-transplant was D+/R- which carries high risk for CMV infection and disease.
Differential diagnosis in the index case and such scenario : · CMV pneumonitis. · PJP pneumonia. · Miliary TB. · Other viral infection: influenza, HSV, RSV, CXOVID-19, varicella–zoster infection and parvovirus B19 infection. · Bacterial infection.
How do you manage this case? 1. Hospital admission is required to keep and maintain optimum oxygen saturation. 2. Detailed history and relevant clinical examination: PH of chronic cough or TB. Looking for evidence of retinitis as it may be a concomitant of CMV pneumonitis. 3. Investigations(1): · Serologic tests that detect CMV antibodies (IgM and IgG) via ELISA. · Detection of the CMV pp65 antigen in leukocytes( typically expressed only during viral replication). · Quantitative CMV PCR (COBAS Amplicor Monitor Test). · Tissue diagnosis:Intracellular inclusions surrounded by a clear halo may be demonstrated with various stains (Giemsa, Wright, hematoxylin-eosin, Papanicolaou). This gives the appearance of an “owl’s eye”. · Current methods to detect and diagnose Pneumocystis infection; BAL for PCR,Loop-mediated isothermal amplification (LAMP),Flow cytometry,ELISA technique to detect immunoglobulin (Ig), IgM, and IgG antibodies against Pneumocystis jirovecii.Antigen and biomarker assays for detection of PJP and serum LDH may help in diagnosing PJP. · To screen for HIV and TB. · The followings may be required: to obtain sputum via BAL or saline nebs and to examine the secretion for AAFB, culture &sensitivity and to look for viral intracellular inclusions. 4. Drug therapy for CMV pneumonitis:The drug of choice for treatment of CMV disease is intravenous ganciclovir, although valganciclovir may be used for nonsevere CMV treatment in selected cases.The length of treatment varies, for as long as 2-4 weeks from the end of the induction period, depending on the clinical status of the patient(2).Foscarnet 5. Foscarnet is a DNA chain inhibitor of phosphorylation. It has been used to treat ganciclovir-resistant viruses. 6. There is an increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation(3). 7. Prophylaxis to be provided to the patient when having positive CMV serology results. Positive findings on blood cultures, pp65 antigenemia, and CMV PCR have been used as markers for the initiation of therapy. 8. Prophylaxis should continue for 90 to 180 days(4). References 1. Medscape Drugs & Diseases > Infectious DiseasesCytomegalovirus (CMV) Workup Updated: Jul 07, 2021 Author: Ricardo Cedeno-Mendoza, MD; Chief Editor: Michael Stuart Bronze, MD. 2. MedscapeDrugs & Diseases > Infectious DiseasesCytomegalovirus (CMV) Treatment & Management Updated: Jul 07, 2021 Author: Ricardo Cedeno-Mendoza, MD; Chief Editor: Michael Stuart Bronze, 3. MD.Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026. 4. Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TM, Campos SV, Ramos JF, Latif AZ, Litvinov N, Maluf NZ, Caiaffa Filho HH, Pannuti CS, Lopes MH, Santos VA, Linardi Cda C, Yasuda MA, Marques HH. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015 Jul;70(7):515-23. doi: 10.6061/clinics/2015(07)09. Epub 2015 Jul 1. PMID: 26222822; PMCID: PMC4496754.
What is your differential diagnosis?
The main differential in this immunocompromised patient is PCP pneumonitis versus CMV pneumonitis.
This patient is hypoxic with dry cough and bilateral lung involvement.all these in favour of PCPrather CMV pneumonitis.
Being the patient has a dry cough; this will put the PCP on the top of the list.
PCP affect the alveoli, and usually, this part of the lung not causing mucous.
Acquisition and transmission — Numerous animal and human studies suggest that Pneumocystis is transmitted by the airborne route. Acquisition of new infections in humans can most likely occur by person-to-person spread. Individuals with normal immune systems may have asymptomatic lung colonisation and may serve as a reservoir for the spread of Pneumocystis immunocompromised hosts.
Solid organ transplantation — Approximately 5 to 15 per cent of patients who undergo solid organ transplantation develop PCP without prophylaxis. The rates are lowest in renal transplant recipients and highest among lung and heart-lung transplant recipients.
How do you manage this case?
This patient need admission to MICU with MDT approach including the ID treansplant team and pulmonologist for possible bronchoscopy
need full rutine work up including the CMP.CBC,LDH,FULL VIRAL PANEL ,LFT,BLOOD AND URINE CULTUER .
keep him on o2 15 liter and reduce his immunosuppression dose and hold MMF
1- a case of pneumonia
DD
a- Bacterial: streptocoocus, TB (unlikely with dry cough), Legionella and Pseudomonas
b– Viral: CMV, influenza, COVID-19
c- Fungal:Pneumocystis jirovecii(most likely)(hypoxia and dry cough ) , Histoplasma, Cryptococcus.
2- Management:
a- hospitalization and maintain adequate oxygen saturation.
a- Proper history taking including exposure to infected persons, travelling, etc
b- full examination: including assessment of the oxygen saturation satus
c- Full labs: CBC, RFT, LFT, septic work-up including assessment of viral (CMV viral load) and fungal culture.
d- MDT including pulmonolgist, infectious disease and nephrologist
e- reduce IS specially antimetabolite (MMF and azathioprin) and in severe case CNI
and maintain steroids.
f- Start empirical treatment with IV antibiotics to cover the community acquired pneumonia, till the culture results
g- maintain cotrimoxazole to cover PCP
h- modify management according to the culture results
consider bronchoscopy and BAL in non-responders
What is your differential diagnosis? This is a post renal transplant patient in the first six months post transplantation presenting with respiratory symptoms and fever , the spectrum of potential pulmonary pathogens is wide, certain points in the clinical evaluation like onset, the presence of hypoxia, nature of cough, chest x ray findings will help shorten the list and in management of the patient. Differential diagnosis
1. CMV : Why it is number one differential diagnosis? · The presentation in the first 4 months post transplantation. · The high risk of CMV disease in the post-transplant period of being D+/R-
· Clinical symptoms and/or signs of pneumonia are seen in CMV pneumonitis such as, hypoxia as in this patient · The new infiltrates on imaging which is bilateral and diffuse and extensive ground glass lesions goes more with CMV pneumonitis than PJP. Putting in mind these lesion seen in this CXR are nonspecific and other differential diagnoses should be considered
2. We should definitely consider pneumocystis J Pneumonia: · Risk of infection is PJP is greatest in the first 6 months, need to know from the history whether he is on PJ prophylaxis or not and what prophylaxis as pentamidine prophylaxis is associated with more infection and if the patient immunosuppressive treatment has been increased recently especially corticosteroids pulses. · The presence of marked hypoxia is with PJP · The presence of mild clinical findings on examination will go with PJP · ONSET: The sub-acute illness goes with PJP. · The presence of bilateral reticulonodular granular shadowing is suggestive of PJP, although it is usually perihilar and less than what is seen in this CXR. · CBC : neutropenia NB: important to put in mind that both CMV and PJN can give rise to this clinical and radiological findings and both can coexist in this type of patients. Others to be considered: 3. Bacterial infections: such as staphylococcal, klebsiella and pseudomonas pneumonia. Usually the onset is acute in bacterial infections and the CXR findings are focal or diffuse consolidation which is not seen here in this index case. Bacterial infections should always be considered as it can coexist with other viral or fungal infections. 4. Fungal infections such as invasive aspergillosis Which include a. sub-acute invasive aspergillosis which is not the case here as it runs an indolent chronic course of necrotizing aspergillosis. b. Aspegillous broncho- pneumonia with x ray features of in the peribronchial tree which is not the case here. c. Angioinasive aspergillosis: which present with fever, pleuretic chest pain and hemoptysis which is not the case here. The CXR would show multiple or solitary pulmonary infiltrates with areas of infarcts. 5. Miliary Tuberculosis: · Needs to know the origin of the patient and previous history of contact with patient with tuberculosis and past history of active tuberculosis. · His state of latent tuberculosis (IGRA test) before receiving the transplant and whether he received treatment for latent tuberculosis before transplantation or not. · The onset is usually subacute to chronic with loss of weight which is not the case here. · The chest x- ray in this index case can be due to Miliary tuberculosis. 6. Nocardiais: The history is usually as in tuberculosis with fever sweats and loss of weight CXR: are not typical in this index as it gives cavitatory consolidation. Management: 1. Multidisciplinary: that include transplant team, pulmonologist, infectious disease physician, microbiogist and ICU physician. 2. Patient should be managed in the ICU setting and managed accordingly. (ABG) 3. Do CBC with differential white blood count, ESR,CRP 4. LFT, RFT. 5. HRCT chest may be more specific and may sow features of an underlying disease 6. Blood cultures 7. CMV serology 8. Aspegillous IGg antibodies 9. Quantitative PCR for CMV in blood 10. PCR for tuberculosis in the blood 11. Level of serum lactate dehydrogenase 12. BAL sent for: · Microscopy and stains( Gram stain and Giemsa or methamine silver for PJ and ZN stain) · Bacterial and fungal cultures · PCR for CMV, Pneumocystis J , for tuberculosis and Aspergillosis · Fungal biomarkers such as Galactomannan 13. According to the results of preliminary investigation and waiting for the results of more specific investigations, the patient should be stared on a. Intravenous broad spectrum antibiotics in collaboration with the microbiologist according to the latest sensitivity of suspected bacteria. b. IV ganciclovir according to level of renal function with montoring of CBC and RF. c. IV cotrimoxazole as this is preferred to be started early in the disease.
OUR CASE; 65 yr old male 4/12 post KTR Cadaveric donation. Donor +VE for CMV, Recipient -VE for CMV
Presentation. Non productive cough. Fever Desaturating on room air. Heterogenous CXR.
DDX.
PCP CMV pneumonitis. Miliary TB. Lymphocytic interstitial pneumonia Viral pneumonia including COVID 19 infection. MAC infection.
MGT.
1Multidisplinary team – Transplant team, Infectious disease team, Pulmonologist, Critical care team. 2.Admit the pt to ICU and supplement oxygen to keep the SP02 >90% 3.Do appropriate investigations; -LDH – reflects degree of lung injury, elevated to more than 220U/L in PCP. -PITC to rule out other causes of immunosuppression. -Quantitative PCR for PCP -Bets D glucan- assess fungal infection- Candida, PCP, Aspergillosis. -Covid 19 PCR -Sputum induction for – MCS, Gene xpert,,Toluidine staining For PCP -PFTS – Decreased DLCO less than 75 % in PCP. -BAL or lung biopsy for histology, culture and staining to investigate for PCP,TB,CMV and Aspergillosis. -Others ; CMV PCR and VL,BGA,FHG,ESR,UECS,Tac levels 4.Modify immunosuppression, decrease anti metabolites by up to 50% or stop them in active infection, Stop CNI if in severe sepsis and increase steroids doses to stress doses while in severe infection. 5.Start on broad spectrum antibiotics to cover community acquired pneumonia awaiting the confirmatory diagnosis. 6.Considering the pt is immunosuppressed and PCP is high on the list start High dose septrin and appropriately renal dose it depending on UECS. Considering immunosuppressive state, treat for 21 days Other options for tx include Dapsone + pyrimethamine +leucovorin ,Atovaquone and aerolised pentamidine. 7.For CMV we will start IV ganciclovir for 5-7 days then switch to valganciclovir. 8.For TB we will start anti TBS and be cognizant of drug interactions in choosing regimen.
This looks PCP and will be managed as such unless the diagnostic tests yield other results which will then determine the treatment.
REF;
N Goto et al – PCP in kidney transplantation.-Transplant infectious disease, vol 13,issue 6,31st oct 2011,pg 551-558 Kreystal De Kyzer et al -Human CMV and Kidney Transplantation, A clinician’s update. -American journal of kidney diseases,vol58,issue 1;july 2011,pg118-126
A 65-year-old man with a fever (38 °C) and non-productive cough 4 months after cadaveric transplantation. CMV positive to CMV negative recipient Oxygen saturation on air was reported at 82%.
Oxygen saturation on air was reported at 82%.
► Exercise induced Hypoxaemia, often severe and out of proportion to clinical findings
-Dry cough
-Dyspnea
-Fever—often low grade
This chest X-Ray shows widespread small nodular ground glass opacities with
cystic changes.
The DD would be according to the most common :
1- The Most Common Fungal: Pneumocystis jirovecii(most likely)(hypoxia and dry cough ) , Histoplasma, Cryptococcus..
2- Viral: Respiratory viruses like Influenza, parainfluenza and Herpesviruses like CMV (D+/R- CMV => CMV pneumonia, ..
3- Bacterial: community acquired like streptococcus, tuberculosis,,,(unlikely => dry cough)..
Treatment is usually for a period of about 21 days.
Management of TB :
A Protocol of 2 months of INH, RIF, PZA, & EMB followed by ,
a continuation phase of 4 months of INH & RIF.
EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF.
Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (eg, advanced age).
Management of CMV :
Reduction of immunosuppression => Antimetabolites to be decreased by 50% or stopped, CNI doses to be adjusted as per trough levels.
Antiviral therapy:
1- IV Ganciclovir has had a major impact on the mortality and morbidity of CMV disease.
2- High doses of IVIG (0.5 g/kg body weight) have been used in conjunction with
Ganciclovir for the treatment of pneumonitis.
3- Secondary prophylaxis after treatment of disease has been assessed, although
evidence in support of this strategy is limited
If BAL or Biopsy Positive for CMV :
=>TTT with intravenous ganciclovir (5mg/kg IV 12 HR, to be adjusted according to
Cr CL)=> It should be continued for minimum 2 weeks
=> Can be changed to oral valganciclovir, if improves earlier, and until resolution of clinical symptoms and radiological findings with clearance of CMV in blood, if present
=>CBC and serum creatinine should be monitored weekly during the treatment.
=>If no response in 2 weeks, assess for ganciclovir resistance and shift to Foscarnet and
=>Add CMV immunoglobulin or intravenous immunoglobulin (IVIG) .
=>Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2
months in patients with high-risk of relapse.
Managment of influenza :
Influenza A or B =>give (Oseltamivir) Tamiflu 75 mg po bid for 5-10 days
Supportive care: Intravenous fluids, nutrition.
References:
Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
UK guideline on prevention and management of cytomegalovirus (CMV) infection and disease following solid organ transplantation April 2022.
ATS/CDC/IDSA clinical practice guidelines for drug-susceptible TB, CID 2016:63 (1 October),147.
Shelley A Gilroy; Chief Editor: Pranatharthi Haran Chandrasekar, Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia, Medscape Updated: Nov 04, 2022
Pulmonary complications within the first year after renal transplantation. El-Azem Sadon Amal Abd, Otaibi Torki Al, Nair Prasad, Gheith Osama, El Monem Mohammed Abd, El Tawab Khaled Abd, Maher Ayman. Year : 2020 | Volume: 69 | Issue Number: 4 | Page: 739-746
mutlidislipinary team for pulmonolgist and transplant nephrologist.
Send full chemistrey panel FBC, ESR CRP, PROCALCTIONIN , with sputum culture blood culture ,ask pulmonologist for bronchoscopy and bronchoalvelor lavage /CMV PCR.
icu admission/hoding mmf /doubling dose of steroids or shifting the patient to hydrocortisone bid / keep o2 satuartion above 90.
Tretment according to the cause , but i wil start him from the admission on gram negative antibitis with marcoildes and i will add anti fungal emperically as variconazole till results are out.
if cmv / gancylovir can be strted iv
if pcp i will start bactrim iv /and if allergic to be shifted on pentamidine
if TB rifambicin with inh
if asperigilosis /contiue on variconazole
if covid 19 steroids / and toscializumab may have a role
Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al.
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Ricciardi A, Gentilotti E, Coppola L, Maffongelli G, Cerva C, Malagnino V, Mari A, Di Veroli A, Berrilli F, Apice F, Toschi N, Di Cave D, Parisi SG, Andreoni M, Sarmati L. Infectious disease ward admission positively influences P. jiroveci pneumonia (PjP) outcome: A retrospective analysis of 116 HIV-positive and HIV-negative immunocompromised patients. PLoS One. 2017;12(5):e0176881. [PMC free article] [PubMed]
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Mecoli CA, Saylor D, Gelber AC, Christopher-Stine L. Pneumocystis jiroveci pneumonia in rheumatic disease: a 20-year single-centre experience. Clin Exp Rheumatol. 2017 Jul-Aug;35(4):671-673. [PubMed]
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Amber KT. Balancing the risks and benefits of prophylaxis: a reply to “Pneumocystis jiroveci pneumonia in patients treated with systemic immunosuppressive agents for dermatologic conditions”. Int J Dermatol. 2017 Jan;56(1):e4-e5. [PubMed]
Bennett J, Dolin R, Blaser M. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 9th edition. Elsevier/Saunders; 2015.
Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet. 2005 Jun 18-24. 365(9477):2105-15. [QxMD MEDLINE Link].
Zhang LJ, Hanff P, Rutherford C, Churchill WH, Crumpacker CS. Detection of human cytomegalovirus DNA, RNA, and antibody in normal donor blood. J Infect Dis. 1995 Apr. 171(4):1002-6. [QxMD MEDLINE Link].
Collier AC, Meyers JD, Corey L, Murphy VL, Roberts PL, Handsfield HH. Cytomegalovirus infection in homosexual men. Relationship to sexual practices, antibody to human immunodeficiency virus, and cell-mediated immunity. Am J Med. 1987 Mar 23. 82(3 Spec No):593-601. [QxMD MEDLINE Link].
What is your differential diagnosis?
the current indexed case4 months post kidney transplantation from seropositive Donor to the negative recipient with URT symptoms including dry cough, fever, severe hypoxemia, and bilateral infiltration as shown in CXR the DDX here will be wide Including atypical viral infections like CMV Pneumonitis, also PJP should be considered as important DDX, especially with severe hypoxia at presentation, dry cough, PJP in non-HIV immunosuppressed patients have more sever clinical course including prolong hospital stay and ICU admission and high mortality rate compared to HIV related PJP(1).
CT chest would help as well
community-acquired pneumonia is less likely, and Drug-induced pneumonitis (if he is on m TOR inhibitors). Need to know about the type of induction IS like alemtuzumab is one of the monoclonal biological agents that prolonged lymphopenia and whether the patient received a CMV prophylaxis course and TMX prophylaxis and his current maintenance IS type and dosing. How do you manage this case?
We need to go for HRCT as the most frequent CT findings are bilateral, ground-glass changes with apical predominance and peripheral sparing in non-HIV-immunocompromised patients with PJP, signs of consolidation are detected more frequently on CT and cystic changes less frequently – than in HIV-positive patients with PJP. The range of other radiological features seen in PJP includes a combination of ground glass and consolidative opacities, cystic changes, linear reticular opacities like our case, solitary or multiple nodules, and parenchymal cavities() With treatment, the vast majority of these changes resolve.
The dry cough will affect the accuracy of staining methods for the diagnosis of PJP as its highly dependent on the quality of the respiratory specimen, sample processing, the reaction of the specimen to the stain chosen, and the skill of the laboratory viewer. The lower burden of P. jirovecii in non-HIV-immunocompromised patients, and they might already be on prophylaxis Therapy remains a challenge for diagnosis difficulties with isolating and culturing this pathogen, by microscopic examination of respiratory specimens. by using various staining methods is used to visualize and identify the morphological structures of P. jirovecii. Methenamine silver and toluidine blue preparations stain only the cyst wall and do not allow the detection of trophozoites. However, Giemsa stains detect all life stages of P. jirovecii. Direct and indirect immunofluorescent assays (DFA, IFA) are specific for different life stages, depending on the antibody used.
Comparative studies have shown DFA and IFA to be the most sensitive stains for P. jirovecii in sputum and bronchoalveolar lavage, with sensitivities of 97% and
90% respectively.8 These assays are also commercially Staining methods have now largely been supplanted by highly sensitive molecular techniques, using semi- or
fully quantitative polymerase chain reaction (PCR) targeting P. jirovecii-specific genes. (3) A meta-analysis of PCR
studies has shown a pooled sensitivity of 99% and specificity of 92% in the non-HIV patient population(4). The patient needs to do saline induced sputum sample for PJP PCR and preferred to go for bronchoscopy with BAL for cytology, culture and cmv pcr, PJP PCR, and galactomannan Bronchoalveolar lavage fluid from immunosuppressed non-HIV-infected patients shows lower concentrations of organisms but higher inflammatory scores (2).
according to the results will direct our management also need to adjust the current IS therapy by stopping the antimetabolites and continuing on tacrolimus-based IS with stress dose steroids and monitor with u&e, CMV PCR, FBC, and CXR, CT chest as fu after completing the treatment course, TMP-SMX is the drug of choice for the treatment of PJP with its proven clinical efficacy, cost, and availability of both the IV and oral formulations, TMPSMX is the preferred therapy for mild, moderate, and severe disease for all patients with PJP (grade B recommendation), duration of therapy for 21 days in sever pjp preferred to use IV route to its use only limited in case of side effect, renal impairment, and myelosuppression. Alternative agents for PJP treatment will be dapsone, pentamidine, and atovaquone.
Arterial oxygenation at diagnosis was recognized as the best prognostic indicator of survival. Adjunctive corticosteroid therapy commenced at the time of PJP therapy prevented the early decline in oxygenation that occurs after initiation of PJP therapy in patients with moderate to severe PJP (arterial-alveolar difference >35 mmHg or an arterial oxygen pressure<70 mmHg (1). References
1. Consensus guidelines for diagnosis, prophylaxis, and management of Pneumocystis jirovecii pneumonia in patients with hematological and solid malignancies, 2014L. Cooley,1 C. Dendle,2,3 J. Wolf,4,5 B. W. Teh,6 S. C. Chen,7,8,9 C. Boutlis10,11 and K. A. Thursky6,12
2. Limper AH. Alveolar macrophage and glycoprotein responses to Pneumocystis carinii. Semin Respir Infect 1998; 13:339–47.
3. Robberts FJ, Liebowitz LD, Chalkley LJ.Polymerase chain reaction detection of Pneumocystis jiroveci: evaluation of assays. Diagn Microbiol Infect Dis 2007;58: 385–92.
4. Lu Y, Ling G, Qiang C, Ming Q, Wu C, Wang K, et al. PCR diagnosis of Pneumocystis pneumonia: a bivariate meta-analysis. J Clin Microbiol 2011; 49:4361–3.
5.Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother2007; 13: 1–7.
also, we should consider the possibility of combined infection with both CMV and PJP in this case as the presentation and risk factors plus the radiological finding are highly suggestive of PJP in addition to CMV pnemonitis, such combination cosxiste in up to 46% ( 1) .especially after one year of renal transplantation. and the use of t cell depleting agents like alemtuzumab as induction IS.
References
1.Zou J, Wang T, Qiu T, Zhou J, Chen Z, Ma X, Jin Z, Xu Y, Zhang L. Single-center retrospective analysis of Pneumocystis jirovecii pneumonia in patients after deceased donor renal transplantation. Transpl Immunol. 2022 Jun;72:101593. doi: 10.1016/j.trim.2022.101593. Epub 2022 Apr 5. PMID: 35367619
3. A 65-year-old man was admitted with a fever (38°C) and non-productive cough 4 months after cadaveric transplantation. CMV positive to CMV negative recipient oxygen saturation on air was reported at 82%. CXR shows widespread bilateral reticulonodular opacities.
Bacterial – nosocomial bacteria, community acquired bacteria, MTB (primary and reactivation of latent infection), non-tuberculous mycobacteria
Chest infections post kidney transplant are most common in the first 6 months with a peak at around 3 months. In the first month, the common causes are gram negative bacterial infections, aspiration and septic emboli.
In the 2nd to 6th month, common etiologies are viral (CMV, HSV, EBV), fungal (PCP, aspergillus) and tubercular infections. Viral infections can also predispose to fungal infections.
How do you manage this case?
– Detailed history i.e., hemoptysis, chest pain, comorbidities, history of acute rejection, previous chest infection, immunosuppressive therapy
CMV pneumonia – Valganciclovir (renal adjusted dose – depending on the patients eGFR)
PCP pneumonia – 21-day treatment with high dose cotrimoxazole ± steroids; other agents which can be used include IV Pentamidine, Clindamycin + Primaquine, Dapsone, oral Atovaquone
Tuberculosis – initiate on anti-TBs, bearing in the drug-drug interactions between Rifampicin and Tacrolimus
Immunosuppressive therapy – half/ hold the dose of antimetabolites and dose the CNI appropriately as guided by the trough levels
References
1.Ahmad Z, Bagchi S, Naranje P, Agarwal SK, Das CJ. Imaging spectrum of pulmonary infections in renal transplant patients. The Indian journal of radiology & imaging. 2020 Jul-Sep;30(3):273-9. PubMed PMID: 33273760. Pubmed Central PMCID: PMC7694710. Epub 2020/12/05. eng.
2.Mangalgi S, Madan K, Das CJ, Singh G, Sati H, Kanwar Yadav R, et al. Pulmonary infections after renal transplantation: a prospective study from a tropical country. Transplant International. 2021;34(3):525-34.
3.Pulmonary complications within the first year after renal transplantation. El-Azem Sadon Amal Abd, Otaibi Torki Al, Nair Prasad, Gheith Osama, El Monem Mohammed Abd, El Tawab Khaled Abd, Maher Ayman. Year : 2020 | Volume: 69 | Issue Number: 4 | Page: 739-746
PCP is associated with thick/sticky sputum and this will make it difficult to be coughed up. This make PCP unique from typical pneumonia
Because the sputum is is hard to come out , the examination will be very difficult unless you induce the sputum (less sensitive diagnostic method) or you go for bronchoscopy and BAL. (National Organization of rare diseases NORD, 2020-08-10)
. PCP usually resides in alveoli and interstisium in lower respiratory tract other reason is the thick and gelatinous secretion. This make it difficult to cough up.
I reviewd many article, i didnot find any clear explanation, but I think may be due to fungal cause and trouble breathing that make chest wall muscles are unable to take sputum sample .
Sputum sample may be difficult and bronchoalveolar lavage or even biopsy can be done
Pneumocystis carina is a ubiquitous fungus and opportunistic resident of the Broncho alveolar lumen of men and a variety of other mammalian species.
The diagnosis can be definitively confirmed by histological identification of the causative organism in sputum or Broncho alveolar lavage (lung rinse).
Staining with toluidine blue, silver stain, periodic acid-Schiff stain, or an immunofluorescence assay shows the characteristic cysts it cause interstitial pneumonia.
That’s why common symptom dry cough And Bronchoscopy with Broncho alveolar lavage increase th the yield of diagnosis in case of dry cough.
– P. jirovecii is transmitted by airborne route, around ¾ of cases had the organism since early childhood (by the age of 4 years) which become latent and can be reactivated once the immunity is compromised, on the other hand ¼ of cases may not acquire the organism in childhood and acquire it later in life through person to person airborne transmission. (1)
– Pneumocystis is exclusively present within the lung alveoli, and once infection develops it presents with alveolitis sparing the bronchial tree, thus cough is usually dry. (2)
What is the impact of the symptom of dry cough on sputum examination?
– Diagnosis of PCP depends on the detection of the cystic or trophic forms in respiratory secretions by immunofluorescent staining (the organism cannot be cultured) , PCR has a disadvantage of not differentiating between infection and colonization.
– Because the cough is dry, and patient is usually in respiratory distress, so obtaining an optimal specimen by ordinary cough may be impossible, so it should be done using one of the following ways:
1- Induction of cough using hypertonic saline with sensitivity ranging from 55- 90%. (3)
2- ET aspirates in mechanically ventilated patients with sensitivity of 92%. (4)
3- BAL with sensitivity of 90-100%. (5)
References
1. Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics 1978; 61:35.
2. Catherinot E, Lanternier F, Bougnoux ME, et al. Pneumocystis jirovecii Pneumonia. Infect Dis Clin North Am 2010; 24:107.
3. Willocks L, Burns S, Cossar R, Brettle R. Diagnosis of Pneumocystis carinii pneumonia in a population of HIV-positive drug users, with particular reference to sputum induction and fluorescent antibody techniques. J Infect 1993; 26:257.
4. Alvarez F, Bandi V, Stager C, Guntupalli KK. Detection of Pneumocystis carinii in tracheal aspirates of intubated patients using calcofluor-white (Fungi-Fluor) and immunofluorescence antibody (Genetic Systems) stains. Crit Care Med 1997; 25:948.
5. Levine SJ, Kennedy D, Shelhamer JH, et al. Diagnosis of Pneumocystis carinii pneumonia by multiple lobe, site-directed bronchoalveolar lavage with immunofluorescent monoclonal antibody staining in human immunodeficiency virus-infected patients receiving aerosolized pentamidine chemoprophylaxis. Am Rev Respir Dis 1992; 146:838.
PJP is primarily an alveolar pathogen. Pneumocystis jirovecii has a preference for infecting the lung in at-risk individuals. Microscopic examination reveals that Pneumocystis attaches to Type I alveolar epithelium, which allows the fungus to transition from its small trophic form to the larger cystic form. Adherence of Pneumocystis to alveoli is not the singular cause of diffuse alveolar damage, but rather it is the host’s own inflammatory response that causes significant lung injury and impaired gas exchange, leading to hypoxia and possibly respiratory failure.
The impact of dry cough on sputum examination is the need for obtaining respiratory secretion via BAL, ET suctioning if on mechanical ventilation or via using saline nebs for conscious patients. Reference: NIH, national Library of medicine Pneumocystis Jirovecii Pneumonia Justina Truong; John V. Ashurst.
PCP is associated with dry cough. Brochoscopy/ brochoalveolar lavage can be helpful. Molecular methods of detection include polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and antibody-antigen assays. These can be performed on sputum , nasal or oropharygeal washes
1-The hallmark of infection due to P. jirovecii is the presence of marked hypoxemia, dyspnea, and cough with a paucity of physical or radiologic findings.
The typical radiographic features of PCP are diffuse, bilateral, interstitial infiltrates
Pneumocystis pneumonia is characterized by a gradual onset with shortness of breath and/or difficulty breathing. This disorder may be accompanied with fevers, night sweats, weight loss and dry cough. Dry cough is one distinction from typical pneumonia because spit (sputum) is too thick to become productive, therefore productive cough is not as common in PJP. Uncommonly, the PJP fungus can spread to other body organs such as the liver, kidney and spleen as the disease progresses.
In susceptible (immunocompromised) hosts, the organism occurs in massive numbers, filling the alveolar spaces and eliciting an active response of the alveolar macrophages and phagocytosis. the alveolar septum is thickened and there is an interstitial plasma cell and lymphocyte infiltration. The infection results in impaired ventilation and severe hypoxia.
2-Since Pneumocystis cannot be cultured, definitive diagnosis requires detecting and identifying the organism by polymerase chain reaction assays of respiratory specimens, dye staining, or fluorescein antibody staining
Testing in this manner requires a microscopic examination of a patient’s sputum or bronchoalveolar lavage fluid. These samples should only be obtained when safe and if the patient is stable.
-Dry cough is one distinction from typical pneumonia because sputum is too thick to become productive, therefore productive cough is not as common in PJP. -sputum exam is difficult with dry cough , but sputum can be collected bybronchoalveolar lavage( BAL)
Reference Phan et al .Pneumocysitis pneumonia. NORD2018
As my colleagues have mentioned, the secretions in PCP are thick, and hence difficult to come out. Hence, sputum needs to be induced, or a bronchoalvelolar lavage (BAL) is required. If the patient is intubated, tracheal secretions can be assessed for pneumocystis.
it seems it is thick sputum because the diagnosis usually made by BAL which is the sample of choice or induced sputum as routine sputum is associated with poor result to diagnose PCP
– The cough is typically dry/ non-productive since the sputum becomes too thick/ viscous to be coughed out.
– This dry cough helps distinguish PCP from other typical pneumonias.
What is the impact of the symptom of dry cough on sputum examination? (1)
Making a definitive diagnosis of PCP can be challenging at times e.g.,
– HIV/ AIDS patients have fewer neutrophils and a higher number of organisms present in their sputum and BAL fluid. This makes the diagnosis easier or more likely attainable.
– However, immunocompromised patients who are HIV negative, are likely to have a lower organism burden in their sputum or BAL fluid samples hence making diagnosing difficult.
_PCP usually has dry cough as it mainly causes alveolitis with sparing of bronchi, and has viscid and difficult to be produced sputum .
_ Dry cough makes it difficult to examine sputum and makes sputum reproductive methods as
1_ use of hypertonic saline nebulizer to induce cough
2_ use of bronchoscopy and BAL
3_ use of endotracheal tube aspiration in. Ventilated case.
-PCP is associated with a dry cough due to the viscous nature of its sputum thats not easily expectorated.
-Dry sputum means less accurate results on sputum examination post induction unless bronchoscopy +/- bronchoalveolar lavage is done which again is challenging in a patient immunosuppressed with respiratory distress. The approximate sensitivities of sputum results are; Sputum induction ;-55-90%,Endotracheal aspiration-~90%,Bronchoalvealr lavage >90%.
REF;
Pifer et al ;PCP infection; Evidence of high prevalence in normal and immunosuppressed children.
Levine SJ et al; Diagnosis of PCP by multiple lobe, site directed BAL with immunofluorescence monoclonal antibody staining in HIV Pts receiving pentamidine chemoprophylaxis.
Stager C et al; Detection of PCP in Tracheal aspirate of intubated pts using calcofluor- white(Fungi flow)
and immunofluorescence antibody staining.Critical care med.1997;25;948
PCP associated with dry cough because the sputum is thick and sticky and it is difficult to expectorate that s way the cough is dry and this may explain the sever hypoxia .
as the cough if dry this make the diagnosis depending on sputum is in sensitive , to enhance the the sensitivity we need , induced sputum or even broncho alveolar lavage .
Bilateral lung infiltration in post kidney transplant patient with hypoxia and fever indicate severe pneumonia most likely differential is : – PCP is the most likely diagnosis esp with the presence of dry cough and hypoxia
Differential diagnoses include
– Bacterial pneumonia (Haemophilus spp., Streptococcus pneumoniae, ‘atypical’ infections such as Mycoplasma, Legionella and Chlamydia, –Mycobacterial infections, Nocardia), -Fungal infections (Cryptococcus, Histoplasma, Coccidioides) . –CMV pneumonia and other viral infection like covid 19
How do you manage this case?
Multidisciplinary team approach including ICU consultant ,Pulmonologist, Nephrologist ID consultant and Sclinical pharmacist.
Start with ABC resuscitation,maintain oxygen saturation and vitals, ABG , ICU consultation with full history and examination.
Laboratory tests include full blood count renal and liver function test ,inflammatory markers ,induced sputum by bronchoalveolar lavage PCR for PCP, culture and gram stain .Blood culture and PCR for CMV AND covid 19 .
Prograf level .
Radiology :CT chest Renal US.
Treatment :
ICU or HDU admissionwith respiratory support:The goal of therapy is the correction of the hypoxaemia. High flow oxygen should be given via standard masks and oxygen saturation should be monitored closely in moderate to severe disease .CPAP or mechanical ventilation as needed .
Drug therapy : The drug of choice is Cotrimoxazole (trimethoprim-sulphamethoxazole) at a dose of 120 mg /kg/day intravenous in four divided doses for 21 days started IV for better response then continuing on oral cotrimoxazole . Alternatives to cotrimoxazole in patients intolerant of cotrimoxazole:
Intravenous pentamidine is as effective as cotrimoxazole but with higher toxicity , and is given at a dose of 4 mg kg−1.
Clindamycin(450–600 mg 6 hourly, oral or i.v.) plus primaquine(30 mg day−1 orally) has comparable efficacy with cotrimoxazole in mild to moderate disease Side-effects include skin rashes and antibiotic-associated diarrhoea. Primaquine can cause methaemoglobinaemia and haemolysis in patients with G6PD deficiency.
Dapsone (100 mg day−1) plus trimethoprin (20 mg kg−1day−1) is a suitable alternative for mild to moderate cases.Side-effects include rash and haemolytic anaemia. Although the side-effects of cotrimoxazole are usually ascribed to sulphamethoxazole, many reactions may also be due to the trimethoprim moiety.
Oral atovaquoneis better tolerated than cotrimoxazole , but in clinical trials has shown higher failure rates in part due to its unreliable absorption. A new liquid suspension with improved bioavailability has been introduced, but whether efficacy is improved remains unanswered. The new dosing regimen is 750 mg (5 ml) twice daily for mild to moderate disease. The drug should be taken with meals (preferably with a high fat content) to enhance absorption.
Failure of cotrimoxazole therapy : If the patient is deteriorating despite intravenous cotrimoxazole, complications like pulmonary oedema,pneumothorax, superinfection, or other opportunistic infections should be excluded, as in the differential diagnosis above. Failure of cotrimoxazole will leads to a poor prognosis. Controlled trials are largely lacking, but alternatives are: (i) addition or substitution with intravenous pentamidine (ii) addition of oral dapsone or atovaquone (iii) substituting with oral clindamycin and primaquine, or (iv) salvage therapy with trimetrexate and folinic acid (leucovorin) rescue . Corticosteroids: Corticosteroids should be used for this patient if assessed as moderate to severe PCP and should be commenced together with anti-Pneumocystis therapy to increase survival and prevent the development of acute respiratory failure . It is suggested by some authors that steroid use in moderate cases should be for PaO2 (9.3 kPa or an alveolar–arterial pressure of 4.7 kPa) . In the case of ventilated patients it is found to reduced mortality from 84% to 39% . The recommended doses are oral prednisolone 50–80 mg day−1 for at least the first 5 days, tapering off over the next 2–3 weeks . In severe disease, intravenous hydrocortisone should initially be used. Adjustment of immunosuppresion :
-Continue on CNI at lower trough. – Reduction of the dose of antimetabolite (by 50%) , stopped if the patient is deteriorating. – Steroids to be continued or even increased if there is risk of rejection .
This chest X-Ray shows widespread small nodular ground glass opacities with cystic changes.
The differential diagnoses include:
Pneumocystis jirovecii pneumonia (PJP), the most likely one here.
Pulmonary tuberculosis (PTB)
CMV pneumonitis
===========================
·How do you manage this case?
BAL fluid microscopy for PJP
PCR for Pneumocystis DNA
A blood test to detect β-D-glucan can also help diagnose PCP
Further imaging studies, including CT chest
PCR for CMV
CMV QNAT in BAL fluid can be used as a less invasive tool for diagnosing CMV pneumonia, especially if performing a transbronchial biopsy would be risky.
Sputum (collected by BAL) for acid fast bacilli
Sputum culture
A blood test to detect β-D-glucan can also help diagnose PCP
TreatmentPJP
O2 therapy.
The most commonly used anti-pneumocystic medication is cotrimoxazole (trimethoprim/sulfamethoxazole). TMP/SMX can cause side effects such as rash & fever.
A regimen consisting of an intensive phase of 2 months of INH, RIF, PZA, & EMB followed by a continuation phase of 4 months of INH & RIF. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (eg, advanced age).
Treatment of CMV Disease
Reduction of immunosuppression
Antiviral therapy:
IV Ganciclovir has had a major impact on the mortality and morbidity of CMV disease.
High doses of IVIG (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the treatment of pneumonitis.
Secondary prophylaxis after treatment of disease has been assessed, although evidence in support of this strategy is limited
References
Shelley A Gilroy; Chief Editor: Pranatharthi Haran Chandrasekar, Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia, Medscape Updated: Nov 04, 2022
ATS/CDC/IDSA Clinical Practice Guidelines for Drug-Susceptible TB • CID 2016:63 (1 October) • e147
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION April 2022
Full blood count – may show leucocytosis, lymphopenia.
Serum procalcitonin – may be elevated in bacterial pneumonia.
Electrolyte, urea and creatinine – to assess kidney function.
Arterial blood gas analysis – may how hypoxemia, acidosis.
Serum beta D glucan – elevated in PCP
covid 19 PCR
Bronchoalveolar lavage PCR for CMV DNA, PCP microscopy, genexpert
Treatment of PCP
IV Septin 15-20mg/kg/day in 3 to 4 divivided doses adjusted for renal function for 21 days. Alternative regimen includes; Trimethoprim+ Dapsone, Primaquine+Clindamycine, Atovaquone, Pentamidine
Adjunctive corticosterids at 40mg orally twice daily and start tapering down after 5 days.
1-How do you manage this case? ————————————————————————–
We must follow the standard clinical approach in treating kidney transplant recipients presented with severe pneumonia which include ;
A- For early onset pneumonia (the presented case );
moxifloxacin, ganciclovir, and trimethoprim-sulfamethoxazole (TMP-SMX) .
B-For late onset pneumonia ; moxifloxacin plus ganciclovir .
C- The guidelines recommend antifungal therapy in cases of suspicion or confirmed fungal infection.
D-The dosages of all the drugs should be adjusted based on the allograft function.
E- The antimicrobial should adjusted within 24 h after the results of the microbiological cultures and serum tests became available.
F-Reduction immunosuppressant ;
1-None ICU admission;
Withdrawn of anti proliferative agent ,continue CNI and steroids .
2-ICU admission;
In critically ill patients. all the immunosuppressants should be withdrawn on admission to the ICU, methylprednisolone (1 mg/kg every 12 h) can be initiated, followed by gradual tapering . Calcineurin inhibitors can be resumed at a low dose when the intravenous methylprednisolone dose was reduced to 1.0 mg/kg/d.
G-The management of other aspects of care, such as blood glucose control, nutritional support, thromboembolic prophylaxis, sedation, and analgesia, was performed according to the current guidelines .
The index patient is a recent (4 month post-transplant), CMV positive to CMV negative cadaveric transplant, who presented with fever, non-productive cough, and hypoxia (82% oxygen saturation on room air). The chest x ray shows diffuse reticulo-nodular shadows. The clinical symptoms are suggestive of pneumonia.
The differential diagnosis in such a scenario would be (1):
b) Fungal: Pneumocystis jirovecii, histoplasma, Cryptococcus
c) Bacterial: community acquired like streptococcus, tuberculosis etc.
d) Parasitic
Bacterial etiology of the clinical picture is unlikely (no expectoration).
In view of hypoxia and non-productive cough, probability of PCP is high (2). In view of D+/R- CMV status, CMV pneumonia is also a possibility which may present with patchy ground glass opacities, small nodules, or consolidation (3,4).
How do you manage this case?
The management of the index case involves:
1) A detailed history and clinical examination
2) Laboratory testing including complete blood count, renal function tests, liver function tests, C reactive protein, blood culture, chest X ray, influenza testing (if in season) and other respiratory viral testing (biofire), Calcineurin inhibitor (CNI) trough levels (if on CNIs)
3) Induced sputum examination for cytology, gram stain and acid fast bacilli stain, and culture
4) High resolution computed tomogram (HRCT) of chest.
5) CMV PCR testing: In view of D+/R- status.
6) Admission in intensive care unit (ICU): With oxygen therapy in view of hypoxia.
7) Bronchoscopy with bronchioalvelar lavage with or without transbronchial lung biopsy: For stain and culture, as well as PCR for respiratory viruses, CMV, pneumocystis etc, and histopathological analysis.
8) Empiric initial treatment:
If influenza season: Antiviral against influenza (Oseltamivir) till the results for respiratory virus panel is available.
Empirical antibiotics: Beta lactam agent and agent against intracellular organisms should be started.
Considering the clinical status, empirical anti PCP treatment in form of co-trimoxazole and steroids (if hypoxemia with oxygen saturation <70% on room air) should be started pending the investigation results. Anti-PCP treatment can be stopped once investigations for pneumocystis are negative.
9) Immunosuppression: Antimetabolites to be stopped, CNI doses to be adjusted as per trough levels.
10) Further management as per the laboratory reports: If BAL or biopsy shows CMV, treatment with intravenous ganciclovir (5mg/kg IV 12 hourly, to be adjusted according to creatinine clearance). It should be continued for minimum 2 weeks (can be changed to oral valganciclovir, if improves earlier), and until resolution of clinical symptoms and radiological findings with clearance of CMV in blood, if present (5). Complete blood count and serum creatinine should be monitored weekly during the treatment. If no response in 2 weeks, assess for ganciclovir resistance and shift to Foscarnet and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) (5). Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse.
1) Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
2) Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587. doi: 10.1111/ctr.13587. Epub 2019 Jul 1. PMID: 31077616.
3) Kang EY, Patz EF Jr, Müller NL. Cytomegalovirus pneumonia in transplant patients: CT findings. J Comput Assist Tomogr. 1996 Mar-Apr;20(2):295-9. doi: 10.1097/00004728-199603000-00024. PMID: 8606241.
4) Moon JH, Kim EA, Lee KS, Kim TS, Jung KJ, Song JH. Cytomegalovirus pneumonia: high-resolution CT findings in ten non-AIDS immunocompromised patients. Korean J Radiol. 2000 Apr-Jun;1(2):73-8. doi: 10.3348/kjr.2000.1.2.73. PMID: 11752933; PMCID: PMC2718167.
5) Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
–Management
Hypoxia with dry cough ,fever , and having a kidney donor whom was CMV-positive and the recipient was CMV-negative represent a risk factor in the current case rendering Pneumocystitis pneumonia most likely diagnosis
Detailed history and examination need to be done to assess the patient’s general condition and assess the graft function
MDT has to be involved including with the transplantation team a pulmonologist .
ICU admission with suitable oxygen supply as oxygen sat <80% and monitoring of vitals and fluid chart Labs
Complete blood count, albumin, liver enzymes and electrolytes, inflammatory markers
Blood culture and EBV and CMV blood tests
Gamma interferon to exclude TB
PCR for COVID 19
Kidney function tests ,e GFR, urine analysis
Immunosuppressive level(MMF, Tac)
PCR for PCP from Bronchoalveolar lavage Radiology
CT chest
Renal US Treatment
Trimethoprim-sulfamethoxazole is the first-line therapy ( 15 to 20 mg/kg IV ) switching to oral after clinical improvement.
Pentamide 4 mg/kg IV o.d is the second-line therapy for severe cases
Or Primaquine plus Clindamycin for severe cases
Iv Gancilclovir 5 mg/kg BID for 14-21 days afterwards oral valganciclovir 900 mg BID can be given for coverage of high risk CMV infection
Broad spectrum antibiotic coverage
Copious hydration guided by fluid chart
,Immunosuppressive as MMF ,Tac can be reduced or stopped with following graft function ,
KDIGO Guidelines for PCP prophylaxis recommend TMP-SMX as a first-line therapy for 3–6 months after renal transplant
Reference
-Varnas D, Jankauskienė A. Pneumocystis Jirovecii Pneumonia in a Kidney Transplant Recipient 13 Months after Transplantation: A Case Report and Literature Review. Acta Med Litu. 2021;28(1):136-144. doi:10.15388/Amed.2020.28.1.5
Differential diagnosis:
1-viral pneumonities due to CMV
2-Miliary tuberculosis
3-Interstitial pneumonities
4- PCP Mangement :
1- Detailed history and examination
2- To do CBC ,Urine analysis ,RFT plus electrolyte ,viral screen ,CMV screen ,TB screen ,CRP ,
Liver function test ,US, blood culture and urine culture .
3- Start iv antibotices
4- Oxygen Treatment if this pt has CMV pneumonities :
Iv valgancilovir
Reference:
Hand book of kidney transplant
Pneumonia in post transplant recipient has wide differential diagnosis
· It may be viral ,bacterial ,fungal ,or parasitic but in this case The radiographic features can narrow the differential diagnosis
· Diffuse, bilateral infiltrates suggest CMV, respiratory viruses, Mycoplasma, Legionella, and Pneumocystis jirovecii (PJP).And Ground glass or mixed ground glass/micronodular infiltrate raises concern for PJP and CMV
Management
1. Hospitalization 2. Stabilization 3. Respiratory support 4. Initial Evaluation include
History
• Recent hospitalizations or illnesses
• Social/exposure history
• Immunization status
• Comorbid conditions
• Current degree of immunosuppression
• Exposure history indicative of possible pathogen Labs
• Complete blood count with differential-inflammatory markers
• Electrolyte and kidney function
• Liver function testing
• Influenza testing (if in season) and other respiratory viral
• Blood culture – Sputum cultures
5-Based on history and intial evaluation we may need to proceed to expanded evaluation
9-Antibacterial therapy is the cornerstone of the initial empiric therapy.
Þ acombination therapy with a beta‐lactam agent (±MRSA and ±anipseudomonal ) and an agent active against intracellular organisms (Mycoplasma in and Legionella ) Then adjust according to clinical and microbiological findings.
Þ During influenza season, empiric administration of an antiviral drug active against influenza
Routine prophylaxis has increased the risk for unusual pathogens that are resistant to prophylactic agents including fluoroquinolone-resistant streptococci, other multidrug-resistant bacteria, azole-resistant molds, and ganciclovir-resistant cytomegalovirus (CMV)
Glucocorticoids play an important role in the pathogenesis of pneumonia due to depression of phagocytic function of alveolar macrophages and neutrophils, decreased mobilization of inflammatory cells into areas of infection, and alterations in antigen presentation and lymphocyte mobilization. These effects increase the risk of bacterial and fungal infections (including those due to Pneumocystis jirovecii, Nocardia spp, and Aspergillus spp) and the risk for pulmonary involvement in the setting of certain herpes virus infections (eg, CMV, varicella zoster virus)
The agents used to suppress T lymphocyte function include the calcineurin inhibitors (eg, cyclosporine, tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (eg, sirolimus, everolimus) used in organ and hematopoietic cell transplantation. These predispose to herpesvirus infections (CMV, herpes simplex, and varicella-zoster) and community-acquired respiratory viruses, fungal infections (including Cryptococcus, Pneumocystis, and Aspergillus spp), and parasites (eg, Strongyloides, Toxoplasma, and Trypanosoma cruzi) CMV infection predisposes to fungal infections including Pneumocystis and Aspergillus
1-Concomitant viral infection pulmonary or systemic viral infection is associated with subsequent pneumonia has been described best for cytomegalovirus (CMV), influenza, and severe acute respiratory syndrome coronavirus 2.
2-Pneumocystis pneumonia (PCP) is most common in patients receiving glucocorticoids as a part of a chemotherapeutic or maintenance regimen
3-Invasive CMV disease in the immunocompromised host with pulmonary infiltrates.
4-The lungs in systemic infections tuberculosis, Nocardia spp, and Cryptococcus spp
5-The lungs can also be a site for hematogenous spread of infection (eg, septic emboli due to Staphylococcus aureus or gram-negative bacteremia). Peripheral pulmonary lesions in the lungs can be a clue that there is important disease elsewhere (eg, line sepsis, hepatosplenic candidiasis, infective endocarditis)
6- Noninfectious etiologies for pulmonary infiltrates are common in immunocompromised patients, including pulmonary embolus, tumor, radiation pneumonitis, cancer, fibrosis, atelectasis with pulmonary edema, drug allergy or toxicity, and pulmonary hemorrhage
7- infection in the community (eg, respiratory viruses, tuberculosis)
the individual (eg, travel history, sexual history, prior infections, occupational exposures)
8-drug-induced lung disease may reflect hypersensitivity to chemotherapeutic agents, sulfonamides, or other agents.
Methotrexate, bleomycin, and procarbazine can cause a syndrome of nonproductive cough, fever, dyspnea, and pleurisy with skin rash and blood eosinophilia. Chest radiographs generally demonstrate diffuse reticular infiltrates.
Cyclophosphamide may cause a syndrome of pulmonary disease with interstitial inflammation and pulmonary fibrosis that occurs subacutely over weeks to months.
9-Transfusion-associated leukoagglutinin reactions (transfusion-related lung injury [TRALI]) are uncommon, but transient pulmonary infiltrates may occur following transfusions.
10-Allograft rejection, chronic lung allograft dysfunction (CLAD), or primary graft dysfunction in lung transplant recipients can also mimic pulmonary infection.
11-Post transplant lymphoproliferative disorders may present with pulmonary nodules or lymphadenopathy.
2-How do you manage this case?
Diagnostic approach — The initial evaluation for immunocompromised patients with fever with or without pulmonary findings, at a minimum, should include:
Rapid assessment of vital signs, including oxygen saturation
Complete blood count with differential
Electrolytes, blood urea nitrogen, and creatinine
Blood cultures (minimum of two sets, with at least one peripheral set and one set from any indwelling catheter)
Urine sediment examination and culture
Sputum for Gram stain, fungal smears, and cultures
Imaging of the lungs (chest radiography or, if possible, chest computed tomographic scanning) and imaging of any symptomatic site (eg, abdomen)
Skin examination, looking for evidence of metastatic infection
CMV quantitative molecular testing is often valuable; other viral polymerase chain reaction (PCR) assays as appropriate to the individual (adenovirus, parvovirus B19, severe acute respiratory syndrome coronavirus 2)
Consideration of sample collection for nonculture-based diagnostic tools (eg, specific molecular and antigen tests such as Aspergillus or Pneumocystis PCR, cryptococcal antigen), Aspergillus galactomannan, beta-1,3,-glucan, whole genome sequencing)
Lung sampling — An invasive diagnostic procedure such as bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsy, percutaneous needle biopsy, video-assisted thorascopic biopsy (VATS)
Nasal washings or swabs (direct fluorescent antibody and viral cultures) may be used for the diagnosis of community-acquired viral infections due to influenza, parainfluenza, adenovirus, metapneumovirus, and respiratory syncytial virus. Treatment
aminoglycosides, fluoroquinolones, and/or vancomycin) recommended as a standard part of the initial regimen
trimethoprim-sulfamethoxazole (TMP-SMX) as the preferred medication for the treatment of Pneumocystis pneumonia (PCP)
Adjunctive glucocorticoids using adjunctive glucocorticoids in patients without HIV who, while breathing room air, have an arterial blood gas measurement that shows a partial pressure of oxygen <70 mmHg or an alveolar-arterial (A-a) oxygen gradient ≥35 mmHg or hypoxemia on pulse oximetry (eg, room air oxygen saturation <92 percent)
Infection control − Hospitalized patients with PCP should be cared for using standard precautions, although they should not be placed in the same room with other immunocompromised individuals due to the potential for person-to-person spread.
4 months post- KT, CMV mismatch D+/ R-, presented with symptoms suggestive for pneumonia ( fever, non-productive cough) with hypoxia 82 % Spo2. CXR showed; diffuse, bilateral, interstitial infiltrates.
Differential diagnosis is the setting of immunocompromised host:
-PJP pneumonia.
-Viral pneumonia; CMV, HSV, Covid .
-Bacterial pneumonia
-Tuberculosis.
– Fungal infection.
-Drug-induced Interstitial pneumonitis.
How do you manage this case?
Further history is needed about the induction therapy, current Is regimen, CMV prophylaxis and PJP prophylaxis, any recent virus load as part of pre-emptive therapy. Work up required: –CBC with differential, CRP, pro-calcitonin.
– VBG
– RFT,LFT.
– Blood culture.
– Respiratory culture, and viral panel.
– COVID PCR
– Immunosuppression level Tacrolimus level.
– Viral load; CM PCR, , EBV PCR.
– BAL for microscopy, staining, CMV, PJP and aspergillus
– CT chest.
– LDH
– serum levels of beta-D-glucan.
Management:
– HDU / ICU; Stabilized the patient
– ABC; O2 and respiratory support.
– Patient should be managed empirically till we have the results.
Cover for bacterial pneumonitis:
– generally start broad spectrum antibiotics then guided by culture.
As the patient is high risk for CMV pneumonitis;
-Treatment is mandatory in all cases of tissue invasive CMV disease, irrespective of viral load
-IV gancyclovir IV5 mg/kg BID for 14-21 days followed by oral valganciclovir 900 mg BID ( adjust for eGFR)
-All patients with serious tissue invasive CMV disease should be treated with intravenous GCV
– Monitoring of CMV PCR .
–All treatment should continue for at least 2 weeks after obtaining 2 negative CMV PCR, or until resolution of symptoms and for a minimum of 14 days.
– Switch to second line if there is GCV resistance. if CMV PCR count has not fallen by ≥ 1 log copies/ml after 2 weeks of therapy or if there is no clinical improvement despite treatment.
– Consider CMV immunoglobulin or IVIG in case of pneumonitis (our case).
– Continue on prophylactic dose of Valganciclovir 900 mg OD for 3 months. Management of IS:
-Stop/reduce (by 50%) azathioprine/MMF/myofortic
-Do not discontinue CNI unless there is evidence of life-threatening infection
-Corticosteroids are generally continued
– Monitoring graft function closely for any rejection. Cover For PCP;
-TMP/SMX PO for 3 months and consider alternative if patient is allergic. References: – CMV in Kidney Transplantation lecture by Prof. Ahmed Halawa
– Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
– UK guideline on prevention and management of CMV in SOT.
Taking in consideration the high risk of infection in the first 3-6 months following transplantation- due to induction immunosuppressive therapy, the clinical presentation and CXR indicates disseminated/bilateral pulmonary infection of the lungs which could be:
2- How do you manage this case?
Initial step in this clinical scenario is management of hypoxia by oxygen therapy, cs pulmonologist, ICU cs, hemodynamic support.
Basic laboratory studies including renal function test, ABG, blood culture, sputum culture, PCR-CMV, inflammatory markers, liver function test, urine analysis and culture, swab for COVID-10, nasal/throat swab for influenza A and B.
CT chest is very helpful in differentiation the etiology of infection and could be diagnostic in some infections.
Bronchoscopy with BAL for CMV, PCP, Tb, ASPERIGELLUS, is diagnostic however, in the context of severe hypoxia, bronchoscopy cannot be performed.
Empirical treatment should cover both viral and bacterial infection:
IV ganciclovir or oral valganciclovir is the first-line treatment for CMV disease.Immunosuppression doses should be decreased: reduce MMF/MPA by 50%, prednisolone is continued with the same dose and can be increased if hypotension occurs, keep CNI within therapeutic levels, reduce dose if in the upper limit of normal or if level is high.Anti-CMV medication should be continued for two weeks following CMV viremia clearance.In addition to anti-CMV therapy, we should initiate PCP medication while awaiting blood and sputum cultures and PCR results.
TMP/SMX is administered as follows: 20mg/kg/day in 4 doses or (TMP/SMX) 5mg/kg/day in 3 doses plus oral Dapson 100 mg qd.
1-What is your differential diagnosis?
-CMV Pneumonitis (most likely)
-Pulmonary Fungal Infection;
(Pneumocystis jirovecii (formerly P. carinii) pneumonia)
(Pulmonary aspergillosis)
-Respiratory viruses;
Respiratory syncytial virus, adenoviruses, and human metapneumovirus
COVID-19 – ARDS
-Idiopathic Pneumonia Syndrome
-Tuberculous pneumonia (M. haemophilum and M. avium complex)
-Drug-induced interstitial pneumonitis( mTOR)
2-How do you manage this case?
-Maintain the O2 above 94% by giving High flow O2 & Request ABG,
-Check Vital signs, to evaluate the need for ICU or high dependency unit.
-Multidisciplinary Teams (Nephrology / ICU / Pulmonology / ID)
–Further Investigations;
CBC (search for leukopenia and thrombocytopenia)
CRP (often normal)
Liver function tests, and Renal function tests.
(CMV PCR) – As the patient is at high risk for CMV.
BAL and send for respiratory panel (Influenza type A,B, Adenovirus ,covid-19 , etc) & BAL staining for PCP.
Full septic screen (including sputum C/S) -Management;
If proven to be a CMV tissue invasive disease (cmv pneumonitis);
–Consider decreasing the IS; (stop the antiproliferative medication, and decrease the CNI by 50%, with monitoring Graft Functions. -IVganciclovir(5 mg/kg every 12 hours) for 2-3 weeks; should be used in place of valganciclovir. (after ID recommendations)
-IV ganciclovir can be transitioned to oral valganciclovir once the patient has demonstrated clear clinical improvement, viral loads are down-trending, and the patient can tolerate/absorb oral medications.
-While treating with either ganciclovir or valganciclovir, we monitor the serum creatinine at regular intervals in case dose adjustment is needed.
-The addition of cytomegalovirus immune globulin (CytoGam) to antiviral therapy might theoretically improve treatment response. -Monitoring on therapy; Viral load / Renal functions / Blood cell counts. -Gancyclovir ( intolerant or resistant);
-Resistance to ganciclovir should be considered in recipients who fail to improve clinically and/or virologically after two weeks of adequate doses of antiviral therapy or who have recurrent relapses following treatment.
-Factors that raise the likelihood of ganciclovir resistance include prolonged antiviral use, lack of prior CMV immunity (CMV D+/R-), and inadequate antiviral drug selection or dosing (eg, treatment with oral ganciclovir or subtherapeutic dosing of IV ganciclovir. -Resistance testing ;Genotypic resistance testing should be performed in patients with suspected ganciclovir resistance (UL97 mutation & UL54 mutations).
-Switching the immunosuppressive regimen to one that includes an mTOR inhibitor (eg, sirolimus, everolimus)
–Foscarnet 60 mg/kg IV every 8 hours (or 90 mg/kg IV every 12 hours), with adjustment for renal dysfunction.
-It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet.
-An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity. -References;
-UP TO DATE,
-Oxford Specialist Handbooks of Renal Transplantation,
PCR assay of respiratory specimen, either induced sputum +/- BAL for PCP, CMV, AFB
Plasma PJP and CMV PCR
COVID- 19 PCR
Beta-D-glucan
Given the clinical presentation and high suspicion of PJP treatments should be start empirically, IV septrin, adjust dose according to renal function. Alternative if patient is allergic to septrin.
Adjunctive steroid if PaO2 <70 mm Hg in RA or an alveolar gradient of >35 mm Hg.
Reduction of immunosuppression. Withhold antimetabolite, check CNI level
Laboratory test to check FBC, renal function, LFTS and inflammatory markers. Blood culture.
Monitor progress and response to treatment, escalate level of care if sever disease needing respiratory support.
Monitor graft function
Following treatment ensure patient on prophylaxis for total of 6 months post-transplant.
Treatment would vary if investigation showed -ve PCP.
This is a patient who has a pneumonia based on the symptoms of cough, fevers and hypoxia four months after transplant
It would be important to get a further history about
Pneumocystis prophylaxis and CMV prophylaxis
The CXR is showing increased bronchopulmonary lung markings and ground glass opacities
The differential diagnosis includes:
PJP pneumonia
Viral pneumonias:
CMV pneumonitis
Varicella pneumonitis
Bacterial pneumonitis
Tuberculosis
Management
The patient will need further work up:
CBC
CRP
Procalcitonin
HRCT
Bronchoscopy and bronchoalveolar lavage
PJP PCR
Silver methenamine stain for PJP on the BAL
CMV PCR
BAL for gen expert for TB
Arterial Blood Gases
Treatment
Prop up the patient
Oxygen
Definitive treatment will depend on the cause
The transplant team will have to determine whether reduction in immunosuppressants is mandated taking in to account that it’s only four months after transplant. If is an opportunistic infection and the patient is very sick, immunosuppression reduction is necessary
If it is PJP pneumonitis, the patient needs to be started on high dose septrin for three weeks
If the patient has CMV on the BAL, he will require IV Ganciclovir for five to seven days then valganciclovir
Hypoxemia — The presence or absence of hypoxemia can assist in the differential diagnosis of pulmonary infiltrates in immunocompromised patients. Hypoxemia with an elevation in lactic dehydrogenase or beta-1,3-glucan and minimal radiographic findings are common in Pneumocystis pneumonia (PCP), whereas the absence of hypoxemia with pulmonary consolidation is more common in nocardiosis, tuberculosis, and fungal infections until later in the course.
Combination of both dry cough and dyspnea on minimal exertion raise the index of suspicion of PCP and require further investigation to confirm the diagnosis
You are right but do you think CMV pneumonitis can not cause hypoxaemia?
The bottom line is to expand our thoughts in managing these patients. This case is a high risk of CMV infection/disease because D+/R- but the overall picture should be put in mind including immunological evaluation whether the case received any depleting agents for induction, rejection episodes, biochemical results and microbial diagnosis to reach the correct diagnosis.
Why do I strongly think it is a PCP, or at least PCP should be excluded?
The presence of hypoxia and dry cough in at risk patient (immunocompromised) with CXR showing diffuse, bilateral, interstitial infiltrates is typical for PSC infection
The presence of discrepancy between CXR finding (mild infitrates) and clinical situation (severe hypoxemia) is one of the criteria suggestive of PSCOne symptom in the scenario may direct your attention to PCP. What is it?
Dry cough and fever are common also in CMV pneumonitis, but the presence of hypoxemia is highly suggestive of PSC as it presents as interstitial infiltrates like interstitial lung disease
Why do I strongly think it is a PCP, or at least PCP should be excluded?
PCP should be ruled out as the patient is immunocompromised with fever , dry cough and hypoxia with diffuse infiltrate in CXR. One symptom in the scenario may direct your attention to PCP. What is it?
The presence of hypoxia at rest with chest infiltrate
Why do I strongly think it is a PCP, or at least PCP should be excluded?
In a recently transplanted (4 months back) patient (higher levels of immunosuppression) presenting with fever, non-productive cough and hypoxia (oxygen saturation 82% on room air) and chest x-ray showing diffusely reticulo-nodular shadows, pneumocystis pneumonia (PCP) should be excluded.
Thank you , Prof, at least we covered him with PCP treatment while waiting for the results as highlighted in number 5 regarding management of this case
How do you manage this case?Management is MDT; nephrologist, intensivist, pulmonologist, virologist, pharmacist, social worker & counsler. The steps are ;
1.Admission to ICU
2 Stop immune suppression e.g., stop anti-metabolites (MPA or AZA), keep CNI and steroids
3.Oxygen support 15l/min non re-breather mask
4.Broad specturm antibiotics, cover the atypical pneumoinas
5.Increase the dose of co-trimoxazole (CTX) porphylaxis to therapeutic dose until the diagnosis is cleared
6.IV fluids and nutrition
7.IV PPI cover against stress ulcers
8.Confirmation of the diagnosis;
CMV PCR
Broncoscopy & BAL ( including CMV PCR on the BAL)
9.Other complimentary tests ; sputum, FBC, UECs (eGFR), LFT, blood sugars, blood cultures, urine cuturea and the inflammatory makers
10.Tacrolimus level
11.Allograft U/S including doppler in case of AKI
12.Anti-viral therapy in case of confirmed CMV:
IV gancycolvir 5mg/kg bid for 5 days followed by oral valgancyclovir 900 mg od until 2 X PCR negative
Adjust the drug doses according to the renal function
Monitor for haematologic toxicity by FBC
13.Discuss the risk of acute rejection after reduction of immune suppression
14.Review immune-suppression after resolution of CMV
PCP should be excluded because ;
Immune compromised
time-line after transplantation ( 1-6months)
Dry cough
Hypoxemia
CXR findings of bilateral of interstitial pneumonia
One symptom in the scenario may direct your attention to PCP. What is it?
Dry cough is a typical symptom for PCP specially in associated with fever in the setting of immune compromised patient
Practically this patient initially is going to be covered for every thing possible , including miliarly tuberculosis (i.e umbrella treatment) until he is sorted out and this may take some time because he may even be too sick for a diagnostic procedures such bronchoscopy and cooperation will be an issue.
Another point is that; immune compromised patient who present with pulmonary symptoms and signs is usually difficult specially in resource limiting setting due to wide range of differential diagnosis and antibiotic approach. This is usually the bases of the umbrella treatment, just hit it them all !
Hypoxia, that can gradually progress into respiratory failure along with it’s association with fever ,dry cough In D+/R- for CMV renders PCP more likely
Why do I strongly think it is a PCP, or at least PCP should be excluded?
The presence of hypoxia and dry cough in at risk patient (immunocompromised) with CXR showing diffuse, bilateral, interstitial infiltrates is typical for PSC infection
The presence of discrepancy between CXR finding (mild infitrates) and clinical situation (severe hypoxemia) is one of the criteria suggestive of PSC
One symptom in the scenario may direct your attention to PCP. What is it?
Dry cough and fever are common also in CMV pneumonitis, but the presence of hypoxemia is highly suggestive of PSC as it presents as interstitial infiltrates like interstitial lung disease
-Pneumocystis pneumonia(PCP;); is a potentially life-threatening infection that occurs in immunocompromised individuals. -So, it is very important to exclude it in this case. The clinical manifestations of PCP are most commonly gradual in onset, and are characterized by fever (80 to 100 percent), cough (95 percent), and dyspnea (95 percent) progressing over days to weeks. -Approximately 5 to 10 percent of patients are asymptomatic. -The cough is generally nonproductive. -The average patient has pulmonary symptoms for about 3 weeks before presentation. -Oxygen desaturation can occur with exercise and is highly suggestive of a diagnosis of PCP. Chest radiographs– -Chest x-rays are initially normal in up to one-fourth of patients with PCP. -The most common radiographic abnormalities are diffuse, bilateral, interstitial, or alveolar infiltrates. -Upper lobe infiltrates and pneumothoraces can also be seen.
Dry cough and Oxygen saturation on air was reported at 82%.
Other symptoms are:
► Exercise induced Hypoxaemia, often severe and out of proportion to clinical findings -Dry cough
-Dyspnea -Fever—often low grade
-Chest examination often normal. Crepitations may be present on auscultation, but clinical features of consolidation are unusual
Lungs are the second most common site of acquired CMV infection, after kidneys.
CMV pneumonitis presents with nonspecific symptoms such as low-grade fever, shortness of breath, and dry cough.
Be asymptomatic (subclinical CMV infection) or symptomatic and appear as “CMV disease” in kidney transplant recipients.
A fourth classification of CMV disease includes tissue-invasive CMV disease (with organ involvement), which most frequently results in enteritis or colitis but can also lead to hepatitis, retinitis, meningitis, pneumonitis, or allograft nephritis.
Similar to our patient, CMV illness without organ involvement frequently manifests as fever, malaise, myalgia, leukopenia, or thrombocytopenia.
==================================================================== What is your differential diagnosis?
Chest xray PA view showing bilateral symmetrical nodular distribution involve all lung zones denoting post CMV pneomonic changes.
Other CMV pnemonic changes which preferred seen by High resolution CT include:-
Ground glass opacities.
Confluent consoldation.
Bronchiectasis.
Interstitial reticulation without air space opacification.
D.D: Is broad but in the immunocompromised patients consider:-
Pneumocystis jirovecii pneumonia.
Other forms of viral pneumonias(COVID-19 and post-COVID syndromes,EBV,
Fungal infections- Aspergillus, Cryptococcus, Histoplasma capsulatum, and Coccidioides
1- General health of the patient’s condition stabilizing(improve O2 by high flowoO2 and administer an antipyretic ).
2- Consultation with Plumologist and if need too with ICU team.
3- CMV pneumonitis can be accurately diagnosed by quantitative PCR performed in the plasma combined with a lung specimen (biopsy/bronchial wash/bronchoalveolar lavage).
Investigation :-
CBC to detect (leukopenia and thrombocytopenia).
Urine analysis
ABG OR VBG —–R.acidosis.
KFT ,LFT.CRP.
Electrolyte(Na,Ca,K).
Blood and sputum culture .
Abdominal and pelvic U/S with dopplex —– esp.kidney transplant.
CMV-PCR
High resolution chest CT
Treatment
IV ganciclovir or its prodrug, oral valganciclovir,is the first-line treatment for CMV illness.
These medications work by preventing viral DNA polymerase from extending DNA.
The level of immunosuppression must be reduced as part of the CMV disease treatment (Stop/reduce (by 50%) azathioprine/MMF/myofortic)but prednisolone was continued.
Anti-CMV therapy should continue for 2 weeks after clearing of CMV viraemia
Oral vGCV/ IV GCV dose is reduced in renal impairment
Monitoring graft function closely during CMV disease.
The reduction of immunosuppression increases the risk for rejection, monitoring of kidney function is warranted to guide the use of immunosuppression.
GCV 5mg/kg bd IV for 14-21 days especially if there is reduced absorption e.g. diarrhoea OR IV GCV for 5 days followed by oral vGCV for 2-3 weeks or until 2 x CMV DNA by PCR are negative.
Ganciclovir Resistance
If CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks of therapy or if there is no clinical improvement despite treatment:-
1-Exclude other causes of symptoms
Switch to second line
2- Foscarnet (nephrotoxic; it can result in metabolic changes as well as cardiac arrhythmias and genital ulcerations).
3- Cidovir (nephrotoxic and causes neutropenia, metabolic acidosis and ocular hypotony).
4- Letermovir is a newly approved anti-CMV antiviral which inhibits the viral terminase complex.
5- It interacts with immunosuppression, requires dose adjustment in renal and hepatic impairment and can be used with other anti-CMV medications.
6- Maribavir is a promising new antiviral against the viral UL97 kinase.
Reduced haematotoxicity and nephrotoxicity compared to GCV and VGCV and so could eventually replace these older compounds.
7- Co-administration of with GCV is not advised as Maribavir is an inhibitor of the UL97 enzyme required for anabolism of the latter.
Reduction in immunosuppression
CMVIG can be used to induce a passive immunity. Resistant infection and side effects to VGC .
Request genotypic resistance and
Adoptive immunotherapy.
Prophylaxis
A standard 3-month course of antiviral prophylaxis is effective for prevention of CMV disease in high-risk patients, however late onset CMV is a significant problem.
Late-onset CMV disease is estimated to occur in approximately 30% of D+/R- transplant recipients and is associated with increased morbidity and mortality.
The IMPACT study demonstrated that prolonging valganciclovir (vGCV) prophylaxis (200d vs. 100d) decreased CMV disease at one-year post-transplant.
4- Radtke J, Dietze N, Spetzler VN, et al. Fewer cytomegalovirus complications after kidney transplantation by de novo use of mTOR inhibitors in comparison to mycophenolic acid. Transpl Infect Dis. 2016;18:79–88.
5- Paya C et al. Am J Transplant 2004; 4:611-620
6- Limaye et al. Transplantation 2004 78(9):139
7- Humar et al. Am J Transplant 2010; 10: 1228-1237
8- UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
A kidney biopsy shows interstitial infalamation with owel’s eye appearance, the golerulus shows mesangial hypercellularity and a thickened GBM. What is your differential diagnosis? CMV disease – owl’s eye The risk factors in our case are old age of the recipient, received ATG after evident ACR. Cellular rejection Diabetic nephropathy Light chain disease
How do you manage this case? Investigations: CBC, Kidney function test (BUN, creat, Na, K, Cl), Liver function test, LDH, serum calcium, total protein and albumin, urinalysis, CRP, ESR, RF. Serology and viral PCR Treatment: Reduce immunosuppressive medications: MMF by 50%, keep lower therapeutic CNI level, continue on steroid, with careful follow up of kidney function. Anti CMV viral therapy iv ganciclovir till the viral load undetectable then oral valgancyclovir for at least 6 months with continued monitoring of viral load. IVIG/MCVIG is a good option to treat CMV, and may reduce the inflammation. The use of m-TOR inhibitor might be of value.
The pathologist queried grade 1 ACR. Would your management differ? No, as the patient is known to had steroid resistant ACR, and had received ATG lastly. I would not give him another shot of ATG. However; the prognosis is poor with this old age recipient, and impaired graft function.
What is the association between this condition and ACR? It was thought that patients with CMV experience more ACR episodes, but lately this was eliminated by a systemic analysis of the CMV associated ACR, that showed slight non-significant increased ACR with CMV infection either by protocol biopsy or indicated biopsies. The etiology of CMV induced rejection are: – Production of interferon-ϒ during the inflammatory process increases the expression of major histocompatibility (MHC) class I and II molecules on both vascular endothelial and tubular epithelial cells. – CMV may express molecules similar to MHC class I and II antigens priming the immune response against the allograft. – the alloantigen independent pathway of rejection by increasing co[1]stimulatory molecules on APCs, vascular endothelial cells, tubular epithelial cells and T-lymphocytes. – Elevated anti- endothelial cell antibodies have been reported in a small group of renal and cardiac allograft recipients coincident with CMV infection. This may indicate an increased risk of humoral response.
References: (1) CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023. (2) Erdbruegger U, Scheffner I, Mengel M, Schwarz A, Verhagen W, Haller H, Gwinner W. Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant. 2012 Jan;27(1):435-43. doi: 10.1093/ndt/gfr306. Epub 2011 Jun 28. PMID: 21712490.
Management :
1- Further invstigations :
2- CBC : leucopenia , thrombocytopenia supporting the diagnosis of CMV pneumonitis .
3- Sputum culture and sensitivity. BAL for CMV PCR
4- CMV PCR in sputum and blood.
5- High resolution CT chest
6- Monitoring of graft function for detection of early graft rejection .
7- ICU admition , IV fluid , fluid balance , broad spectrum antibiotics
8- Decrease the dose of IS drugs and stop antiproliferative drugs as MMF
9- Its mostly a case of CMV pneumonitis ( as CXR show diffuse ground glass opacities and CMV R-D+ status).Start treatment with IV gancyclovir 5 mg /kg bdIV for14-21 days followed by oral valgancyclovir with monitoring of CMV PCR . Treatment should continue for at least 2 weeks after obtaining 2 negative CMV PCR results.
-For Pneumocystitis jerovi with TMPSMX 80/400 PO for 3 months.
For bacterial pneumonitis : broad specrtumantibiotics giuded by C&S.
Ref
1- CMV in kidney transplantation . prof. Ahmed Halawa.
Early post cadaveric renal transplant, with cough for the last 4 months , and O2 desaturation 82% on RA.
Description of the CXR: diffuse alveolar infiltrates. Early post cadaveric renal transplant.
Given that the donor was IgG + ve and the recipient IgG –ve for CMV with high chance of transmission top on the list would be MCV pneumonitis/ pneumonia. Other differential diagnosis:
Pneumocystis carinii pneumonia (PCP).
Miliary Tuberculosis.
Viral Pneumonitis – Corona viruses, HZV,
Fungal infections- Aspergillus, Cryptococcus, Histoplasma capsulatum, and Coccidioides
Nocardia spp.
Malignancy – lymphoma, PTLD.
Pulmonary edema.
How do you manage this case?
First, rescue his oxygen saturation, antipyretic, hydration, bronchodilators. Investigations: Laboratory:
CBC, Kidney function test (BUN, creat, Na, K, Cl), Liver function test, LDH, serum calcium, total protein and albumin, urinalysis, CRP, ESR, RF.
Sputum culture and AFB, and blood cultures,
Arterial blood gases. Imaging: CT chest abdomen and pelvis. Pulmonary consultation– bronchoscopy for Broncho-alveolar lavage analysis gram stain and culture and biopsy. Skin and CNS sampling skin lesions or cerebrospinal fluid (CSF) may demonstrate Cryptococcus spp or mycobacterial infection before microbiologic data from sputum or lung biopsy specimens are available. viral load and monitoring
Treatment:
(1) Decrease immunosuppressive medications if hemodynamically stable- decrease MMF by 50-75% of the dose, keep the CNI at lower therapeutic level required, and stress dose steroid. If hemodynamically unstable I would stop MMF.
(2) Antibiotics: IV anti staph –vancomycin + wide spectrum covereage Piperacillin-tazobactams, or carbamenems and anti viral therapy (corona virus).
It is proposed that the patient would be on CMV and PCP prophylaxis at this time as in our center the patient continued on CMV prophylaxis in this high risk (D+/R-) CMV for 6 months, and PCP prophylaxis for 6 months.
If it is CMV then I would consider IV ganciclovir for 10-14 days then shift to oral with frequent monitoring of the viral load, if continued to be detectable >/= 1 log copies, or no clinical improvement,then ganciclovir resistant species is considered for this therapeutic measures would be:
– Foscarnet , Cidovir, Letermovir, or Maribavir.
– CMV IG – particularly in this case (pneumonitis).
– Request genotypic resistance.
– Adoptive immunotherapy.
If it is PCP Cotrimethixazole (TMP-SMX)20mg/kg/day in 4 divided doses, or (TMP-SMX) 5mg/kg/day in 3 divided doses + oral Dapson 100 mg qd.
If allergic to TMP-SMX : Primaquine: 30 mg (base) orally once per day+ Clindamycin: 900 mg IV every eight hours, or Atovaquone 750 mg orally twice daily (must be taken with food), or Pentamidine 4 mg/kg IV once daily.
All with oral prednisolone 40 mg x2 for 5 days followed by 40 mg x1 for 5 days then 20 mg x1 for 11 days then tapper down.
If miliary TB isoniazide, rifampin, pyrazinamide, and ethambutol for two months then isoniazid and rifampin for 4 months (total 6 months).
Or Rifapentine-moxifloxacin four-month regimen.
If PTLD Stop one of the immunosuppressive medications used MMF, CNI and reduce the other, or switching to m-TOR inhibitor.
Based on the biopsy histopathology result and extent of involvement – to be discussed with hemato-oncologist.
Rituximab could be the only treatment required.
Radiotherapy is another treatment option.
R-CHOP/ABVD can be a treatment option base on the pathology result.
Adoptive immunotherapy may be usefull but might increase the risk of rejection.
However; PTLD’s carry a poor prognosis with 50% mortality.
References:
(1) UpToDate- Approach to the immunocompromised patient with fever and pulmonary infiltrates.
(2) Shah N, Eyre TA, Tucker D, Kassam S, Parmar J, Featherstone C, Andrews P, Asgari E, Chaganti S, Menne TF, Fox CP, Pettit S, Suddle A, Bowles KM; Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol. 2021 May;193(4):727-740. doi: 10.1111/bjh.17421. Epub 2021 Apr 20. PMID: 33877688.
(3) UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION.
In a patient with a kidney transplant who has had a seropositive donor for 4 months, a CXR reveals bilateral large lung infiltrates. The differentials are;
Viral infections.( CMV,HSV,VZV, EBV) covid-19
Bacterial infections, T.B, Nocardia
Fungal infections and opportunistic infections; Listeria, Aspergillus, Pneumocystis jiroveci How to manage the case;
As this patient is very high risk D+/R- he was supposed to be CMV prophylaxis .
He needs to be investigated for ganciclolvir resistant. Investigations are including;
CBC, CRP, CMV PCR, BAL, Blood culture, T.B DOT. ABGs. And testing for COVID-19 also renal function
CT chest, TREATMENT
Reduction of immunosuppresion by decreasing the dose of CNI and stopping the anti metabolite but this method apply case to case and patient and his family should be aware of graft detoriation.
Anti-viral therapy ganciclovir 5mg/kg
CMV viral loads weekly or biweekly while on therapy, minimum duration of therapy is two weeks
Follow up investigation CBC for neutropenia, RFT for graft function. Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:93.
Lecture of pro. Ahmed Halawa
An further course of suppressive therapy, consisting of valganciclovir 900 mg once daily, may be continued for an additional 1 to 3 months, or longer if necessary, following the successful suppression of viral replication.
Renal insufficiency calls for dose modifications.
What is your differential diagnosis?
Chest x-ray showing bilateral multiple small nodules scattered in the lung fields with pulmonary infiltrates with free costophrenic angles. With these symptoms, high risk of CMV infection (D+/R-) and radiological signs, I will put CMV pneumonitis (tissue invasive) in the top of differential diagnoses
*CMV is the most frequent organism infecting the SOT
*CMV pneumonitis commonly manifests as diffuse interstitial infiltrates, but focal and even nodular infiltrates are described in up to one-third of patients
*CMV may cause severe pneumonia with ARDS requiring ICU admission
*The main risk factor is primary infection
How do you manage this case?
*MD approach and a pulmonologist involvement
*Full history and examinations
*Lab: CBC, RFT and electrolytes, LFT, RBS, urine analysis, ESR, CRP, blood culture, and ABG
*Imaging: HRCT chest
*CMV viral load (a negative plasma or whole-blood does not exclude tissue-invasive disease)
*Induced sputum or bronchoscopy for BAL for inclusion bodies, and CMV viral load and culture (demonstrate organism in lung tissue). Stain for AFP and PCP
ICU admission and O2 therapy
Treatment:
Immunosuppressions:
*Reduce (by 50%) or stop azathioprine/MMF/myofortic (discontinue CNI only if there is evidence of life-threatening infection). Continue steroids
*Monitor graft function closely and discuss the risk of acute rejection with the patient
*Review the dosing of immunosuppression following resolution of CMV disease
Antiviral:
*Treatment is mandatory regardless to viral load if confirmed to be CMV-tissue invasive pneumonitis
*Give intravenous GCV (bioavailability, 5mg/kg bd) for a minimum of of 14 days and for 2 weeks and continue until resolution of symptoms and two tests of CMV DNA by PCR are negative. Do viral load first after 2 weeks and then weekly. Reduce the dose in renal impairment
*Do CBC twice weekly (neutropenia)
*CMV immunoglobulins
1. *Be aware of ganciclovir resistance if there is no clinical improvement despite treatment or CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks. If confirmed, stop ganciclovir and give Intravenous Foscarnet for at least 3 weeks after virology advice (newer agents Letermovir and Maribavir may be an alternative)
Reference
1. Patricia Muñoz et al. Fever in Organ Transplant Recipients. Antimicrobe.
2. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
3. Basinger J, Kapp ME. Cytomegalovirus pneumonia as pulmonary nodules. Autops Case Rep. 2022
4. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
1- CXR showing bilateral massive lung infiltrate suspected CMV disease in renal transplanted patient since 4 months from seropositive donor.
can be differentiated from other viral infections as well as fungal infection or bacterial infection …it is pneumonitis
2-management:
BAL bronchoalveolar lavage and histological detection of CMV if owl eye appearance appeared
CMV PCR
blood culture
EBV PCR
stop azathioprine of MMF
continue steroid
stop CNI in life threating condition
intravenous ganciclovir until symptoms resolved and no longer detection of CMV DNA in the blood minimum 14 days
follow up weekly by CMV PCR
treatment of CMV continued for 2 weeks after clearance of the virus from the blood
oral can be initiated after finishing iv ganciclovir for 2 weeks , and can be continued until symptoms disappeared and CXR become clean and CMV cleared from blood
This a post-transplant patient 4 months now with suspected suspected lung infection based on the physical findings and the CXR (bilateral pulmonary infiltrates). He was CMV negative and the donor was positive which put him at high risk for CMV infection and disease. CMV pneumonitis is a serious disease with high mortality. This situation could have been avoided by the use of CMV prophylaxis in this high risk patient. It is important to keep in mind the time line after transplantation for better formulation of the differential diagnosis. This man now in his 4th months and the differential diagnosis from after one months to 6 months are:
Management is MDT; nephrologist, intensivist, pulmonologist, virologist, pharmacist, social worker & counsler. The steps are ;
1.Admission to ICU
2 Stop immune suppression e.g., stop anti-metabolites (MPA or AZA), keep CNI and steroids
3.Oxygen support 15l/min non re-breather mask
4.Broad specturm antibiotics, cover the atypical pneumoinas
5.Increase the dose of co-trimoxazole (CTX) porphylaxis to therapeutic dose until the diagnosis is clearfied
6.IV fluids and nutrition
7.IV PPI cover against stress ulcers
8.Confirmation of the diagnosis;
CMV PCR
Broncoscopy & BAL ( including CMV PCR on the BAL)
9.Other complimentary tests ; sputum, FBC, UECs (eGFR), LFT, blood sugars, blood cultures, urine cuturea and the inflammatory makers
10.Tacrolimus level
11.Allograft U/S including doppler in case of AKI
12.Anti-viral therapy in case of confirmed CMV:
IV gancycolvir 5mg/kg bid for 5 days followed by oral valgancyclovir 900 mg od until 2 X PCR negative
Adjust the drug doses according to the renal function
Monitor for haematologic toxicity by FBC
13.Discuss the risk of acute rejection after reduction of immune suppression
14.Review immune-suppression after resolution of CMV
Source;
Prof Halawa lecture
Hand book of kidney transplantation by Gabriel Danovitch 6 edtition
To confirm the diagnosis, we need to take details history of presenting illness, its duration and any contact with sick person recently.
Detailed history of immunosuppression, induction, prophylactic medications specifically for CMV and PCP. Weather he is still on prophylaxis or stopped( many centers give prophylactic valgancicolovir for 6months for high risk patients like this case) which will make CMV pneumonia less likely.
Any previous infection, or rejection.
Donor history, any diagnosed infection, like TB.
Routine investigations, CBC,Renal and liver panel. Septic workup, including blood culture, sputum, urine, and broncho alveolar lavage (BAL), specially if no sputum or patient is intubated, if possible and to send it for CMV, PCP, culture and TB
Serum CMV PCR ( but can be negative in almost 50% of cases).
If confirmed CMV pneumonia, management includes:
Reduction of immunosuppression, starting anti metabolite, then CNI if no improvement.
Anti viral treatment with IV ganciclovir 5mg/kg bid, then oral 900mg bid, when tolerated adjusted for renal function. For 3-4 weeks, till negative CMV result for 2consequative weeks, then prophylactic dose 2-3 months.
Involvement of Infectious disease, pulmonology and ICU consultant.
If other bacterial, fungal or PCP to be treated accordingly with the help of ID consultant interested in transplantation.
Gradually resuming his immunosuppression to their pre-morbid levels (after improvement). Some experts may keep anti metabolite on a lower level specially if no history of rejection and standard immunological risk.
It could be:
· CMV pneumonitis
· Miliary TB
· Pneumocystis carinii
Other tests required:
· CMV PCR
· Sputum culture
· AFB smear and culture
· Respiratory viral screening
· Might need bronchoalveolar lavage if all negative
Rx:
Based on laboratory findings, the cause can be identified and treatment can be initiated.
The most important differential diagnosis is CMV pneumonitis
Other viral infections including influenza and Covid
Bacterial pneumonia
Pneumocystitis carenii pneumonia
How do you manage this case?
Diagnosis
Routine lab should be done including CBC, C reactive protein, liver and kidney function test
Blood gas
Blood and sputum culture including fungal cultures, beta d glucan
CMV PCR
CXR, may need high resolution CT chest
In case of CMV pneumonitis
The main tool in diagnosis of CMV infection or disease is PCR with sensitivity 100% in D+/R-
Occasionally PCR is negative in tissue invasive disease and the only way for diagnosis is tissue biopsy and histopathological examination,
In CMV pneumonitis 30% of cases has negative PCR and the main diagnosis is by BAL
Treatment in case of CMV pneumonitis
Together with circulatory support and ventilator support ranging from nasal O2 up to mechanical ventilation, 3 main lines of treatment available for treatment of CMV infection and disease
A- Reduction of immunosuppression
In the form of reduction of the dose (by 50%) or stopping the antimetabolite (in severe and non-responding disease) since kidney can survive without antimetabolite
Keep CNI at lower trough (do not play with CNI)
Continue steroids
In case of very high risk patients for rejection, or if the patient develop rejection, the main treatment will be high dose steroids
Resume lower dose of antimetabolite only in high risk patients for rejection after PCR is negative for 2 successive samples 1 weeks apart
Close follow up of PCR weekly for 1 month after starting low dose antimetabolite
B- Antiviral therapy
Indications of antiviral therapy includes :
PCR> 35 copies/ml in symptomatic patient
PCR > 1000 copies in a seronegative recipient (high risk), or sero positive recipient (low risk) with rising titer during follow up
PCR > 5000 copies/ml whatever the serostatus of the recipient
So in the current case just detectable CMV either in blood or in BAL is an indication for treatment
Medications used for treatment of CMV infection
1- Oral valgancyclovir
In a dose of 900 mg twice daily
Indicated in asymptomatic cases and in mild to moderately symptomatic cases, provided the patient can take oral
Follow up CBC, renal function test and CMV PCR weekly during treatment
2- IV gancyclovir
In a dose of 5mg/kg/12 hours
In symptomatic severe and life-threatening cases and in pediatric patients
Severe disease is defined as viral load of >10000 copies/ml or the presence of tissue invasive disease
Follow up CBC, renal function test and CMV PCR weekly during treatment
3- CMV immunoglobulin or IVIG
Given only in life-threatening infection not responding to IV gancyclovir (gancyclovir resistance)
Gancyclovir resistance is defined as failure of the fall of PCR by > 1 log with treatment
When to stop treatment (3 prerequisites required)
The drug is given for a minimum of 3 weeks (usual duration of therapy 3-4 weeks)
Risk factors for CMV recurrence include high initial viral load, slow reduction of viral load with treatment, resistance (persistent viremia), severe disease with multi-organ involvement, use of concurrent treatment for rejection and the unuse of prophylaxis
After treatment of CMV prophylaxis should be initiated using valgancyclovir in a dose of 900 mg daily for 1-3 months
So … in the current patient
I will stop antimetabolite and reduce the dose of CNI to achieve lower trough level
Start IV gancyclovir for the total duration or till the condition stabilize (after 5 days) and the patient can take oral at that times switch to oral can be done
Follow up PCR weekly and stop treatment after 21 days of treatment provided the patient is symptom free and PCR negative for 2 successive samples.
After that I will continue on once daily valgancyclovir in a dose of 900 mg daily for 1-3 months to prevent recurrence
The decision to resume antimentabolite is according to patient immunological risk, if high risk I will resume 50% of the dose with close follow up of CMV PCR weekly for 1 month after initiation of the drug
What is your differential diagnosis?
Pneumocystosis, miliary-type pulmonary tuberculosis, invasive fungal disease, respiratory viral diseases (COVID-19, Influenza), bacterial pneumonia (including atypical agents).
However, the patient is at high risk for developing CMV pneumonitis due to the epidemiological context, there is no description of prophylaxis or preemptive treatment in this case.
How do you manage this case?
Admission to intensive care for monitoring and adequate respiratory support.
Respiratory isolation in negative pressure (risk of tuberculosis, COVID-19, and Influenza).
Non-invasive methods for diagnosis (urinary antigen for Histoplasmosis, IGRAs for Tuberculosis, PCR detection for CMV, Influenza, COVID-19). Request laboratory routine, arterial blood gases, and procalcitonin.
Consider diagnostic bronchoscopy (depending on clinical conditions) for lavage viral load count, AFB, Ziehl Neelsen, PCP for PCP, galactomannan, biopsy, and immunohistochemistry.
Decrease immunosuppression.
Start Ganciclovir 5mg/kg/dose every twelve hours (depending on renal function) due to high-risk CMV epidemiological link (Positive donor/Negative recipient). Evaluate enriched immunoglobulin for CMV in this case.
Due to the high risk of tuberculosis in Brazil, evaluate the household epidemiological issue and the history of relatives or people living with the patient who may be undergoing treatment.
Look for findings compatible with the established disease (cytopenia, malaise, jaundice, changes in liver enzymes, etc.).
Differential diagnosis
Most likely diagnosis is CMV pneumonitis.
Others: PCP
Military TB
ARDS after pneumonitis
Covid 19 pneumonia
Management
Admit in ICU and start on oxygen to maintain saturation above 94%.
Blood works: Complete blood count looking for anaemia, neutropenia and thrombocytopenia
Renal function test for renal dosing of the drugs
Liver function test
Covid 19 PCR
CRP, PCT
BAL for gram staining and culture
CMV PCR in blood/plasma
CXR is suggestive of CMV pneumonitis but not diagnostic requires a BAL histology looking for inclusion bodies.
Reduce by 50% or withdraw the antimetabolites(MMF/AZA)
Maintain the CNI and steroids.
Initiate IV ganciclovir 5mg/kg renal dose can switch to per oral valaganciclovir when clinically possible. Treat for at least 2 weeks.
Monitor CMV DNA every week until not detectable or resolution of symptoms.
What is your differential diagnosis ?
A 65-year man, with cadaveric transplantation, CMV D +/R _ , having fever (38 °C) and non-productive cough with oxygen saturation on air to be 82%, and bilateral infiltrates on XRAY chest. Likely possibility in the above case will be CMV pneumonia, however, other differentials which can be considered include: PCP ,other viral pneumonias like( COVID-19,Influenza),fungal infection, bacterial pneumonia ,drug induced interstitial pneumonias or Miliary tuberculosis. How do you manage this case?
Admission in ITC –Applying oxygen to keep O2 above 94% .Detailed history and examination followed by thorough evaluation to find the cause :Complete blood picture( leukopenia , lymphopenia and thrombocytopenia in viral pneumonia)ESR,CRP , pro-calcitonin level,Blood Culture and Sputum for Gram stain ,AFB, Genexpert and culture and DIC profile including D-Dimers and fibrinogen.ABGs to check for type II Resp.Failure and hypoxia. HRCT Chest to see the extent of involvement .Other specific tests include :PCR for CMV in blood, Sputum for PCP, COVID-19, EBV and HIV,b-galactomannan. BAL if there is no sputum production or above sputum test inconclusive and should be sent for PCP(methamine silver staining ),PCR for CMV DNA.
First thing in the management will be to reduction in immunosuppressant especially anti-metabolite –MMF or azathioprine that is to be reduced or sometimes stopped, while CNIs to be halved .However, steroids can be increased r continued at the same dose. Then specific treatment is according to the cause. As in the above case likely diagnosis is CMV pneumonia so IV Ganciclovir in a dose of 5 mg/kg per day for minimum 02 weeks or until two consecutive viral loads are undetectable. Patient can be switched to oral valganciclovir once the patient start tolerating oral intake. Sometimes Cytogam (CMV Immunoglobulin)may be needed if no response.Frequent monitoring of drug levels to detect rejection early and weekly levels of PCR for CMV DNA needed . In resistant cases, other antivirals like Cidofvir or foscarnet may be needed. REFERENCES:
1-Professor Ahmed Halawa Lecture.
2-Requião-Moura LR, deMatos AC, Pacheco-Silva A. Cytomegalovirus infection in renal transplantation: clinical aspects, management and the perspectives. Einstein (Sao Paulo). 2015 Jan-Mar;13(1):142-8.
sputum induction with hypertonic saline and treatment for PCP is TMP-SMX (15-20MG/KG IN 3-4 divided doses.Other alternatives include TMP plus dapsone,inhaled pentamidine ,Atovaquone suspension.
Steroids if hypoxemia PaO2 <60mmHg or R.R >25/min
This is a tissue invasion, hence treatment is needed and a consultation will be sent to the pulmonologist for joint care
Admit ICU
Commence intranasal oxygen/ CPAP if not responding
Reduce by 50% or stop all antimetabolites (AZA, MMF)
Continue CNI inhibitors and steroid
I.v Gancyclovir 5mg/kg 12 hours (according to the renal function) for 5 days, then follow by valacyclovir 900mg BID for 2-3 weeks or until two tests of CMV DNA by PCR are negative
IvIG can be used since is a pneumonitis
Other immunosuppression could be reduced if the infection persists
Close monitoring of renal function.
References
CMV in kidney transplantation Lecture by Ahmed Halawa
A 65-year-old man was admitted with a fever (38 °C) and non-productive cough 4 months after cadaveric transplantation. CMV positive to CMV negative recipient Oxygen saturation on air was reported at 82%.
CXR: shown mixed alveolar-interstitial infiltrative opacification(ground-glass appearance). What is your differential diagnosis?
CMV pneumonitis /ARDS. Pneumocystis jirovecii pneumonia.
Other viral pneumonitis. How do you manage this case?
To send basic investigations (CBC, CRP, RFT, LFT, Blood C/S).
To check immunosuppression level such as tacrolimus level .
To send Respiratory viral panel.
To send CMV PCR. Imaging :
CT chest is important.
Broncho alveolar lavage (BAL) result that is CMV positive is a common method for diagnosis which shown Owle eyes CMV inclusion bodies.
If CMV pneumonitis(tissue invasive CMV) is confirmed, we should start our treatment irrespective to CMV viral load :
1-ABC support.
2-Respiratory clinician should be involved.
3-Stop anti-proliferative medications and stop CNI if condition worsening.
4-We should start IV GCV till critical status pass after that continue oral GCV for 14 days, till complete resolution of clinical manifestation and CMV DNA not more be detected.
5-PJP should follow the general rule of RI with sulphamethoxazole. References:-
1- Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients, Up To Date 2023.
2- CMV in Kidney Transplantation Lecture By: professor Ahmed Halawa.
ARDS post Pneumonitis
Infection ( CMV, COVID-19, Bacterial infection, Pnumocystic carini , TB)
Drug induced pneumonitis
How do you manage this case?
History and examination for vital state to role out septic shock
CBC for evidence of leukopenia and lymphpenia, ESR, PLT count, CRP, pro calcitonin level , serum lactate and ABG, INR and fibrinogen level, Renal function and PBF and blood cultures.
Serology for CMV IgM, IgG and DNA PCR, test for COVID-19, EBV and HIV, HCV and HsAg
CT chest and high resolution CT for chest, Pulmonary function test
Maintain airways and circulation, good IVF and input/ output chart
serial drug level and DSA level
Reduce immunosuppressive therapy to 50% and shift steroid to Dexamethasone
Consider antiviral therapy and antibiotics
1- maintain the O2 above 94% by giving High flow O2.
2- Do an ABG to check the degree of respiratory acidosis.
3- check the vital signs, to evaluate the need for ICU or high dependency unit
4- consultations for the ID and chest teams
5-full CBC (search for leukopenia and thrombocytopenia, which support the diagnosis of CMV disease), CRP (often normal), liver function tests, and renal function tests.
6- As the patient is at high risk for CMV, send an urgent CMV PCR that, if negative, does not exclude tissue-invasive CMV.
7- BAL and send for respiratory panel(Influenza type A,B, HHV, Adenovirus,etc)
Management:
If proven to be a CMV tissue invasive disease:
Consider decreasing the IS(stop the antiproliferative medication, and decrease the CNI by 50%, but look for AR.
treatment for at least 2 weeks with IV gancyclovir or until the CMV PCR negative. tissue invasive disease may require 4-6 weeks.
CMV immunoglobulins for severe cases, particularly pneumonitis.
Cidofvir or foscarnet alternative to Gancyclovir( intolerant or resistant)
Oxford Specialist Handbooks of Renal Transplantation
bilateral involvement of both lungs in this pattern in a kidney transplant patient with immunosuppression would pertain the following differential diagnosis:
1] bacterial broncho pneumonia.
2]CMV pneumonia.
3] PCJ pneumonia
4]Malignant infiltration.
5]Tuberculous pneumonia
6] pulmonary hemorrhage .
7] respiratory distress syndrome.
8]Vasculitis process.
9]pulmonary thromboembolism.
presence is fever and desaturation are not specific for any diagnosis. How to approach:
First of all, the patient has to be admitted to intensive care unit as he is featuring O2 desaturation. Full blood gas analysis has to be performed to highlight respiratory failure type.
Complete blood count, CRP and pro-calcitonin. blood culture
Sputum for gram stain, Culture and sensitivity. sputum for AFB.
sputum for PCR for CMV and PCJ and TB.
Blood for PCR for CMV , PCJ and TB.
blood for PP65 which is specific for CMV infection.
immunological tests for cANCA, pANCA, ABM antibodies. ANA, Complement C3, C4
Doppler of lower limbs veins and CT angiography and CT thorax. Treatment of CMV pneumonia:
Ganciclovir intravenous. is the treatment of choice.
5 mg/kg per day for 2-3 weeks.
follow up of PCR for CMV DNA . Immunosuppressants:
During acute infection, Mycophenolate has to be stopped temporarily, CNi halved and continue with same or even larger doses of corticosteroid.
References:
1]Luiz Sergio Azevedo et al.Cytomegalovirus infection in transplant recipients.Clinics (Sao Paulo). 2015 Jul; 70(7): 515–523.
· What is your differential diagnosis? Pneumonia/ bacterial or viral Bacterial including TB Viral including CMV Pneumonitis Secondary metastasis from other primary site malignancies · How do you manage this case? · Maintain him on oxygen and if requires intubation. · Confirm the diagnosis by sputum culture, Bronchoalveolar lavage · Reduction of immunosuppression · Stopping MMF · Reducing tacrolimus/cyclosporin · If life threatening all immunosuppressant should be stopped. Initiation of antiviral therapy 1. Intravenous ganciclovir
2. Very high doses of intravenous hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with ganciclovir for the treatment of pneumonitis
check PCR of CMV DNA it helps in identifying the degree of viraemia and may help to decide the duration of treatment. CMV viral load after to be checked 2 weeks of treatment and repeat at a minimum interval of 7 days
In practice the duration of therapy is decided by:
· The clinical response.
· PCR measurements, at least two weeks full dose treatment is recommended, with a longer duration of treatment if there is not a prompt fall in viral load.
relapse is common in approximately 1/3rd of patients after treatment with ganciclovir .
hence Secondary prophylaxis after treatment of disease is usual practice. but deciding the duration of treatment is controversial some prescribe it for 1 month others for 3 months. there are no randomized trials to inform this strategy.
References:
KDIGO guidlines
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION 2020
How do you manage this case?
1) Oksigen supplementation and support the airways
2) Immunosuppression reduction- withholding mycophenolate, lower target tacrolimus
3) Blood culture, sputum culture, sputum for PCP and sputum for AFB
4) To start this patient on IVI Ganciclovir (as evidence of tissue invasive disease)
An induction dose of 5 mg/kg twice a day in the setting of normal kidney function for 14 to 21 days with resolution of CMV PCR
The maintenance dose is 5 mg/kg per day, or if the patient is fully recovered, can consider valganciclovir treatment as an outpatient. Maintainance dose of 900 mg daily.
The patient presented with fever and non productive cough, hypoxia and bilateral interstitial infiltrate
Differential diagnosis
PCP
CMV
TB
How manage
Full investigations
FBC, LFT, KFT,blood culture and sputum culture, TB culture, drug level , urine analysis and culture, CMV DNA by PCR
Bronchoscopy, BAL, chest CT
ICU admission
O2 therapy
Good hydration and broad spectrum antibiotics
If PCP give TMP-SMX in high dose
If CMV give IV Ganciclovir followed by oral Valganciclovir
The probable differential diagnosis is mainly PCP vs CMV pneumonia or ARDS.
PCP main characteristic is being early post-transplant especially after heavy induction and high doses of immunosuppression initially, and the presence of dry cough signifies this.
In cases of CMV positive donor serology against CMV negative recipient per worldwide protocols adopt prophylactic measures in the form of antivirals for at least 6 months to 1 year,besides monthly screening for CMV serology making CMV disease diagnosis unlikely.
Confirmation of diagnosis is done by negative CMV serology , BAL is positive for PCP as well as tissue biopsy.
Management of this case primarily needs reduction of immunosuppression, oxygen supply by mechanical ventilation, treatment by TMP using to renally adjusted doses.
CxR showing Bilateral interstitial hilar extending from hilum.
What is your differential diagnosis?
PCP infection
Cytomegalovirus infection
Viral Pnemonia
ARDS
Tuberculosis
Mycoplasma infection
Managment
Diagnosis-The diagnosis of PCP should be considered in patients with risk factors for PCP who present with pneumonia and suggestive radiographic findings. Microbiologic identification of the organism when possible . Detection of the organism in respiratory specimens is most commonly achieved by microscopy with staining of an induced sputum specimen or BAL fluid .The serum beta-D-glucan assay can be used as an adjunct to the diagnosis of PCP.
Treatment–
The dose of TMP-SMX for patients with normal renal function is 15 to 20 mg/kg (dosing is based upon the TMP component intravenously or orally daily in three or four divided doses. Dose may need to be adjusted if creatinine clearance changes during therapy. Patients should receive intravenous therapy until they are clinically stable (eg, PaO2 ≥60 mmHg, respiratory rate <25) and have a functioning gastrointestinal tract. For renal dose adjustment recommendations, refer to TMP-SMX drug information.
Duration-21 days
The differential diagnosis include:
1-CMV pneumonitis
2- TB
3-PCP
4- Malignancy
Management :
full investigations including CT scan of the chest and bronchoscopy +/- tissue biopsy
Give IV valganciclovir
Pneumocystis PneumoniaTMP-SMX is the drug of choice for therapy; drug allergy should be documented before resorting to alternative therapies. Adjunctive corticosteroids may be useful early. Routine PJP prophylaxis is recommended for at least 6-12 months post-transplant, preferably with TMP-SMX.
reference
Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of PracticeJay A Fishman 1, Hayley Gans 2; AST Infectious Diseases Community of Practice
Affiliations expand
What is your differential diagnosis?
1. PJP: Immunocompromized patient presenting with desaturation, dry cough and fever.
2. CMV pneumonitis: D+/R-
3. Covid 19
4. Atypical pneumonia
5. Influenza or Para influenza
6. Herpes simplex virus
7. Pulmonary TB
8. Fungal infection
9. ARDS
How would you manage this case?
o MDT approach involving pulmonologist, ICU and Nephrologist
o ITU admission and O2 support
o Detailed history and full physical examination
o Supportive treatment with IV fluids and Nutritional support
o Initial investigations including FBC,ESR, CRP, RFTs. LFTs, and blood culture including TB cultures. Check for Tacrolinus trough level transplant graft US.
o Viral throat swab to diagnose viral infections including COVID 19, Influenza and para-influenza and Mycoplasma pneumonia
o Urine sample for Legionella urinary antigen
o CMV-DNA by PCR test(D+/R-)
o Bronchoscopy & BAL ( including CMV PCR on the BAL)
o Immunosuppression modification: stop anti-metabolites and continue on CNIs and steroids.
o Broad spectrum antibiotics including cover for atypical pneumonia
o Definitive treatment:
o In case of CMV: IV gancycolvir 5mg/kg BD for 5 days followed by oral valgancyclovir 900 mg od until 2 X PCR are negative.If no response in 2 weeks, assess for ganciclovir resistance and shift to Foscarnet and additional CMV IVIG.
o In case of PJP: TMP-SMT given initially IV at a high dose of 15 to 20 mg/kg IV then switching to oral treatment after clinical improvement. Second-line therapy is pentamide 4 mg/kg IV OD with comparable efficacy but worse safety profile .Primaquine plus Clindamycin for severe cases. Increasing steroid dose can be useful in severe hypoxia(Sat <70%)
o Monitor graft function during treatment
References:
1) Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545.
2) Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587
3. Dominykas Varnas and Augustina Jankauskienė.Pneumocystis
Jirovecii Pneumonia in a Kidney Transplant Recipient 13 Months after
Transplantation: A Case Report and Literature Review.Acta Med Litu. 2021;
28(1): 136–144.
4 month after cadaveric transplantation
fever (38 °C) and non-productive cough CMV D+/R-
Saturation on air was 82%.
CXR shows diffuse interstitial infiltrates
● What is your differential diagnosis?
Immunocompromised patient with pneumonia and dry cough associated with
Hypoxia and infiltrates in the CXR would make one suspect PCP
Other differential diagnosis include:
CMV pneumonia
Baterial pneumonia
TB
Other viral pneumonia as covid 19
● How do you manage this case?
Laboratory evaluation
CBC,CRP, ABG, TST, IGRA, PCR for CMV , PCJ, and covid 19 , liver tests and renal function.
Chest CT scan
Supportive management as hydration and oxygen.
In PCP pneumonia:
TMP-SMX IV with high doses in case of PCP and pentamide in case that doesn’t response to TMP-SMX
Steroid can be useful in severe hypoxia
In CMV pneumonia:
IV GCV switching to oral GCV when there is improvement
65-year-old man transplanted
patient was admitted with a fever (38 °C) dry cough and Oxygen saturation on air was
reported at 89%.
CMV positive to CMV negative recipient
CXR was done showing fine
bilateral interstitial infiltrates with ground-glass opacities more central sparing subpleural space.
Dry cough with hypoxia early on presentation with the x ray findings
in transplant recipient suggests PCP infection.
*Differential diagnosis
PCP.
CMV.
COVID- 19.
Bacterial pneumonia.
TB
*Investigation
-Cbc, CRP
-ABG
-Kidney function test
– Tuberculin skin test (TST) and
Interferon-gamma release assay.
-PCR tests for SARS-CoV-2.
-PCR for PCP,CMV,EBV.
-sputum and blood cultures
-Chest CT scan.
*Management
-oxygen supply to increase saturation .
-adjust immunosuppression.
– In case of PCP, treatment with TMP-SMX is the first-line therapy with 15 to 20 mg/kg IV, switching to oral after clinical improvement.
-Second-line therapy for
severe cases would be pentamide 4 mg/kg IV o.d., though with comparable
efficacy but worse safety profile .
– Primaquine plus Clindamycin for severe cases.
-Atovaquone or Dapsone/TMP for mild to moderate cases are
third-line options that can be considered for patients who do not tolerate the
above treatments or show no clinical improvement.
– Prednisone if oxygen saturation
declined to < 70 mmhg on room air.
*Reference
Dominykas Varnas and Augustina Jankauskienė.Pneumocystis
Jirovecii Pneumonia in a Kidney Transplant Recipient 13 Months after
Transplantation: A Case Report and Literature Review.Acta Med Litu. 2021;
28(1): 136–144.
What is your differential diagnosis?
The differential diagnosis is CMV pneumonitis or PCP.
How do you manage this case?
Routing lab test to be performed including the microbiological and biochemistry test. Bronchoscopy is performed.
Adequate hydration and upon confirmation of the diagnosis of CMV pneumonitis; IV ganciclovir followed by oral valganciclovir is given.
In case of PCP diagnosis; High dose co-trimoxazole with steroid
Q1: The differential diagnosis for this immunosuppressed patient presented four months after TX with dry cough, fever, and hypoxemia and diffuse, bilateral infiltrates are:
1. Pneumocystis jirovocii pneumonia.
2. CMV pneumonitis
3. Other viral infections: influenza, RSV, parainfluenza
4. Fungal infection (Aspergillus, Mucormycosis, cryptococcus)
5. Bacterial infections (with low probability)
Q2: management includes:
1. ICU admission
2. Stop antimetabolite, maybe reduce CNIs
3. Oxygen supplementation
4. Therapeutic dose of cotrimoxazole for PCP (15-20mg/kg/day → divided every 6-8 hours)
5. Broad spectrum antibiotics
6. Appropriate hydration and nutrition
7. Dose of PPIs for stress ulcers-preventive
8. Diagnostic test
What is your differential diagnosis?
65-year-old male, 4 months post-renal-transplant, CMV D/R -ve/+ve, presented with Fever (38), low oxygen saturation at 89% associated with dry cough.
Chest x-ray: bilateral prominent broncho-vascular markings and perihilar infiltrates, few pneumatoceles are seen.
Differential diagnosis includes:
1- Fungal infection like PJP is the first possible DD because of clinical manifestations mainly fever, dry cough and low oxygen saturation associated with minimal chest X-ray finidings.
2- Aspergillosis.
3- Viral infection: CMV, EBV, Covid-19.
4- Bacterial infection.
5- TB pneumonia.
How do you manage this case?
General Non-specific measures:
1- Hypoxia: Oxygen, serial ABG, escalation to non-invasive ventilation (CPAP or BIPAP)
2- Keep ITU in the loop in case of deterioration.
3- Fever: anti-pyretic.
Septic work up:
1- CRP, Blood culture, urine culture, induced sputum culture.
2- CMV PCR, PJP PCR
3- Serum beta D-glucan: is non-specific but if positive it supports diagnosis of fungal infection.
4- Metagenomic next generation sequencing.
5- CT-Chest
6- Bronchoscopy and broncho-alveolar lavage: PJP can be detected using stains like Giemsa, modified Grocott, Weigert-Gram, or methenamic silver.
Modification of immunosuppression medications:
1- Consider stopping MMF or Azathioprine.
2- Monitor level of CNIs, aiming at lower target level.
3- Consider increasing steroids especially if hypoxic.
Specific treatment for PJP:
1- PJP lines of treatment includes TMP/SMX (either IV or orally 15-20mg/Kg/day divided on 12 hours, course for 2-3 weeks), using steroids if ABG shows hypoxaemia PaO2 below 70mmHg.
2- If patient is allergic to TMP/SMX, alternatives include Atovaquone, Dapson, or Primaquine, or IV pentamidine.
Treatment of other pathogens according to results of septic work up.
Monitor for side effects of medications
Monitor renal functions and electrolytes.
Reference:
Uptodate.
□Differential diagnosis
1 – CMV Pneumonia
2- Bacterial cause of pneumonia
3- Other viral causes of pneumonia (covid19)
4- fungal pneumonia
5- TB
6- pcp
□Management
● the patient should be admitted to ICU.
● monitoring the vital signs (RR- sat-…)
● O2 supply
● laboratory tests: CBC – CRP- CREA- LFT-
● Sputum samples for staining and culture
●BAL test for (PCP- CMV and other viral herpes and influenza )PCR and culture
●CMV PCR blood test
●HIV status study
●Antibiotics (empirical treatment)
●intravenous ganciclovir until the minimum 2 weeks then it will be changed by oral valganciclovir until the clinical manifestations are improved and the . If there is no response after 2 weeks of treatment, we should assess for ganciclovir resistance CMV and shift to an other type of drugs
We should remember that a prophylaxis treatment with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse.
●Immunosuppression reduction is necessary. MMF should be stopped, and adjust the tacrolimus treatment by monitoring the level of CNI and the renal function
●PCP treatment should be started , then , after the laboratory test results become available, it can be withholded
CXR show multiple tiny cysts all over lungs
PCP- caused alveolar infection and sparing of other bronchi
so there is minimal or sputum
DRY COUGH is difficult to diagnose microbiologically as sputum samples are not available;
sputum can be induced with hypertonic saline
invasive test like ET samples or BAL can establish the diagnosis
This recipient renal transplant patient is suffering from a 4 monty history of symptoms and signs suggestive of pneumonia in the form of fever, dry cough, desaturation as well as Chest Xray findings reticulo nodular shadows.
On top of DD is CMV pneumonitis based on the history that CMV positive donor donated his kidney to a CMV negative recipient so high possibility of CMV transmission.
Differential Diagnosis
Viral : CMV, influenza, para influenza, Herpes
Bacteria : streptococcus
Parasites : PCP
Management of this case :
1st step is to transfer the patient to an ICU due to desaturation and critical condition and start resuscitation with O2 and Iv fluids
1. Full detailed history and full general examination.
2. Routine lab tests, inflamatory markers, Virology screen esp CMV PCR
3 HRCT
4 sputum examination for gram stain, cytology, TB C&S may be a bronchoalveolar lavage is required
Regarding Empirical treatment
We shall start empirical antibiotics to cover for Bacterial infections
Based on symptoms and signs and history of transplantation and desaturation we shall start PCP empirical treatment in the form of cotrimoxazole and steroids if o2 saturation drops below 70%
As well as oseltamivir for influenza virus
If CMV is confirmed
Start ganciclovir 5mg/kg IV every 12 hours with dose modifications according to Creatinine clearance continued for 2 weeks then may be shifted to vanganciclovir for 1 to 2 months
If resistance to ganciclovir shift to Foscarnet or IVIG
Secondary prophylaxis with vanganciclovir for 1 to 2 months in high risk patients for recurrence
1- What is your differential diagnosis?
A- CMV pneumonitis .
B- Milliary TB .
C- Pneumocystis jirvocii pneumonia .
D- MTOR inhibiter induced pneumonitis .
E- Other viral infection ( Influenza, Parainfluenza, Respiratory Syncytial virus, )
F- Bacterial – Atypical: Mycoplasma pneumoniae,
G- Fungal infection (Cryptococcus Aspergillus spp; Mucormysosis )
2- How do you manage this case?
Management include
Admission to ICU with MDT management . may need immunsupresive drug manipulation (stop cellcept and azathioprine ), adequate hydration and monitoring .
A- History and medical record :
– Past medical history
– Viral serology state before transplantation for example CMV serology .
– Crossmatch result , DSA , and immune supresant used for induction ( depleting agent or not )
– Prophylaxis used or not – what and for how long ( methprim, valagancyclovir , nystatin drops….)
– Associated symptoms .
B- Examination :
– General examination ( any skin rash, lymph adenopathy )
– Vital signs ( PR, BP, RR , TEMPRETURE, SPO2 ..)
– Systemic examination ( organomegally )
c- investigation :
– CBC
– CRP
– BIOCHEMISTRY ( B urea , S creatinine , TSB , SGPT, SGOT, Alkaline phosphatase, )
– Q NAT for CMV ,
– Sputum , induced sputum ,bronch alveolar lavage , LDH , β-D-Glucan (BDG), and even lung biopsy to diagnose Pneumocystis jirvocii pneumonia .
– Sputum for AFB , culture and sensitivity, tuberculin skin test, PPD skin test , skin anergy test – for tuberculosis .
d- treatment
should be according to underlying diagnosis .
1- Anti-viral therapy in case of confirmed CMV:
IV gancycolvir 5mg/kg bid for 5 days followed by oral valgancyclovir 900 mg od until 2 X PCR
negative
Adjust the drug doses according to the renal function
2- Anti PCP if confirmed
Trimethoprim-sulfamethoxazole (TMP-SMX): 15-20 mg/kg/day of the TMP component given IV in divided doses every 6-8 h; lower doses may be sufficient. In milder disease, two double-strength tablets can be given po tid 21 days is preferred to avoid disease progression and relapse
Adjunctive steroids: in patients with hypoxemia (pAO2 < 70 mm Hg on room air) Corticosteroid therapy should be considered early for maximum benefit, ideally within 72 hours of initiating antimicrobial therapy. The optimal dose of corticosteroids would be 40-60 mg of prednisone (or equivalent) for 5-7 days before gradual tapering over 7-14 days is recommended to avoid rebound pneumonitis.
REFFERENCE:
Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TM, Campos SV, Ramos JF, Latif AZ, Litvinov N, Maluf NZ, Caiaffa Filho HH, Pannuti CS, Lopes MH, Santos VA, Linardi Cda C, Yasuda MA, Marques HH. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015 Jul;70(7):515-23. doi: 10.6061/clinics/2015(07)09. Epub 2015 Jul 1. PMID: 26222822; PMCID: PMC4496754.
Differential diagnosis:
CMV Pneumonitis
PCP Pneumonia
Management:
1. MDT approach
2. ICU admission
3. Reduction of immunosuppression: stop MMF/AZA, continue CNI and steroids, and discuss the risk of rejection.
4. CNI levels measurement
5. Broad spectrum antibiotics and IV ganciclovir if CMV PCR positive
6. BAL for PCP
7. Septic workup: blood and urine cultures
8. Optimizing volume status and preventing AKI.
PCP should be excluded because the patient is immunocompromised, timeline is fist six months of transplant and patient has dry cough with hypoxia.
This can be either CMV pneumonitis or PCP (PJP). We may need CT, BAL and PCR to ensure the diagnosis.
Bilateral miliary mottling shadow involving whole lung field in chest x-ray with given scenerio i have following differentials-
– CMV pneumonitis
– Pneumocystis carinei pneumonia
-Miliary TB
– Lymphangitis carcinomatosis
-Oxygen inhalatiion to maintain adequate SpO2 >95%.
-ABC assesment and associated supportive treatment.
Investigations:
– CBC, CRP, ABG
– HRCT of chest
– Broncoscopy
– BAL- for CMV PCR, PCP PCR & gene Xpert for TB.
Quantiferon TB gold test
Treatment:
Definitive treatment according to cause
CMV pneumonitis
a) RIS
– Stop/ reduce (by 50%) azathioprine/ MMF/ myofortic
– Continue corticosteroid
– CNI can be continue unlesd life threatening infection.
b) Anti CMV therapy
– I/V gancyclovir – 5 mg/ kg bd for 5 days followed by oral valgancyclovir for 2-3 weeks or until 2× CMV DNA by PCR are negative.
– If there is reduced absorption e.g- diarrhoea I/V GCV for 14- 21 days.
– Dose adjustment acvording to renal function
c) Monitoring of graft function
PCP
High dose co- trimoxazole with steroid
Differential Diagnosis:
This patient with low grade fever and non-productive cough would have following differential diagnosis
Given the clinical picture and radiographical picture, it seems to be more of
“PCP induced pneumonia”
Management of the case:
15-20 mg/kg/day of the TMP component given IV in divided doses every 6-8 h; lower doses may be sufficient. In milder disease, two double-strength tablets can be given po tid
in patients with hypoxemia (pAO2 < 70 mm Hg on room air)
Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation
Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587. doi: 10.1111/ctr.13587. Epub 2019 Jul 1. PMID: 31077616.
Viral(CMV , Covid 19, adenovirus)
bacterial like miliary TB
apportunistic infection like PCP and aspergillosis.
Sputum (either induced or BAL) examination for PCP cyst or trophozoit and for AFB and PCR.
CMV PCR
HRCT
complete investigation
improve oxygenation, hydration, AB , specific treatment accordingly.
This is an 65 year old , S/P renal transplantation , from D+ CMV to R – CMV presented with fever , dry couph , hypoxia and bilateral interstitial infiltration .
1- CMV pneumonitis
2- PCP
3- TB
4- A typical bacterial infection
5- Less likely fungal infection
nt
This patient needs admission to ICU , with MDT involvements
detailed history should be taken including , type of induction therapy , maintenance immunosupression , is he on PCP prophylaxis or not ? , is he toke CMV prophylaxis post transplantation or not ??
1- Trimethoprim-sulfamethoxazole (TMP-SMZ) given in a high dose, combined with corticosteroids in patients with moderate to severe infections.
2- If there is allergy or side effects to trimethoprim-sulfamethoxazole, alternative drugs can be used including; Dapsone , Inhaled pentamidine , Atovaquone , Primaquine combined with clindamycin , Combined dapsone and trimethoprim , Pyrimethamine and sulphadiazine.
3- Prophylaxis is highly efficacious in preventing PJP in transplant patients.
4- Overall, with prompt treatment, survival is good (50-95%), relapses are common.
GCV 5 mg / Kg x 2 for 14 – 21 day or IV GCV for 5 days followed by oral vGCV for 2 – 3 weeks
References :
1) Up to date
2) Prof Ahmad Halwah Lecture
the given patient is a post transplant patient 4 months ago… The details of induction agent is not mentioned…He has now presented with fever cough which is non productive and desaturation on room air…He is also a recipient of CMV Positive to CMV negative cadaveric transplant….
Chest X ray shows bilateral diffuse reticulo nodular opacities
The differential diagnosis are
The management includes investigation and treatment
renal function, CBC< LDH, LFT needs to be monitored…LDH levels are known to bee increased with PCP… It is important to assess and monitor renal function while on therapy for renal transplant…It is important to rule out concomittant bacterial sepsis in a renal transplant patient and I will keep them on empirical antibiotics…Throat swab could be done for infuenza, covid… Induced sputum can be tested for AFB, gram stain and culture.. CT chest can confirm the above changes…
Bronchoscopy will be ideal to diagnose…. but in view of hypoxia it would not be possible to perform the same ….
Patient needs to be stopped with antimetabolite, Tacrolimus level needs to be checked and dose needs to be monitored….
Empirical steroids should be given in IV form…
cotrimoxazole 160/800mg 2 tablets twice a day or in the intravenous preparation twice a day should be given….once the clinical resolution is better oral tablets maybe switched over to…..
CMV can be confirmed only by doing BAL and tissue diagnosis by lung biopsy demonstrating invasive lung disease with owl eye inclusion bodies…Mere presence of CMV DNA PCR is not diagnostic of CMV related lung disease… Patient needs to be started on IV Ganciclovir 5mg/kg IV twice a day for 5 days and later switch over to oral valganciclovir 900mg twice a day…Oral CMV prophylaxsis with Tab valgan 900mg once a dya is then recommended
In this patient i would start both IV Cotrimoxazole and IV ganciclovir initially and later decide on the clinical response based on therapy and clinical signs…
.
PCP is associated with thick sputum which cannot be expectorated ..And as it is not able to diagnose we need BAL with special stains to diagnose PCP
D/D: PJP, CMV pnumonitis, Milliary TB, ARDS.
Mx: ICU support, O2 saturation maintain, after stabilised the pt, do BAL fluid for Staining or PCR for PJP, do blood PCR for CMV, HRCT, LDH, RFT, LFT.
Immunosuppressant modification ( stop MMF, continue CNI, steroid), intimate both TMP/SMX & oral Valganciclovir, adjunctive steroid…
Back ground
65 years male; Cadaver transplant recipient (organ?)
?? received induction with T cell depleting agent (ATG / Campath)
CMV sero-status – D+/R-: ?? received prophylaxis for CMV and PJP
4 months post-transplant
Low grade Fever, dry cough and respiratory distress with hypoxia
CXR – bilateral diffuse small nodules, milliary mottling, ground glass opacities
1. Clinical and radiological features suggestive of Pneumocystis Jiroveci pneumonia
– dry cough, yet severe hypoxia is the hallmark.
– Cotrimoxazole resistance likely, if the patient is already on prophylaxis
2. CMV pneumonitis – second likely diagnosis
– D+/R- serostatus with high immunosuppression; typical clinical picture, although hypoxia is less severe compared to PJP.
– malaise, weakness, systemic illness, leukopenia & thrombocytopenia are common
3. Milliary Tuberculosis – low grade fever, dry cough, CXR – diffuse milliary mottling; Tb is common in many parts of world – 30-40% people have dormant infection and risk of reactivation following severe immunosuppression and old age
4. ARDS – symptoms pertaining primary source of infection are not mentioned. ARDS secondary to sever Pneumonia would have high grade fever, productive cough, full blown sepsis, hypotension and multi-organ dysfunction
5. Covid-19 – pandemic, high disease prevalence in IS patients
How do you manage this case?
– admission to ICU / HDU
– MDT involvement – Pulmonologist, Intensivist, infectious disease specialist and Microbiologist
– Oxygen supplement on mask 2-5 litres to maintain adequate PaO2
v Nebulisation with Saline and N-acetyl cystine – liquify sputum for drainage, can be used for diagnostic tests
Ø HRCT Chest is the gold-standard imaging modality
central and diffuse distribution and ground-glass pattern with septal thickening with a “crazy paving pattern”.
The hallmark finding of PCP on HRCT scans is diffuse ground-glass opacity, which reflects accumulation of intra-alveolar fibrin, debris, and organisms– “ground-glass” refers to parenchymal opacification, which does not obscure the underlying pulmonary architecture – in bilateral, symmetric, predominantly perihilar distribution and may be geographic or mosaic pattern.
consolidation, halo signs, and nodules (all P< 0.05) were significantly more frequent in patients with cytomegalovirus pneumonia than in those with pneumocystis.
Small nodules (32.5% in cytomegalovirus pneumonia, 6.41% in pneumocystis pneumonia; P< 0.001) without peri-lymphatic distribution were particularly common in patients with cytomegalovirus pneumonia.
Ground-glass opacity, reticulation, and bronchial wall thickening (all P > 0.05) were common in both groups. Diffuse, fine, reticular opacification, pneumatocele, pneumothorax are typical pictures of PJP
Blood Investigations
· ABG, CBC (leukopenia, thrombocytopenia), RFT, LFT, LDH, Tac C0 level
· CMV pp65 antigen – can detect within few hours, high false negative
· CMV-DNA quantitative PCR à Genotype analysis for UL54, UL97 mutation
· HIV serology
· Covid rt-PCR – from nasal and oropharyngeal swab
· Sepsis markers – CRP, Procalcitonin
· LDH – may be elevated in patients with PJP
· Plasma level of 1-3-beta-D-glucan (cell wall component of P. jirovecii) is elevated in patients with PJP – assay can support the diagnosis of PCP in sick patients not fit to undergo BAL or lung biopsy.
(In 282 patients with HIV, diagnosed with PCP, had significantly higher median beta-D-glucan levels than patients without the disease).
Starting empirical treatment covering bacterial, PJP and CMV disease is important in seriously ill patients, before reaching the diagnosis by invasive tests.
– Broad spectrum IV antibiotics (Piperacillin-Tazobactam), IV Gancyclovir and IV/ oral Cotrimoxazole should be started immediately – shall help stabilize the patient.
– IV Hydration – oral intake may not be adequate,
After stabilisation with prompt intravenous therapy, invasive tests can be planned to make the diagnosis and tailor further definitive treatment specific to the disease.
– BAL: Fluid PCR to look for PJP, CMV inclusion body (Owl’s eye)
o Gram stain, AFB and culture (Bactec media)
o Special stain – Crystal violet, Giemsa, Diff-Quik, and Wright stain are used to detect both the trophozoite and cyst forms of PJP
– Trans-brochial Lung Biopsy – yield 100% because of more tissue available; indicated if BAL sample fail to detect organism
Treatment:
Reduction of Immunosuppression: to Stop MMF, may resume at low dose after complete recovery from PJP / CMV disease.
Treatment of PJP depends on the degree of illness determined on the basis of alveolar-arterial gradient: mild (< 35 mm Hg), moderate/severe (35-45 mm Hg), or severe (>45 mm Hg).
Severe disease is also indicated by PaO2 <70mm Hg on room air
Cotromoxazole160/800mg PO daily x 14-21days, till symptoms resolve.
Initial IV TMP-SMX indicated in sick patients (on ventilator), poor oral intake (ill, CNS involvement), not tolerating orally (vomiting, gastritis) or poor absorption due to diarrhoea.
Oral TMP-SMX has been shown to be as effective as intravenous pentamidine and more effective than other alternative treatment regimens.The parenteral route may be considered in patients who present with serious illness or in those with gastrointestinal side effects.
Response to treatment should begin within 4-5 days, may take longer time (up to 8days) to respond in HIV patients. If no response occurs within the expected time, an appropriate alternative regimen should be used.
If symptoms still persist beyond 8days – dose adequacy should be checked and a second-line agents pentamidine, dapsone (with pyrimethamine), or atovaquone may be tried.
Secondary prophylaxis shall be required for at least 6months.
For CMV Pneumonia – second possibility
Intravenous Gancyclovir for 7days – then change to oral Valgancyclovir 900mg twice daily 14-21 days.
If patient improve clinically, check CMV viremia (DNA- PCR or QNAT) after 14days, then every 7days till symptoms resolve.
Frequent monitoring of CBC every week during treatment to look for pancytopenia, which may need GCSF supplement.
Completion of therapy shall be guided by complete resolution of symptoms + clearing of viremia (CMV not detectable in 2 consecutive assays).
Secondary prophylaxis shall be required for at least 6months.
If symptoms do not resolve, increased CMV viremia (PCR / QNAT) to be assessed early (7days) and Gancyclovir resistant infection should be suspected.
Treatment options for GCV-R CMV disease are
IV Foscarnet / IV Cidofovir – high risk of Nephrotoxicity, electrolyte disturbances, seizure.
Other treatment options include CMV hyperimmune globulin with or without Leflunomide.
Reduction in immunosuppression – stop MMF; conversion of CNI à to mTOR-I
Reference:
1. Ali Nawaz Khan. Pneumocystis jirovecii (carinii) Pneumonia Imaging: Practice Essentials. Medscap Updated: Jun 29, 2022
2. Shelley A Gilroy. Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia. Medscap. Nov 04, 2022
3. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. bts.org.uk/uk-guideline-on-prevention-and-management-of-cytomegalovirus-cmv-infection-and-disease-followingsolid-organ-transplantation. 05 July 2022
4. nders Åsberg 1, Atul Humar 2, Halvor Rollag 3, et al. Lessons Learned From a Randomized Study of Oral Valganciclovir Versus Parenteral Ganciclovir Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR Trial. Clin Infect Dis. 2016 May 1;62(9):1154-60. doi: 10.1093/cid/ciw084. Epub 2016 Feb 16.
5. Klompas. Treatment of Ganciclovir Resistant Cytomegalovirus Infection Michael
6. Robin K Avery, Sophie Alain, Barbara D Alexander, et al. Maribavir for Refractory Cytomegalovirus Infections with or without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clinical Infectious Diseases 2022; 75 (4)-15 Aug: 690–701.
A correction has been published: Clinical Infectious Diseases, Volume 76, Issue 3, 1 February 2023, Page 560, https://doi.org/10.1093/cid/ciac970
this patient with low grade fever and non-productive cough would have following differential diagnosis
Given the clinical picture and radiographical picture, it seems to be more of PCP induced pneumonia
Management of the case:
Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587. doi: 10.1111/ctr.13587. Epub 2019 Jul 1. PMID: 31077616.
· What is your differential diagnosis?
· This is very fresh transplantation, although the possibility of CMV is very high in first 12 months post transplantation. And also on the bases of history the patient is immunocompromised, donor was positive for CMV and recipient was negative for CMV, the probability of CMV infection is high so the clinical findings and X ray chest findings, . . The initial finding, clinical features, radiological findings (consolidation, ground glass appearance, cystic lesions) the initial provisional diagnosis would be PCP. suggest CVD disease, other DDs are,
· PCP,
· COVID-19 infection,
· Atypical lower respiratory infection,
· Other viral and bacterial infections.
· How do you manage this case?
· Need further investigation like BAL and biopsy (giemsa stains, immunofluescent assay, PCR HRCT, CULTURE, GRAM STAIN, , COVID-19 RT-PCR, galactomannon.
· Decide the need of intensive care requirements.
· Need other specialty opinion like infectious disease specialist, pulmonologist.
· Supportive care like IV fluid, antipyretics,
· Immunosuppression medication modification,
· And specific to underlying cause, if PCP the drug of choice would be Co-trimoxazole 120mg/kg/day, steroids to decrease inflammatory cascade, if not responding then can be switched to IV pentamidine 4mg/kg OD.
· If CMV then IV genciclovire 5mg/kg BID dose for minimum of 21 days,
· Antibiotic to cover the super impose infection, atypical coverage.
References ;
1. https://www.mdpi.com/2309-608X/8/11/1167.
2. https://bts.org.uk/uk-guideline-on-prevention-and-management-of-cytomegalovirus-cmv-infection-and-disease-following-solid-organ-transplantation/.
3. https://www.mdpi.com/2076-0817/8/4/213.
PCP, CMV virus, covid19, Pulmonary aspergillosis.
Good history and physical examination .
send full investigation [CBC,RFT,S.electrolytic,CMV PCR,]
send ABG , HRCT, COVID 19 PCR,CRP,blood culture and sensitivity.
treatment:
O2,if patient vitaly stable if not ICU admission
Trimethoprim-sulfamethoxazole in high dose , increase dose of steroid ,stop cell cept and CNI in high risk patients .
in low risk patients no need to stop immunosuppression and increase dose of steroid .
in moderate risk patients stop cell cept continues CNI and increase dose of steroid .
1-What is your differential diagnosis?
-Pneumocystis jirovecii (formerly P. carinii) pneumonia) (most likely).
-CMV Pneumonitis.
-Pulmonary aspergillosis.
-Respiratory viruses;
Respiratory syncytial virus, adenoviruses, and human metapneumovirus
COVID-19 – ARDS.
-Idiopathic Pneumonia Syndrome.
-Tuberculous pneumonia (M. haemophilum and M. avium complex)
-Drug-induced interstitial pneumonitis( mTOR)
2-How do you manage this case?
-Maintain the O2 above 94% by giving High flow O2 (BIPAP CPAP) & Request ABG,
-Check Vital signs, to evaluate the need for ICU or high dependency unit.
-Multidisciplinary Teams (Nephrology / ICU / Pulmonology / ID).
-Further Investigations;
CBC (search for leukopenia and thrombocytopenia)
CRP (often normal) – LDH
Liver function tests, and Renal function tests.
BAL staining for PCP (Gomori methenamine silver (GMS) staining)& serum beta-D-glucan assay .
BAL and send for respiratory panel (Influenza type A,B, Adenovirus ,covid-19 , etc).
(CMV PCR) – As the patient is at high risk for CMV.
Full septic screen (including sputum C/S).
-Management;
Treatment of PJP;
-Trimethoprim-sulfamethoxazole (TMP-SMZ) given in a high dose, combined with corticosteroids in patients with moderate to severe infections.
-If there is allergy or side effects to trimethoprim-sulfamethoxazole, alternative drugs can be used including;
–Dapsone , Inhaled pentamidine , Atovaquone , Primaquine combined with clindamycin , Combined dapsone and trimethoprim , Pyrimethamine and sulphadiazine.
-Prophylaxis is highly efficacious in preventing PJP in transplant patients.
-Overall, with prompt treatment, survival is good (50-95%), relapses are common.
Treatment of CMV tissue invasive disease (cmv pneumonitis);
-Consider decreasing the IS; (stop the antiproliferative medication, and decrease the CNI by 50%, with monitoring Graft Functions.
-IV ganciclovir (5 mg/kg every 12 hours) for 2-3 weeks; should be used in place of valganciclovir. (after ID recommendations)
-IV ganciclovir can be transitioned to oral valganciclovir once the patient has demonstrated clear clinical improvement, viral loads are down-trending, and the patient can tolerate/absorb oral medications.
-While treating with either ganciclovir or valganciclovir, we monitor the serum creatinine at regular intervals in case dose adjustment is needed.
-Monitoring on therapy; RFTS / LFTS / Blood cell counts / LDH.
-References;
Up To Date; diagnosis of Pneumocystis pneumonia in patients without HIV: Aug 02, 2022.
Sorrry; this wrong entery
this answer of scenario (1) in week (5)
Differential diagnosis:
(i) Most likely this is a case of pneumocystis jirovecii pneumonia
(ii) CMV pneumonia
(iii) Pulmonary Tuberculosis
(iv) Covid 19 pneumonia
(v) ARDS
Management:
Need to confirm the diagnosis prior to specific treatment
Investigation:
Treatment:
General: Oxygen, Broad spectrum antibiotic, Nutrition
Specific: According to confirm diagnosis
Reference:
1. Zuhair M, Smit S, Wallis G, Jabbar F, Smith C, B, Griffiths P Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Reviews in Medical Virology 2019; 29: 2034
2. Wentworth BB, Alexander ER. Sero epidemiology of infections due to members of the herpes virus group. Am J Epidemiol 1971; 94: 496-507.
3. Shelley A Gilroy. Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia.Medscap. Nov 04, 2022
Recipient with fever ,non-productive cough 4 months and desaturation after cadaveric transplantation. CMV positive to CMV negative recipient
With bilateral diffuse infiltrate on cxr
What is your differential diagnosis?
At top of list Pneumocystis carinii pneumonia (PCP)
Viral infection : CMV pneumonia ,Covid 19 , influenza a,b …
Miliary Tb
Bacterial infection
How do you manage this case?
Full history and physical examination
CBC , KFT, LFT ,urine analysis,LDH ,serum electrolytes,Blood culture,induced sputum for culture ,PCR for viral infections
HR chest CT
Trimethoprim-sulfamethoxazole — We recommend trimethoprim-sulfamethoxazole (TMP-SMX) as the treatment of choice for PCP of any severity in patients without HIV .
The dose of TMP-SMX for patients with normal renal function is 15 to 20 mg/kg (dosing is based upon the TMP component and expressed as mg/kg per day of TMP) intravenously or orally daily in three or four divided doses. Dose may need to be adjusted if creatinine clearance changes during therapy. Patients should receive intravenous therapy until they are clinically stable (eg, PaO2 ≥60 mmHg, respiratory rate <25) and have a functioning gastrointestinal tract.
For patients with allergy to TMP-SMX, desensitization should ideally be performed since TMP-SMX is the most effective regimen. However, if the patient has a history of a severe allergy (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis), TMP-SMX should be avoided and desensitization should not be performed.
DD:Pneumonia in immunodompromised
Work up:
‘CT chest ,respiratory panel ,AFB ,TB sputum culture,BAL ,CMV PCR
Treatment:
‘According to the cause :If cMV disease ,gancixlovir IV ,if PCP :sulphmerhoxazole /trimethoprim ,pentamidine ,atovaquine
Why the case is more likely PCP because of dry cough and hypoxia which is not correlated with CXR ,
Why PCP causes dry cough?because PCP infection causes thick ,sticky sputum
Unfortunately I am late in replying so now I know that it is PCP pneumonia hinted by dry cough and marked hypoxia.We can consider CMV pneumonia is in such a scenario as well.
The fact that sputum is sticky and think and difficult to expectorate makes cough as dry. BAL can confirm the diagnosis.
High dose septran is first line therapy.
Differential diagnosis
In view of hypoxia and non-productive cough, probability of PCP will be my main suspicion. In D+/R- CMV status, CMV pneumonia is also consideration
How do you manage this case?
Investigations
Treatment
Roux A, Gonzalez F, Roux M, Mehrad M, Menotti J, Zahar JR, et al. Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Medecine et maladies infectieuses. 2014 May;44(5):185-98. PubMed PMID: 24630595. Epub 2014/03/19. eng.
Diffuse, bilateral infiltrates point out to a range of etiologies including CMV, PJP, respiratory viruses, Mycoplasma and Legionella,
Ground glass or mixed ground glass/micronodular infiltrate raises concern for PJP and CMV
complete blood count with differential, electrolyte chemistries, and liver function testing to assess the toxicity risk of empirical antimicrobials
Blood cultures
Testing of urine for Legionella antigens
gram stain and bacterial culture if sputum production is triggered
Bronchoscopy and bronchoalveolar lavage
PJP, CMV PCR
HRCT
Treatment
Oxygen therapy,
if critically ill reduction of immunosuppression is recommended high dose spectrin for PJP
for CMV IV Ganciclovir for five days followed d by oral valganciclovir
_The index case has fever, dry cough and severe hypoxemia together with just bilateral interstitial infiltrates in the CXR that most probably goes with the diagnosis of pneumocystis jirovecii pneumonia.
_Other differential diagnoses includes:
1. Viral pneumonia as COVID 19, CMV pneumonitis (as high risk for CMV infection , D+/R_).
2_ Bacterial pneumonia as staph and stept pneumonia (unlikely, as the fever is low grade and no typical lobar infiltration characteristic of bacterial infection).
3_ TB (unlikely with dry cough )
_ The clinical criteria are highly suggestive of PCP. However, dry cough and absent sputum makes it difficult in diagnosis and Bronchoscopy with BAL is the standard for diagnosis
_Management of the case:
1.MDT is essential (transplant team, pulmonologist, infectious disease specialist, and ICU team).
2_ General supportive care as oxygen, IV fluids.
3_ Reduction of immunosupression (stop anti proliferative as MMF or AzA, reduce dose of CNI as guided by target trough level)
4_ keep on steroids.
5_ ttt of PCP by sulphamethoxazole _trimethoprime (shift from supressive dose to therapeutic dose).
_Required additional investigations:.
_CBC, ESR and CRP.
_blood and sputum culture
_HRCT chest .
_liver and kidney function.
_PCR for CMV and BAL for PCP PCR.
_Close monitoring of graft function.
# What is your differential diagnosis?
Pneumocystis jirovecii pneumonia
Viral pneumonitis (CMV pneumonitis), and other viral infection
Bacterial pneumonitis
Covid 19
Miliay tuberculosis
ARDS
# How do you manage this case?
CBC, ESR,RFT, LFT, ABG, CRP, (MCV and covid 19 PCR)
Blood and sputum culture
C X Ray
CT chest
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection diagnosed in immunocompromized patients. After solid organ transplantation, early infection has decreased as a result of effective prophylaxis, but late infections and even outbreaks caused by interpatient transmission of pneumocystis by air are present in the SOT community. Different risk factors for PJP have been described and several indications for PJP prophylaxis have to be considered by clinicians in patients even years after transplantation. Diagnosis of PJP is confirmed by microscopy and immunofluorescence staining of bronchial fluid but PCR as well as serum ß-D-Glucan analysis have become increasingly valuable diagnostic tools. Treatment of choice is Trimethoprim/sulfamethoxazole and early treatment improves prognosis. However, mortality of PJP in solid organ transplant patients is still high and many aspects including the optimal management of immunosuppression during PJP treatment require further investigations.
Brakemeier S, Pfau A, Zukunft B, Budde K, Nickel P. Prophylaxis and treatment of Pneumocystis Jirovecii pneumonia after solid organ transplantation. Pharmacol Res. 2018 Aug;134:61-67. doi: 10.1016/j.phrs.2018.06.010. Epub 2018 Jun 8. PMID: 29890253.
1-pneumocystis pneumoniafavor
favour by presence of oxygen desaturation, and dry cough in the immunocompromised recipient
2-CMV disease of end-organ disease
this post renal transplant recipient CMV negative from CMV positive donor
3-pulmonary TB needs to be role out
4- atypical pneumonia
5- typical pneumonia (bacterial infection).
6-fungal infection
7- covid-19 infection
1- prof/AHMED Halwa lecture
I like your comprehensive approach
DD
PCP is most probable due to dry cough and associated hypoxia.
Others: CMV,ARDS,TB .
Management:
Reduction of immunosuppression ; D/C MPA &AZA, using CNI and steroids with O2 support.
Suitable dose of co-trimoxazole till diagnosis confirmed.
-Investigations: routine work up in addition to:
HRCT chest, BAL examination; CMV PCR.
In case of confirmed CMV:IV Gancycolvir 5mg/kg bid for 5 days followed by oral Valgancyclovir 900 mg once daily until negative PCR.
Discussion of risk of acute rejection with reduction of immunosuppression.
PCP should thought of considering: immune compromszed patient, time of occurrence(1-6 months),dry cough with hypoxemia; due to thick sticky sputum and CXR findings of bilateral interstitial infiltration.
Dry cough is a typical symptom for PCP specially associated with fever in immune compromised patient.
Please type headings in bold or underline
What is your differential diagnosis?
-The diagnosis is the most likely P jiroveci pneumonia
-CMV pneumonia
-Acute Respiratory Distress Syndrom
-Tuberculosis
How do you manage this case?
Investigations:
-A lactic dehydrogenase (LDH) study is performed as part of the initial workup. LDH levels are usually elevated (>220 U/L) in patients with P jiroveci pneumonia .
-PCR of respiratory fluid, in particular bronchoalveolar lavage (BAL).
-High-resolution computed tomography (HRCT) scanning of chest
Treatment:
The treatment of choice is TMP-SMX, with second-line agents including pentamidine, dapsone (often in combination with pyrimethamine), or atovaquone.
Reference:
Shelley A Gilroy. Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia.Medscap. Nov 04, 2022
I like your comprehensive approach
What is your differential diagnosis?
This will include:
· Viral pneumonitis , like CMV
· ARDS
· Bacterial pneumoonitis
· Fungal infection like Pneumocystis jirovecii Pneumonia
· Tuberculosis
· Cryptococcal infection
· Covid 19
Investigations
These will include-
· Full blood count/ESR, Renal and liver functions
· ABGs
· HRCT Chest
· CMV PCR
· Blood culture
· Sputum Culture
· Covid 19 PCR
How do you manage this case?
For CMV pneumonitis– start IV gancilovir 5 mg/kg for 2-3 weeks
Monitoring by CMV PCR
Continue treatment for 2 week after achieving negative PCR
For PCP pneumonitis
Start Trimethoprim and sulphamethoxazole 80/400 mg oral for three months.
In case of bacteria pneumonitis – brad spectrum antibiotics according to cultures
Review by pulmonologist and Infections disease team
CMV in kidney transplant- Lecture By Prof Halawa
I like your comprehensive approach, but references need to be properly cited. As much as I adore my academic elder brother Ahmed Halawa ,referring to his lecture is not a reference.
Thank you prof Will do in future citations
What is your differential diagnosis?
KTR, with fever and respiratory symptoms beside mottling appearance on CXR. The serostatus of CMV pre-transplant was D+/R- which carries high risk for CMV infection and disease.
Differential diagnosis in the index case and such scenario :
· CMV pneumonitis.
· PJP pneumonia.
· Miliary TB.
· Other viral infection: influenza, HSV, RSV, CXOVID-19, varicella–zoster infection and parvovirus B19 infection.
· Bacterial infection.
How do you manage this case?
1. Hospital admission is required to keep and maintain optimum oxygen saturation.
2. Detailed history and relevant clinical examination: PH of chronic cough or TB. Looking for evidence of retinitis as it may be a concomitant of CMV pneumonitis.
3. Investigations(1):
· Serologic tests that detect CMV antibodies (IgM and IgG) via ELISA.
· Detection of the CMV pp65 antigen in leukocytes( typically expressed only during viral replication).
· Quantitative CMV PCR (COBAS Amplicor Monitor Test).
· Tissue diagnosis:Intracellular inclusions surrounded by a clear halo may be demonstrated with various stains (Giemsa, Wright, hematoxylin-eosin, Papanicolaou). This gives the appearance of an “owl’s eye”.
· Current methods to detect and diagnose Pneumocystis infection; BAL for PCR, Loop-mediated isothermal amplification (LAMP), Flow cytometry, ELISA technique to detect immunoglobulin (Ig), IgM, and IgG antibodies against Pneumocystis jirovecii. Antigen and biomarker assays for detection of PJP and serum LDH may help in diagnosing PJP.
· To screen for HIV and TB.
· The followings may be required: to obtain sputum via BAL or saline nebs and to examine the secretion for AAFB, culture &sensitivity and to look for viral intracellular inclusions.
4. Drug therapy for CMV pneumonitis: The drug of choice for treatment of CMV disease is intravenous ganciclovir, although valganciclovir may be used for nonsevere CMV treatment in selected cases.The length of treatment varies, for as long as 2-4 weeks from the end of the induction period, depending on the clinical status of the patient(2). Foscarnet
5. Foscarnet is a DNA chain inhibitor of phosphorylation. It has been used to treat ganciclovir-resistant viruses.
6. There is an increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation(3).
7. Prophylaxis to be provided to the patient when having positive CMV serology results. Positive findings on blood cultures, pp65 antigenemia, and CMV PCR have been used as markers for the initiation of therapy.
8. Prophylaxis should continue for 90 to 180 days(4).
References
1. Medscape Drugs & Diseases > Infectious Diseases Cytomegalovirus (CMV) Workup Updated: Jul 07, 2021 Author: Ricardo Cedeno-Mendoza, MD; Chief Editor: Michael Stuart Bronze, MD.
2. Medscape Drugs & Diseases > Infectious Diseases Cytomegalovirus (CMV) Treatment & Management Updated: Jul 07, 2021 Author: Ricardo Cedeno-Mendoza, MD; Chief Editor: Michael Stuart Bronze,
3. MD. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
4. Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TM, Campos SV, Ramos JF, Latif AZ, Litvinov N, Maluf NZ, Caiaffa Filho HH, Pannuti CS, Lopes MH, Santos VA, Linardi Cda C, Yasuda MA, Marques HH. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015 Jul;70(7):515-23. doi: 10.6061/clinics/2015(07)09. Epub 2015 Jul 1. PMID: 26222822; PMCID: PMC4496754.
I like your comprehensive approach
What is your differential diagnosis?
The main differential in this immunocompromised patient is PCP pneumonitis versus CMV pneumonitis.
This patient is hypoxic with dry cough and bilateral lung involvement.all these in favour of PCPrather CMV pneumonitis.
Being the patient has a dry cough; this will put the PCP on the top of the list.
PCP affect the alveoli, and usually, this part of the lung not causing mucous.
Acquisition and transmission — Numerous animal and human studies suggest that Pneumocystis is transmitted by the airborne route. Acquisition of new infections in humans can most likely occur by person-to-person spread. Individuals with normal immune systems may have asymptomatic lung colonisation and may serve as a reservoir for the spread of Pneumocystis immunocompromised hosts.
Solid organ transplantation — Approximately 5 to 15 per cent of patients who undergo solid organ transplantation develop PCP without prophylaxis. The rates are lowest in renal transplant recipients and highest among lung and heart-lung transplant recipients.
referrences
uptodate
Please type headings in bold or underline. Writing ‘uptodate’ is not a good enough reference.
1- a case of pneumonia
DD
a- Bacterial: streptocoocus, TB (unlikely with dry cough), Legionella and Pseudomonas
b– Viral: CMV, influenza, COVID-19
c- Fungal:Pneumocystis jirovecii(most likely)(hypoxia and dry cough ) , Histoplasma, Cryptococcus.
2- Management:
a- hospitalization and maintain adequate oxygen saturation.
a- Proper history taking including exposure to infected persons, travelling, etc
b- full examination: including assessment of the oxygen saturation satus
c- Full labs: CBC, RFT, LFT, septic work-up including assessment of viral (CMV viral load) and fungal culture.
d- MDT including pulmonolgist, infectious disease and nephrologist
e- reduce IS specially antimetabolite (MMF and azathioprin) and in severe case CNI
and maintain steroids.
f- Start empirical treatment with IV antibiotics to cover the community acquired pneumonia, till the culture results
g- maintain cotrimoxazole to cover PCP
h- modify management according to the culture results
consider bronchoscopy and BAL in non-responders
Please type headings in bold or underline.
What is your differential diagnosis?
This is a post renal transplant patient in the first six months post transplantation presenting with respiratory symptoms and fever , the spectrum of potential pulmonary pathogens is wide, certain points in the clinical evaluation like onset, the presence of hypoxia, nature of cough, chest x ray findings will help shorten the list and in management of the patient.
Differential diagnosis
1. CMV :
Why it is number one differential diagnosis?
· The presentation in the first 4 months post transplantation.
· The high risk of CMV disease in the post-transplant period of being D+/R-
· Clinical symptoms and/or signs of pneumonia are seen in CMV pneumonitis such as, hypoxia as in this patient
· The new infiltrates on imaging which is bilateral and diffuse and extensive ground glass lesions goes more with CMV pneumonitis than PJP. Putting in mind these lesion seen in this CXR are nonspecific and other differential diagnoses should be considered
2. We should definitely consider pneumocystis J Pneumonia:
· Risk of infection is PJP is greatest in the first 6 months, need to know from the history whether he is on PJ prophylaxis or not and what prophylaxis as pentamidine prophylaxis is associated with more infection and if the patient immunosuppressive treatment has been increased recently especially corticosteroids pulses.
· The presence of marked hypoxia is with PJP
· The presence of mild clinical findings on examination will go with PJP
· ONSET: The sub-acute illness goes with PJP.
· The presence of bilateral reticulonodular granular shadowing is suggestive of PJP, although it is usually perihilar and less than what is seen in this CXR.
· CBC : neutropenia
NB: important to put in mind that both CMV and PJN can give rise to this clinical and radiological findings and both can coexist in this type of patients.
Others to be considered:
3. Bacterial infections: such as staphylococcal, klebsiella and pseudomonas pneumonia. Usually the onset is acute in bacterial infections and the CXR findings are focal or diffuse consolidation which is not seen here in this index case.
Bacterial infections should always be considered as it can coexist with other viral or fungal infections.
4. Fungal infections such as invasive aspergillosis
Which include
a. sub-acute invasive aspergillosis which is not the case here as it runs an indolent chronic course of necrotizing aspergillosis.
b. Aspegillous broncho- pneumonia with x ray features of in the peribronchial tree which is not the case here.
c. Angioinasive aspergillosis: which present with fever, pleuretic chest pain and hemoptysis which is not the case here. The CXR would show multiple or solitary pulmonary infiltrates with areas of infarcts.
5. Miliary Tuberculosis:
· Needs to know the origin of the patient and previous history of contact with patient with tuberculosis and past history of active tuberculosis.
· His state of latent tuberculosis (IGRA test) before receiving the transplant and whether he received treatment for latent tuberculosis before transplantation or not.
· The onset is usually subacute to chronic with loss of weight which is not the case here.
· The chest x- ray in this index case can be due to Miliary tuberculosis.
6. Nocardiais:
The history is usually as in tuberculosis with fever sweats and loss of weight
CXR: are not typical in this index as it gives cavitatory consolidation.
Management:
1. Multidisciplinary: that include transplant team, pulmonologist, infectious disease physician, microbiogist and ICU physician.
2. Patient should be managed in the ICU setting and managed accordingly. (ABG)
3. Do CBC with differential white blood count, ESR,CRP
4. LFT, RFT.
5. HRCT chest may be more specific and may sow features of an underlying disease
6. Blood cultures
7. CMV serology
8. Aspegillous IGg antibodies
9. Quantitative PCR for CMV in blood
10. PCR for tuberculosis in the blood
11. Level of serum lactate dehydrogenase
12. BAL sent for:
· Microscopy and stains ( Gram stain and Giemsa or methamine silver for PJ and ZN stain)
· Bacterial and fungal cultures
· PCR for CMV, Pneumocystis J , for tuberculosis and Aspergillosis
· Fungal biomarkers such as Galactomannan
13. According to the results of preliminary investigation and waiting for the results of more specific investigations, the patient should be stared on
a. Intravenous broad spectrum antibiotics in collaboration with the microbiologist according to the latest sensitivity of suspected bacteria.
b. IV ganciclovir according to level of renal function with montoring of CBC and RF.
c. IV cotrimoxazole as this is preferred to be started early in the disease.
I like your comprehensive approach, but references need to be cited.
OUR CASE;
65 yr old male
4/12 post KTR
Cadaveric donation.
Donor +VE for CMV, Recipient -VE for CMV
Presentation.
Non productive cough.
Fever
Desaturating on room air.
Heterogenous CXR.
DDX.
PCP
CMV pneumonitis.
Miliary TB.
Lymphocytic interstitial pneumonia
Viral pneumonia including COVID 19 infection.
MAC infection.
MGT.
1Multidisplinary team – Transplant team, Infectious disease team, Pulmonologist, Critical care team.
2.Admit the pt to ICU and supplement oxygen to keep the SP02 >90%
3.Do appropriate investigations;
-LDH – reflects degree of lung injury, elevated to more than 220U/L in PCP.
-PITC to rule out other causes of immunosuppression.
-Quantitative PCR for PCP
-Bets D glucan- assess fungal infection- Candida, PCP, Aspergillosis.
-Covid 19 PCR
-Sputum induction for – MCS, Gene xpert,,Toluidine staining For PCP
-PFTS – Decreased DLCO less than 75 % in PCP.
-BAL or lung biopsy for histology, culture and staining to investigate for PCP,TB,CMV and Aspergillosis.
-Others ; CMV PCR and VL,BGA,FHG,ESR,UECS,Tac levels
4.Modify immunosuppression, decrease anti metabolites by up to 50% or stop them in active infection, Stop CNI if in severe sepsis and increase steroids doses to stress doses while in severe infection.
5.Start on broad spectrum antibiotics to cover community acquired pneumonia awaiting the confirmatory diagnosis.
6.Considering the pt is immunosuppressed and PCP is high on the list start High dose septrin and appropriately renal dose it depending on UECS. Considering immunosuppressive state, treat for 21 days Other options for tx include Dapsone + pyrimethamine +leucovorin ,Atovaquone and aerolised pentamidine.
7.For CMV we will start IV ganciclovir for 5-7 days then switch to valganciclovir.
8.For TB we will start anti TBS and be cognizant of drug interactions in choosing regimen.
This looks PCP and will be managed as such unless the diagnostic tests yield other results which will then determine the treatment.
REF;
N Goto et al – PCP in kidney transplantation.-Transplant infectious disease, vol 13,issue 6,31st oct 2011,pg 551-558
Kreystal De Kyzer et al -Human CMV and Kidney Transplantation, A clinician’s update. -American journal of kidney diseases,vol58,issue 1;july 2011,pg118-126
It seems you will start treatment of many conditions at the same time in this patient?
Prof this looks like PCP and I will manage as PCP unless the other requested results direct towards a different diagnosis.
A 65-year-old man with a fever (38 °C) and non-productive cough 4 months after cadaveric transplantation. CMV positive to CMV negative recipient Oxygen saturation on air was reported at 82%.
Oxygen saturation on air was reported at 82%.
► Exercise induced Hypoxaemia, often severe and out of proportion to clinical findings
-Dry cough
-Dyspnea
-Fever—often low grade
This chest X-Ray shows widespread small nodular ground glass opacities with
cystic changes.
The DD would be according to the most common :
1- The Most Common Fungal: Pneumocystis jirovecii(most likely)(hypoxia and dry cough ) , Histoplasma, Cryptococcus..
2- Viral: Respiratory viruses like Influenza, parainfluenza and Herpesviruses like CMV (D+/R- CMV => CMV pneumonia, ..
3- Bacterial: community acquired like streptococcus, tuberculosis,,,(unlikely => dry cough)..
How do you manage this case?
1- A detailed history and clinical examination
2- Routein Labs:
CBC RFTs, LFTs, CRP, ESR, Septic Screen(Sputum, blood , urine Cs), COVID -19 ,
influenza A, B Screen, CXRY …..
3- Fiberoptic Bronchoscopy For BAL fluid microscopy for PJP, PCR
for Pneumocystis DNA ..
4- Blood to detect β-D-glucan can also help diagnose PCP(Galactomannan test)
5- Blood CMV PCR
6- Sputum : for acid fast bacilli
Management of PJP:
1st : O2 therapy to keep spo2 >92%.
The most used anti-PJP medication is cotrimoxazole (TMP/SMX ).
Other medications that are used, alone or in combination, in those who cannot
tolerate TMP/SMX include:
(Pentamidine, Atovaquone, Dapsone , Primaquine & Clindamycin )
Treatment is usually for a period of about 21 days.
Management of TB :
A Protocol of 2 months of INH, RIF, PZA, & EMB followed by ,
a continuation phase of 4 months of INH & RIF.
EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF.
Pyridoxine (vitamin B6) is given with INH to all persons at risk of neuropathy (eg, advanced age).
Management of CMV :
Reduction of immunosuppression => Antimetabolites to be decreased by 50% or stopped, CNI doses to be adjusted as per trough levels.
Antiviral therapy:
1- IV Ganciclovir has had a major impact on the mortality and morbidity of CMV disease.
2- High doses of IVIG (0.5 g/kg body weight) have been used in conjunction with
Ganciclovir for the treatment of pneumonitis.
3- Secondary prophylaxis after treatment of disease has been assessed, although
evidence in support of this strategy is limited
If BAL or Biopsy Positive for CMV :
=>TTT with intravenous ganciclovir (5mg/kg IV 12 HR, to be adjusted according to
Cr CL)=> It should be continued for minimum 2 weeks
=> Can be changed to oral valganciclovir, if improves earlier, and until resolution of clinical symptoms and radiological findings with clearance of CMV in blood, if present
=>CBC and serum creatinine should be monitored weekly during the treatment.
=>If no response in 2 weeks, assess for ganciclovir resistance and shift to Foscarnet and
=>Add CMV immunoglobulin or intravenous immunoglobulin (IVIG) .
=>Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2
months in patients with high-risk of relapse.
Managment of influenza :
Influenza A or B =>give (Oseltamivir) Tamiflu 75 mg po bid for 5-10 days
Supportive care: Intravenous fluids, nutrition.
References:
Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
UK guideline on prevention and management of cytomegalovirus (CMV) infection and disease following solid organ transplantation April 2022.
ATS/CDC/IDSA clinical practice guidelines for drug-susceptible TB, CID 2016:63 (1 October),147.
Shelley A Gilroy; Chief Editor: Pranatharthi Haran Chandrasekar, Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia, Medscape Updated: Nov 04, 2022
Pulmonary complications within the first year after renal transplantation. El-Azem Sadon Amal Abd, Otaibi Torki Al, Nair Prasad, Gheith Osama, El Monem Mohammed Abd, El Tawab Khaled Abd, Maher Ayman. Year : 2020 | Volume: 69 | Issue Number: 4 | Page: 739-746
It seems you will start treatment of many conditions at the same time in this patient?
It seems you will start treatment of many conditions at the same time in this patient?
Differential Diagnosis:
The recipient is:
The chest x-ray show massive lung infiltration, the most suspected diagnosis:
Management of the case:
# General management:
# Workup for diagnosis:
# Specific management;
Reffrences:
Ricciardi A, Gentilotti E, Coppola L, Maffongelli G, Cerva C, Malagnino V, Mari A, Di Veroli A, Berrilli F, Apice F, Toschi N, Di Cave D, Parisi SG, Andreoni M, Sarmati L. Infectious disease ward admission positively influences P. jiroveci pneumonia (PjP) outcome: A retrospective analysis of 116 HIV-positive and HIV-negative immunocompromised patients. PLoS One. 2017;12(5):e0176881. [PMC free article] [PubMed]
2.
Mecoli CA, Saylor D, Gelber AC, Christopher-Stine L. Pneumocystis jiroveci pneumonia in rheumatic disease: a 20-year single-centre experience. Clin Exp Rheumatol. 2017 Jul-Aug;35(4):671-673. [PubMed]
3.
Amber KT. Balancing the risks and benefits of prophylaxis: a reply to “Pneumocystis jiroveci pneumonia in patients treated with systemic immunosuppressive agents for dermatologic conditions”. Int J Dermatol. 2017 Jan;56(1):e4-e5. [PubMed]
How will you provide ‘CMV-specific T-cell transfer’ as you mention in your setting?
What is your differential diagnosis?
the current indexed case 4 months post kidney transplantation from seropositive Donor to the negative recipient with URT symptoms including dry cough, fever, severe hypoxemia, and bilateral infiltration as shown in CXR the DDX here will be wide Including atypical viral infections like CMV Pneumonitis, also PJP should be considered as important DDX, especially with severe hypoxia at presentation, dry cough, PJP in non-HIV immunosuppressed patients have more sever clinical course including prolong hospital stay and ICU admission and high mortality rate compared to HIV related PJP(1).
CT chest would help as well
community-acquired pneumonia is less likely, and Drug-induced pneumonitis (if he is on m TOR inhibitors). Need to know about the type of induction IS like alemtuzumab is one of the monoclonal biological agents that prolonged lymphopenia and whether the patient received a CMV prophylaxis course and TMX prophylaxis and his current maintenance IS type and dosing.
How do you manage this case?
We need to go for HRCT as the most frequent CT findings are bilateral, ground-glass changes with apical predominance and peripheral sparing in non-HIV-immunocompromised patients with PJP, signs of consolidation are detected more frequently on CT and cystic changes less frequently – than in HIV-positive patients with PJP. The range of other radiological features seen in PJP includes a combination of ground glass and consolidative opacities, cystic changes, linear reticular opacities like our case, solitary or multiple nodules, and parenchymal cavities() With treatment, the vast majority of these changes resolve.
The dry cough will affect the accuracy of staining methods for the diagnosis of PJP as its highly dependent on the quality of the respiratory specimen, sample processing, the reaction of the specimen to the stain chosen, and the skill of the laboratory viewer. The lower burden of P. jirovecii in non-HIV-immunocompromised patients, and they might already be on prophylaxis Therapy remains a challenge for diagnosis difficulties with isolating and culturing this pathogen, by microscopic examination of respiratory specimens. by using various staining methods is used to visualize and identify the morphological structures of P. jirovecii. Methenamine silver and toluidine blue preparations stain only the cyst wall and do not allow the detection of trophozoites. However, Giemsa stains detect all life stages of P. jirovecii. Direct and indirect immunofluorescent assays (DFA, IFA) are specific for different life stages, depending on the antibody used.
Comparative studies have shown DFA and IFA to be the most sensitive stains for P. jirovecii in sputum and bronchoalveolar lavage, with sensitivities of 97% and
90% respectively.8 These assays are also commercially Staining methods have now largely been supplanted by highly sensitive molecular techniques, using semi- or
fully quantitative polymerase chain reaction (PCR) targeting P. jirovecii-specific genes. (3) A meta-analysis of PCR
studies has shown a pooled sensitivity of 99% and specificity of 92% in the non-HIV patient population(4). The patient needs to do saline induced sputum sample for PJP PCR and preferred to go for bronchoscopy with BAL for cytology, culture and cmv pcr, PJP PCR, and galactomannan Bronchoalveolar lavage fluid from immunosuppressed non-HIV-infected patients shows lower concentrations of organisms but higher inflammatory scores (2).
according to the results will direct our management also need to adjust the current IS therapy by stopping the antimetabolites and continuing on tacrolimus-based IS with stress dose steroids and monitor with u&e, CMV PCR, FBC, and CXR, CT chest as fu after completing the treatment course, TMP-SMX is the drug of choice for the treatment of PJP with its proven clinical efficacy, cost, and availability of both the IV and oral formulations, TMPSMX is the preferred therapy for mild, moderate, and severe disease for all patients with PJP (grade B recommendation), duration of therapy for 21 days in sever pjp preferred to use IV route to its use only limited in case of side effect, renal impairment, and myelosuppression. Alternative agents for PJP treatment will be dapsone, pentamidine, and atovaquone.
Arterial oxygenation at diagnosis was recognized as the best prognostic indicator of survival. Adjunctive corticosteroid therapy commenced at the time of PJP therapy prevented the early decline in oxygenation that occurs after initiation of PJP therapy in patients with moderate to severe PJP (arterial-alveolar difference >35 mmHg or an arterial oxygen pressure<70 mmHg (1).
References
1. Consensus guidelines for diagnosis, prophylaxis, and management of Pneumocystis jirovecii pneumonia in patients with hematological and solid malignancies, 2014L. Cooley,1 C. Dendle,2,3 J. Wolf,4,5 B. W. Teh,6 S. C. Chen,7,8,9 C. Boutlis10,11 and K. A. Thursky6,12
2. Limper AH. Alveolar macrophage and glycoprotein responses to Pneumocystis carinii. Semin Respir Infect 1998; 13:339–47.
3. Robberts FJ, Liebowitz LD, Chalkley LJ.Polymerase chain reaction detection of Pneumocystis jiroveci: evaluation of assays. Diagn Microbiol Infect Dis 2007;58: 385–92.
4. Lu Y, Ling G, Qiang C, Ming Q, Wu C, Wang K, et al. PCR diagnosis of Pneumocystis pneumonia: a bivariate meta-analysis. J Clin Microbiol 2011; 49:4361–3.
5.Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother2007; 13: 1–7.
also, we should consider the possibility of combined infection with both CMV and PJP in this case as the presentation and risk factors plus the radiological finding are highly suggestive of PJP in addition to CMV pnemonitis, such combination cosxiste in up to 46% ( 1) .especially after one year of renal transplantation. and the use of t cell depleting agents like alemtuzumab as induction IS.
References
1.Zou J, Wang T, Qiu T, Zhou J, Chen Z, Ma X, Jin Z, Xu Y, Zhang L. Single-center retrospective analysis of Pneumocystis jirovecii pneumonia in patients after deceased donor renal transplantation. Transpl Immunol. 2022 Jun;72:101593. doi: 10.1016/j.trim.2022.101593. Epub 2022 Apr 5. PMID: 35367619
Yes, I appreciate that combined infections of CMV and PCP need to be considered in such patients.
I like your clinico-pathological co-relation in light of CT findings.
3. A 65-year-old man was admitted with a fever (38°C) and non-productive cough 4 months after cadaveric transplantation. CMV positive to CMV negative recipient oxygen saturation on air was reported at 82%. CXR shows widespread bilateral reticulonodular opacities.
What is your differential diagnosis? (1, 2)
The pneumonic process on the chest radiograph can be: –
Chest infections post kidney transplant are most common in the first 6 months with a peak at around 3 months. In the first month, the common causes are gram negative bacterial infections, aspiration and septic emboli.
In the 2nd to 6th month, common etiologies are viral (CMV, HSV, EBV), fungal (PCP, aspergillus) and tubercular infections. Viral infections can also predispose to fungal infections.
How do you manage this case?
– Detailed history i.e., hemoptysis, chest pain, comorbidities, history of acute rejection, previous chest infection, immunosuppressive therapy
– Thorough physical examination
– Baseline investigations i.e., FHG, ESR, CRP, procalcitonin, blood culture, urine culture, sputum analysis (gram stain, microscopy, cytology, gene xpert, culture, PCR for respiratory viruses), urine LAM, UECs, LFTs, COVID 19 nasopharyngeal swab PCR, fungal markers (galactomannan, serum LDH, CMV quantitative PCR, Tacrolimus trough levels, blood gas analysis
– Bronchoscopy with BAL ± biopsy
– Imaging i.e., Chest CT scan (HRCT), Graft ultrasound
– Management – requires a multidisciplinary approach i.e pulmonologist, infectious disease specialist, nephrologist, intensivist
– ICU/ HDU care for ventilatory support in view of the low oxygen saturations
– Medications: – depends on the causative agent
References
1.Ahmad Z, Bagchi S, Naranje P, Agarwal SK, Das CJ. Imaging spectrum of pulmonary infections in renal transplant patients. The Indian journal of radiology & imaging. 2020 Jul-Sep;30(3):273-9. PubMed PMID: 33273760. Pubmed Central PMCID: PMC7694710. Epub 2020/12/05. eng.
2.Mangalgi S, Madan K, Das CJ, Singh G, Sati H, Kanwar Yadav R, et al. Pulmonary infections after renal transplantation: a prospective study from a tropical country. Transplant International. 2021;34(3):525-34.
3.Pulmonary complications within the first year after renal transplantation. El-Azem Sadon Amal Abd, Otaibi Torki Al, Nair Prasad, Gheith Osama, El Monem Mohammed Abd, El Tawab Khaled Abd, Maher Ayman. Year : 2020 | Volume: 69 | Issue Number: 4 | Page: 739-746
Why is PCP associated with dry cough?
What is the impact of the symptom of dry cough on sputum examination?
Thank you for your reply, excellent answer.
welcome prof
. PCP usually resides in alveoli and interstisium in lower respiratory tract other reason is the thick and gelatinous secretion. This make it difficult to cough up.
I reviewd many article, i didnot find any clear explanation, but I think may be due to fungal cause and trouble breathing that make chest wall muscles are unable to take sputum sample .
Sputum sample may be difficult and bronchoalveolar lavage or even biopsy can be done
See your colleagues replies especially Ben Lamato and Sherif Yousef
Thanks alot Prof.Halawa
Thank you for your reply
Why is PCP associated with dry cough?
– P. jirovecii is transmitted by airborne route, around ¾ of cases had the organism since early childhood (by the age of 4 years) which become latent and can be reactivated once the immunity is compromised, on the other hand ¼ of cases may not acquire the organism in childhood and acquire it later in life through person to person airborne transmission. (1)
– Pneumocystis is exclusively present within the lung alveoli, and once infection develops it presents with alveolitis sparing the bronchial tree, thus cough is usually dry. (2)
What is the impact of the symptom of dry cough on sputum examination?
– Diagnosis of PCP depends on the detection of the cystic or trophic forms in respiratory secretions by immunofluorescent staining (the organism cannot be cultured) , PCR has a disadvantage of not differentiating between infection and colonization.
– Because the cough is dry, and patient is usually in respiratory distress, so obtaining an optimal specimen by ordinary cough may be impossible, so it should be done using one of the following ways:
1- Induction of cough using hypertonic saline with sensitivity ranging from 55- 90%. (3)
2- ET aspirates in mechanically ventilated patients with sensitivity of 92%. (4)
3- BAL with sensitivity of 90-100%. (5)
References
1. Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics 1978; 61:35.
2. Catherinot E, Lanternier F, Bougnoux ME, et al. Pneumocystis jirovecii Pneumonia. Infect Dis Clin North Am 2010; 24:107.
3. Willocks L, Burns S, Cossar R, Brettle R. Diagnosis of Pneumocystis carinii pneumonia in a population of HIV-positive drug users, with particular reference to sputum induction and fluorescent antibody techniques. J Infect 1993; 26:257.
4. Alvarez F, Bandi V, Stager C, Guntupalli KK. Detection of Pneumocystis carinii in tracheal aspirates of intubated patients using calcofluor-white (Fungi-Fluor) and immunofluorescence antibody (Genetic Systems) stains. Crit Care Med 1997; 25:948.
5. Levine SJ, Kennedy D, Shelhamer JH, et al. Diagnosis of Pneumocystis carinii pneumonia by multiple lobe, site-directed bronchoalveolar lavage with immunofluorescent monoclonal antibody staining in human immunodeficiency virus-infected patients receiving aerosolized pentamidine chemoprophylaxis. Am Rev Respir Dis 1992; 146:838.
Excellent answer
Hi, Dr. Ahmed
I Think
1st :
Mainly related to parenchymal interstitial compromise , the interstitial thickening cause the J receptors to activate => trigger the cough
2nd :
PJP causes pan lobular infection (more interstial part ) rather than centri lobular (airways)
that is my understanding
Please see Ben Lamato’s answer above
1- PCP: associated with thick pus which is difficult to be expectorated
2- this may require bronchoscopy and BAL
There may not be any sputum at all !
PJP is primarily an alveolar pathogen.
Pneumocystis jirovecii has a preference for infecting the lung in at-risk individuals. Microscopic examination reveals that Pneumocystis attaches to Type I alveolar epithelium, which allows the fungus to transition from its small trophic form to the larger cystic form. Adherence of Pneumocystis to alveoli is not the singular cause of diffuse alveolar damage, but rather it is the host’s own inflammatory response that causes significant lung injury and impaired gas exchange, leading to hypoxia and possibly respiratory failure.
The impact of dry cough on sputum examination is the need for obtaining respiratory secretion via BAL, ET suctioning if on mechanical ventilation or via using saline nebs for conscious patients.
Reference:
NIH, national Library of medicine Pneumocystis Jirovecii Pneumonia Justina Truong; John V. Ashurst.
Induced cough is to be made use of.
PCP is associated with dry cough. Brochoscopy/ brochoalveolar lavage can be helpful. Molecular methods of detection include polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and antibody-antigen assays. These can be performed on sputum , nasal or oropharygeal washes
I agree
1-The hallmark of infection due to P. jirovecii is the presence of marked hypoxemia, dyspnea, and cough with a paucity of physical or radiologic findings.
The typical radiographic features of PCP are diffuse, bilateral, interstitial infiltrates
Pneumocystis pneumonia is characterized by a gradual onset with shortness of breath and/or difficulty breathing. This disorder may be accompanied with fevers, night sweats, weight loss and dry cough. Dry cough is one distinction from typical pneumonia because spit (sputum) is too thick to become productive, therefore productive cough is not as common in PJP. Uncommonly, the PJP fungus can spread to other body organs such as the liver, kidney and spleen as the disease progresses.
In susceptible (immunocompromised) hosts, the organism occurs in massive numbers, filling the alveolar spaces and eliciting an active response of the alveolar macrophages and phagocytosis. the alveolar septum is thickened and there is an interstitial plasma cell and lymphocyte infiltration. The infection results in impaired ventilation and severe hypoxia.
2-Since Pneumocystis cannot be cultured, definitive diagnosis requires detecting and identifying the organism by polymerase chain reaction assays of respiratory specimens, dye staining, or fluorescein antibody staining
Testing in this manner requires a microscopic examination of a patient’s sputum or bronchoalveolar lavage fluid. These samples should only be obtained when safe and if the patient is stable.
Reference
Pneumocystis Pneumonia (PCP)
Written by WebMD Editorial Contributors
Medically Reviewed by Jonathan E. Kaplan, MD on December 04, 2021
Yes, marked hypoxia is a prominent feature
-Dry cough is one distinction from typical pneumonia because sputum is too thick to become productive, therefore productive cough is not as common in PJP.
-sputum exam is difficult with dry cough , but sputum can be collected bybronchoalveolar lavage( BAL)
Reference
Phan et al .Pneumocysitis pneumonia. NORD2018
pneumocystis p present exclusively in the alveoli and sparing the bronchi and this explain dry cough and for BAL to aid the diagnosis
As my colleagues have mentioned, the secretions in PCP are thick, and hence difficult to come out. Hence, sputum needs to be induced, or a bronchoalvelolar lavage (BAL) is required. If the patient is intubated, tracheal secretions can be assessed for pneumocystis.
Yes
it seems it is thick sputum because the diagnosis usually made by BAL which is the sample of choice or induced sputum as routine sputum is associated with poor result to diagnose PCP
Xavier Iriart,Marine Le Bouar,Nassim Kamar,Antoine Berry. Pneumocystis Pneumonia in Solid-Organ Transplant Recipients. J Fungi (Basel). 2015 Dec; 1(3): 293–331.
Why is PCP associated with dry cough?
– The cough is typically dry/ non-productive since the sputum becomes too thick/ viscous to be coughed out.
– This dry cough helps distinguish PCP from other typical pneumonias.
What is the impact of the symptom of dry cough on sputum examination? (1)
Making a definitive diagnosis of PCP can be challenging at times e.g.,
– HIV/ AIDS patients have fewer neutrophils and a higher number of organisms present in their sputum and BAL fluid. This makes the diagnosis easier or more likely attainable.
– However, immunocompromised patients who are HIV negative, are likely to have a lower organism burden in their sputum or BAL fluid samples hence making diagnosing difficult.
References
1. Truong J, Ashurst JV. Pneumocystis Jirovecii Pneumonia. StatPearls. Treasure Island FL: © 2022, StatPearls Publishing LLC.; 2022.
_PCP usually has dry cough as it mainly causes alveolitis with sparing of bronchi, and has viscid and difficult to be produced sputum .
_ Dry cough makes it difficult to examine sputum and makes sputum reproductive methods as
1_ use of hypertonic saline nebulizer to induce cough
2_ use of bronchoscopy and BAL
3_ use of endotracheal tube aspiration in. Ventilated case.
-PCP is associated with a dry cough due to the viscous nature of its sputum thats not easily expectorated.
-Dry sputum means less accurate results on sputum examination post induction unless bronchoscopy +/- bronchoalveolar lavage is done which again is challenging in a patient immunosuppressed with respiratory distress. The approximate sensitivities of sputum results are; Sputum induction ;-55-90%,Endotracheal aspiration-~90%,Bronchoalvealr lavage >90%.
REF;
Pifer et al ;PCP infection; Evidence of high prevalence in normal and immunosuppressed children.
Levine SJ et al; Diagnosis of PCP by multiple lobe, site directed BAL with immunofluorescence monoclonal antibody staining in HIV Pts receiving pentamidine chemoprophylaxis.
Stager C et al; Detection of PCP in Tracheal aspirate of intubated pts using calcofluor- white(Fungi flow)
and immunofluorescence antibody staining.Critical care med.1997;25;948
PCP cough – typically dry/non-productive because sputum becomes too viscous to be coughed up. The dry cough distinguishes PCP from typical pneumonia
https://en.wikipedia.org/wiki/Pneumocystis_pneumonia
PCP and Dry Cough:
It causes dry cough as it mainly causes alveolitis with sparing of bronchi, and has viscid and difficult to be produced sputum .
Dry cough and Sputum examination:
Dry cough makes it difficult to examine sputum and makes sputum reproductive methods as
1. Use of hypertonic saline nebulizer to induce cough
2. Use of bronchoscopy and BAL
3. Use of endotracheal tube aspiration in Ventilated case
PCP associated with dry cough because the sputum is thick and sticky and it is difficult to expectorate that s way the cough is dry and this may explain the sever hypoxia .
as the cough if dry this make the diagnosis depending on sputum is in sensitive , to enhance the the sensitivity we need , induced sputum or even broncho alveolar lavage .
Cough – typically dry/non-productive because sputum becomes too viscous to be coughed up. The dry cough distinguishes PCP from typical pneumonia.
The dry cough makes the optimal specimen for sputum difficult so it should be performed with an another test
BAL
ir induced sample
Dry cough and hypoxemia show PCP infection.
What is your differential diagnosis?
Bilateral lung infiltration in post kidney transplant patient with hypoxia and fever indicate severe pneumonia most likely differential is :
– PCP is the most likely diagnosis esp with the presence of dry cough and hypoxia
Differential diagnoses include
– Bacterial pneumonia (Haemophilus spp., Streptococcus pneumoniae, ‘atypical’ infections such as Mycoplasma, Legionella and Chlamydia, –Mycobacterial infections, Nocardia),
-Fungal infections (Cryptococcus, Histoplasma, Coccidioides) .
–CMV pneumonia and other viral infection like covid 19
How do you manage this case?
Treatment :
ICU or HDU admission with respiratory support:The goal of therapy is the correction of the hypoxaemia. High flow oxygen should be given via standard masks and oxygen saturation should be monitored closely in moderate to severe disease .CPAP or mechanical ventilation as needed .
Drug therapy :
The drug of choice is Cotrimoxazole (trimethoprim-sulphamethoxazole) at a dose of 120 mg /kg/day intravenous in four divided doses for 21 days started IV for better response then continuing on oral cotrimoxazole
.
Alternatives to cotrimoxazole in patients intolerant of cotrimoxazole:
Failure of cotrimoxazole therapy :
If the patient is deteriorating despite intravenous cotrimoxazole, complications like pulmonary oedema,pneumothorax, superinfection, or other opportunistic infections should be excluded, as in the differential diagnosis above.
Failure of cotrimoxazole will leads to a poor prognosis. Controlled trials are largely lacking, but alternatives are: (i) addition or substitution with intravenous pentamidine (ii) addition of oral dapsone or atovaquone (iii) substituting with oral clindamycin and primaquine, or (iv) salvage therapy with trimetrexate and folinic acid (leucovorin) rescue .
Corticosteroids:
Corticosteroids should be used for this patient if assessed as moderate to severe PCP and should be commenced together with anti-Pneumocystis therapy to increase survival and prevent the development of acute respiratory failure . It is suggested by some authors that steroid use in moderate cases should be for PaO2 (9.3 kPa or an alveolar–arterial pressure of 4.7 kPa) . In the case of ventilated patients it is found to reduced mortality from 84% to 39% . The recommended doses are oral prednisolone 50–80 mg day−1 for at least the first 5 days, tapering off over the next 2–3 weeks . In severe disease, intravenous hydrocortisone should initially be used.
Adjustment of immunosuppresion :
-Continue on CNI at lower trough.
– Reduction of the dose of antimetabolite (by 50%) , stopped if the patient is deteriorating.
– Steroids to be continued or even increased if there is risk of rejection .
Reference ;
1. Br J Clin Pharmacol. 1999 Jun; 47(6): 605–609. doi: 10.1046/j.1365-2125.1999.00966.x PMCID: PMC2014249PMID: 10383536
2.J Fungi (Basel). 2018 Dec; 4(4): 127. Published online 2018 Nov 22. doi: 10.3390/jof4040127 PMCID: PMC6313306PMID: 30469526
3.Br J Clin Pharmacol. 1999 Jun; 47(6): 605–609.doi: 10.1046/j.1365-2125.1999.00966.x
Yes reduction of immunosuppression is the key step
·What is your differential diagnosis?
===========================
·How do you manage this case?
TreatmentPJP
PTB
Treatment of CMV Disease
References
It seems you will start treatment of many conditions at the same time in this patient?
Differential diagnosis
Management
Treatment of PCP
Reduction of immunosuppression is the key
Hypoxemia with widespread reticulonodular opacities on x -ray.
What is your differential diagnosis?
———————————————————————
1-Bacterial infection ;
Typical and atypical pneumonia .
2-Viral infection ;
CMV ,EBV , adenovirus ,Covid .
3-Fungal infection ;
Pneumocyst carinii
1-How do you manage this case?
————————————————————————–
We must follow the standard clinical approach in treating kidney transplant recipients presented with severe pneumonia which include ;
1-Microbiological diagnostic approach ;
————————————————————
None invasive approach;
a-Blood ,sputum and urine culture .
b-Serum antibodies against EBV ,CMV ,Ligionella and mycoplasma .
c-Galactomannan test( GM test), and Interferon-γ release assays (T-SPOT).
The invasive approach ;
The guidelines recommend fiberoptic bronchoscopy with BAL in patient with negative findings .
2-The therapeutic approach ;
———————————————–
1-The empirical antimicrobial therapy included;
———————————————————————
A- For early onset pneumonia (the presented case );
moxifloxacin, ganciclovir, and trimethoprim-sulfamethoxazole (TMP-SMX) .
B-For late onset pneumonia ; moxifloxacin plus ganciclovir .
C- The guidelines recommend antifungal therapy in cases of suspicion or confirmed fungal infection.
D-The dosages of all the drugs should be adjusted based on the allograft function.
E- The antimicrobial should adjusted within 24 h after the results of the microbiological cultures and serum tests became available.
F-Reduction immunosuppressant ;
1-None ICU admission;
Withdrawn of anti proliferative agent ,continue CNI and steroids .
2-ICU admission;
In critically ill patients. all the immunosuppressants should be withdrawn on admission to the ICU, methylprednisolone (1 mg/kg every 12 h) can be initiated, followed by gradual tapering . Calcineurin inhibitors can be resumed at a low dose when the intravenous methylprednisolone dose was reduced to 1.0 mg/kg/d.
G-The management of other aspects of care, such as blood glucose control, nutritional support, thromboembolic prophylaxis, sedation, and analgesia, was performed according to the current guidelines .
References:
———————————-
1- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358588/ Int J Clin Exp Med. 2015; 8(1): 1324–1332. Published online 2015 Jan 15. Early- and late-onset severe pneumonia after renal transplantation .
2https://ukkidney.org/sites/renal.org/file /Coronavirus%20transplant%20information%2021%20October%202020.pdf
It seems you will start treatment of many conditions at the same time in this patient?
The index patient is a recent (4 month post-transplant), CMV positive to CMV negative cadaveric transplant, who presented with fever, non-productive cough, and hypoxia (82% oxygen saturation on room air). The chest x ray shows diffuse reticulo-nodular shadows. The clinical symptoms are suggestive of pneumonia.
The differential diagnosis in such a scenario would be (1):
a) Viral: Respiratory viruses (Influenza, parainfluenza etc), Herpesviruses (cytomegalovirus, CMV etc)
b) Fungal: Pneumocystis jirovecii, histoplasma, Cryptococcus
c) Bacterial: community acquired like streptococcus, tuberculosis etc.
d) Parasitic
Bacterial etiology of the clinical picture is unlikely (no expectoration).
In view of hypoxia and non-productive cough, probability of PCP is high (2). In view of D+/R- CMV status, CMV pneumonia is also a possibility which may present with patchy ground glass opacities, small nodules, or consolidation (3,4).
The management of the index case involves:
1) A detailed history and clinical examination
2) Laboratory testing including complete blood count, renal function tests, liver function tests, C reactive protein, blood culture, chest X ray, influenza testing (if in season) and other respiratory viral testing (biofire), Calcineurin inhibitor (CNI) trough levels (if on CNIs)
3) Induced sputum examination for cytology, gram stain and acid fast bacilli stain, and culture
4) High resolution computed tomogram (HRCT) of chest.
5) CMV PCR testing: In view of D+/R- status.
6) Admission in intensive care unit (ICU): With oxygen therapy in view of hypoxia.
7) Bronchoscopy with bronchioalvelar lavage with or without transbronchial lung biopsy: For stain and culture, as well as PCR for respiratory viruses, CMV, pneumocystis etc, and histopathological analysis.
8) Empiric initial treatment:
9) Immunosuppression: Antimetabolites to be stopped, CNI doses to be adjusted as per trough levels.
10) Further management as per the laboratory reports: If BAL or biopsy shows CMV, treatment with intravenous ganciclovir (5mg/kg IV 12 hourly, to be adjusted according to creatinine clearance). It should be continued for minimum 2 weeks (can be changed to oral valganciclovir, if improves earlier), and until resolution of clinical symptoms and radiological findings with clearance of CMV in blood, if present (5). Complete blood count and serum creatinine should be monitored weekly during the treatment. If no response in 2 weeks, assess for ganciclovir resistance and shift to Foscarnet and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) (5). Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse.
11) Supportive care: Intravenous fluids, nutrition.
References:
1) Dulek DE, Mueller NJ; AST Infectious Diseases Community of Practice. Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13545. doi: 10.1111/ctr.13545. Epub 2019 Apr 23. PMID: 30900275; PMCID: PMC7162188.
2) Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13587. doi: 10.1111/ctr.13587. Epub 2019 Jul 1. PMID: 31077616.
3) Kang EY, Patz EF Jr, Müller NL. Cytomegalovirus pneumonia in transplant patients: CT findings. J Comput Assist Tomogr. 1996 Mar-Apr;20(2):295-9. doi: 10.1097/00004728-199603000-00024. PMID: 8606241.
4) Moon JH, Kim EA, Lee KS, Kim TS, Jung KJ, Song JH. Cytomegalovirus pneumonia: high-resolution CT findings in ten non-AIDS immunocompromised patients. Korean J Radiol. 2000 Apr-Jun;1(2):73-8. doi: 10.3348/kjr.2000.1.2.73. PMID: 11752933; PMCID: PMC2718167.
5) Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
Yes, I appreciate that antimetabolites need to be stopped.
–Differential diagnsosis
PneumocystitisPneumonia
Tissue invasive CMV pneumonia
Miliary TB
Histoplasmosis
ARDS
–Management
Hypoxia with dry cough ,fever , and having a kidney donor whom was CMV-positive and the recipient was CMV-negative represent a risk factor in the current case rendering Pneumocystitis pneumonia most likely diagnosis
Detailed history and examination need to be done to assess the patient’s general condition and assess the graft function
MDT has to be involved including with the transplantation team a pulmonologist .
ICU admission with suitable oxygen supply as oxygen sat <80% and monitoring of vitals and fluid chart
Labs
Complete blood count, albumin, liver enzymes and electrolytes, inflammatory markers
Blood culture and EBV and CMV blood tests
Gamma interferon to exclude TB
PCR for COVID 19
Kidney function tests ,e GFR, urine analysis
Immunosuppressive level(MMF, Tac)
PCR for PCP from Bronchoalveolar lavage
Radiology
CT chest
Renal US
Treatment
Trimethoprim-sulfamethoxazole is the first-line therapy ( 15 to 20 mg/kg IV ) switching to oral after clinical improvement.
Pentamide 4 mg/kg IV o.d is the second-line therapy for severe cases
Or Primaquine plus Clindamycin for severe cases
Iv Gancilclovir 5 mg/kg BID for 14-21 days afterwards oral valganciclovir 900 mg BID can be given for coverage of high risk CMV infection
Broad spectrum antibiotic coverage
Copious hydration guided by fluid chart
,Immunosuppressive as MMF ,Tac can be reduced or stopped with following graft function ,
KDIGO Guidelines for PCP prophylaxis recommend TMP-SMX as a first-line therapy for 3–6 months after renal transplant
Reference
-Varnas D, Jankauskienė A. Pneumocystis Jirovecii Pneumonia in a Kidney Transplant Recipient 13 Months after Transplantation: A Case Report and Literature Review. Acta Med Litu. 2021;28(1):136-144. doi:10.15388/Amed.2020.28.1.5
I like ‘Immunosuppressive as MMF and Tac can be reduced or stopped with following graft function’.
Differential diagnosis:
1-viral pneumonities due to CMV
2-Miliary tuberculosis
3-Interstitial pneumonities
4- PCP
Mangement :
1- Detailed history and examination
2- To do CBC ,Urine analysis ,RFT plus electrolyte ,viral screen ,CMV screen ,TB screen ,CRP ,
Liver function test ,US, blood culture and urine culture .
3- Start iv antibotices
4- Oxygen
Treatment if this pt has CMV pneumonities :
Iv valgancilovir
Reference:
Hand book of kidney transplant
Pneumonia in post transplant recipient has wide differential diagnosis
· It may be viral ,bacterial ,fungal ,or parasitic but in this case The radiographic features can narrow the differential diagnosis
· Diffuse, bilateral infiltrates suggest CMV, respiratory viruses, Mycoplasma, Legionella, and Pneumocystis jirovecii (PJP).And Ground glass or mixed ground glass/micronodular infiltrate raises concern for PJP and CMV
Management
1. Hospitalization
2. Stabilization
3. Respiratory support
4. Initial Evaluation include
History
• Recent hospitalizations or illnesses
• Social/exposure history
• Immunization status
• Comorbid conditions
• Current degree of immunosuppression
• Exposure history indicative of possible pathogen
Labs
• Complete blood count with differential-inflammatory markers
• Electrolyte and kidney function
• Liver function testing
• Influenza testing (if in season) and other respiratory viral
• Blood culture – Sputum cultures
5-Based on history and intial evaluation we may need to proceed to expanded evaluation
· Serologic and/or antigen evaluation for endemic fungal infection
· Legionella antigen and/or PCR testing
· Fungal biomarker testing (Galactomannan) from serum
· CMV PCR
· Chest CT scan
6-Procedural Evaluation Consider
Þ BAL / Transbronchial biopsy
Þ IR guided biopsy
Þ Open Lung biopsy +/- VATS
7-Tissue speicment testing
Þ Cultures: Bacterial, Fungal, AFB, Viral
Þ Stains: Fungal/PJP directed
8-BALF Specimen Testing
Þ Cultures: Bacterial, Fungal, AFB, Viral
Þ Stains: Fungal/PJP directed (Silver, GMS, etc)
Þ Antigen/Biomarker: Galactomannan; endemic fungi
Þ PCR/DNA: Respiratory viruses, CMV, Mycoplasma spp., Ureaplasma spp., Legionella spp. PJP, Legionella spp., Nocardia spp., Invasive molds
9-Antibacterial therapy is the cornerstone of the initial empiric therapy.
Þ acombination therapy with a beta‐lactam agent (±MRSA and ±anipseudomonal ) and an agent active against intracellular organisms (Mycoplasma in and Legionella ) Then adjust according to clinical and microbiological findings.
Þ During influenza season, empiric administration of an antiviral drug active against influenza
I appreciate your approach
1-What is your differential diagnosis?
Routine prophylaxis has increased the risk for unusual pathogens that are resistant to prophylactic agents including fluoroquinolone-resistant streptococci, other multidrug-resistant bacteria, azole-resistant molds, and ganciclovir-resistant cytomegalovirus (CMV)
Glucocorticoids play an important role in the pathogenesis of pneumonia due to depression of phagocytic function of alveolar macrophages and neutrophils, decreased mobilization of inflammatory cells into areas of infection, and alterations in antigen presentation and lymphocyte mobilization. These effects increase the risk of bacterial and fungal infections (including those due to Pneumocystis jirovecii, Nocardia spp, and Aspergillus spp) and the risk for pulmonary involvement in the setting of certain herpes virus infections (eg, CMV, varicella zoster virus)
The agents used to suppress T lymphocyte function include the calcineurin inhibitors (eg, cyclosporine, tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (eg, sirolimus, everolimus) used in organ and hematopoietic cell transplantation. These predispose to herpesvirus infections (CMV, herpes simplex, and varicella-zoster) and community-acquired respiratory viruses, fungal infections (including Cryptococcus, Pneumocystis, and Aspergillus spp), and parasites (eg, Strongyloides, Toxoplasma, and Trypanosoma cruzi) CMV infection predisposes to fungal infections including Pneumocystis and Aspergillus
1-Concomitant viral infection pulmonary or systemic viral infection is associated with subsequent pneumonia has been described best for cytomegalovirus (CMV), influenza, and severe acute respiratory syndrome coronavirus 2.
2-Pneumocystis pneumonia (PCP) is most common in patients receiving glucocorticoids as a part of a chemotherapeutic or maintenance regimen
3-Invasive CMV disease in the immunocompromised host with pulmonary infiltrates.
4-The lungs in systemic infections tuberculosis, Nocardia spp, and Cryptococcus spp
5-The lungs can also be a site for hematogenous spread of infection (eg, septic emboli due to Staphylococcus aureus or gram-negative bacteremia). Peripheral pulmonary lesions in the lungs can be a clue that there is important disease elsewhere (eg, line sepsis, hepatosplenic candidiasis, infective endocarditis)
6- Noninfectious etiologies for pulmonary infiltrates are common in immunocompromised patients, including pulmonary embolus, tumor, radiation pneumonitis, cancer, fibrosis, atelectasis with pulmonary edema, drug allergy or toxicity, and pulmonary hemorrhage
7- infection in the community (eg, respiratory viruses, tuberculosis)
the individual (eg, travel history, sexual history, prior infections, occupational exposures)
8-drug-induced lung disease may reflect hypersensitivity to chemotherapeutic agents, sulfonamides, or other agents.
Methotrexate, bleomycin, and procarbazine can cause a syndrome of nonproductive cough, fever, dyspnea, and pleurisy with skin rash and blood eosinophilia. Chest radiographs generally demonstrate diffuse reticular infiltrates.
Cyclophosphamide may cause a syndrome of pulmonary disease with interstitial inflammation and pulmonary fibrosis that occurs subacutely over weeks to months.
9-Transfusion-associated leukoagglutinin reactions (transfusion-related lung injury [TRALI]) are uncommon, but transient pulmonary infiltrates may occur following transfusions.
10-Allograft rejection, chronic lung allograft dysfunction (CLAD), or primary graft dysfunction in lung transplant recipients can also mimic pulmonary infection.
11-Post transplant lymphoproliferative disorders may present with pulmonary nodules or lymphadenopathy.
2-How do you manage this case?
Diagnostic approach — The initial evaluation for immunocompromised patients with fever with or without pulmonary findings, at a minimum, should include:
Rapid assessment of vital signs, including oxygen saturation
Complete blood count with differential
Electrolytes, blood urea nitrogen, and creatinine
Blood cultures (minimum of two sets, with at least one peripheral set and one set from any indwelling catheter)
Urine sediment examination and culture
Sputum for Gram stain, fungal smears, and cultures
Imaging of the lungs (chest radiography or, if possible, chest computed tomographic scanning) and imaging of any symptomatic site (eg, abdomen)
Skin examination, looking for evidence of metastatic infection
CMV quantitative molecular testing is often valuable; other viral polymerase chain reaction (PCR) assays as appropriate to the individual (adenovirus, parvovirus B19, severe acute respiratory syndrome coronavirus 2)
Consideration of sample collection for nonculture-based diagnostic tools (eg, specific molecular and antigen tests such as Aspergillus or Pneumocystis PCR, cryptococcal antigen), Aspergillus galactomannan, beta-1,3,-glucan, whole genome sequencing)
Lung sampling — An invasive diagnostic procedure such as bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsy, percutaneous needle biopsy, video-assisted thorascopic biopsy (VATS)
Nasal washings or swabs (direct fluorescent antibody and viral cultures) may be used for the diagnosis of community-acquired viral infections due to influenza, parainfluenza, adenovirus, metapneumovirus, and respiratory syncytial virus.
Treatment
aminoglycosides, fluoroquinolones, and/or vancomycin) recommended as a standard part of the initial regimen
trimethoprim-sulfamethoxazole (TMP-SMX) as the preferred medication for the treatment of Pneumocystis pneumonia (PCP)
Adjunctive glucocorticoids using adjunctive glucocorticoids in patients without HIV who, while breathing room air, have an arterial blood gas measurement that shows a partial pressure of oxygen <70 mmHg or an alveolar-arterial (A-a) oxygen gradient ≥35 mmHg or hypoxemia on pulse oximetry (eg, room air oxygen saturation <92 percent)
Infection control − Hospitalized patients with PCP should be cared for using standard precautions, although they should not be placed in the same room with other immunocompromised individuals due to the potential for person-to-person spread.
I appreciate your comprehensive approach
4 months post- KT, CMV mismatch D+/ R-, presented with symptoms suggestive for pneumonia ( fever, non-productive cough) with hypoxia 82 % Spo2. CXR showed; diffuse, bilateral, interstitial infiltrates.
Differential diagnosis is the setting of immunocompromised host:
-PJP pneumonia.
-Viral pneumonia; CMV, HSV, Covid .
-Bacterial pneumonia
-Tuberculosis.
– Fungal infection.
-Drug-induced Interstitial pneumonitis.
How do you manage this case?
Further history is needed about the induction therapy, current Is regimen, CMV prophylaxis and PJP prophylaxis, any recent virus load as part of pre-emptive therapy.
Work up required:
–CBC with differential, CRP, pro-calcitonin.
– VBG
– RFT,LFT.
– Blood culture.
– Respiratory culture, and viral panel.
– COVID PCR
– Immunosuppression level Tacrolimus level.
– Viral load; CM PCR, , EBV PCR.
– BAL for microscopy, staining, CMV, PJP and aspergillus
– CT chest.
– LDH
– serum levels of beta-D-glucan.
Management:
– HDU / ICU; Stabilized the patient
– ABC; O2 and respiratory support.
– Patient should be managed empirically till we have the results.
Cover for bacterial pneumonitis:
– generally start broad spectrum antibiotics then guided by culture.
As the patient is high risk for CMV pneumonitis;
-Treatment is mandatory in all cases of tissue invasive CMV disease, irrespective of viral load
-IV gancyclovir IV5 mg/kg BID for 14-21 days followed by oral valganciclovir 900 mg BID ( adjust for eGFR)
-All patients with serious tissue invasive CMV disease should be treated with intravenous GCV
– Monitoring of CMV PCR .
– All treatment should continue for at least 2 weeks after obtaining 2 negative CMV PCR, or until resolution of symptoms and for a minimum of 14 days.
– Switch to second line if there is GCV resistance. if CMV PCR count has not fallen by ≥ 1 log copies/ml after 2 weeks of therapy or if there is no clinical improvement despite treatment.
– Consider CMV immunoglobulin or IVIG in case of pneumonitis (our case).
– Continue on prophylactic dose of Valganciclovir 900 mg OD for 3 months.
Management of IS:
-Stop/reduce (by 50%) azathioprine/MMF/myofortic
-Do not discontinue CNI unless there is evidence of life-threatening infection
-Corticosteroids are generally continued
– Monitoring graft function closely for any rejection.
Cover For PCP;
-TMP/SMX PO for 3 months and consider alternative if patient is allergic.
References:
– CMV in Kidney Transplantation lecture by Prof. Ahmed Halawa
– Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
– UK guideline on prevention and management of CMV in SOT.
Yes, I appreciate that antimetabolites need to be reduced or stopped.
1-What is your differential diagnosis?
Taking in consideration the high risk of infection in the first 3-6 months following transplantation- due to induction immunosuppressive therapy, the clinical presentation and CXR indicates disseminated/bilateral pulmonary infection of the lungs which could be:
-Viral: influenza/COVID-19/CMV/other viruses
-Bacterial- in particular PCP, miliary TB
-Fungal- Asperigellosis
2- How do you manage this case?
Initial step in this clinical scenario is management of hypoxia by oxygen therapy, cs pulmonologist, ICU cs, hemodynamic support.
Basic laboratory studies including renal function test, ABG, blood culture, sputum culture, PCR-CMV, inflammatory markers, liver function test, urine analysis and culture, swab for COVID-10, nasal/throat swab for influenza A and B.
CT chest is very helpful in differentiation the etiology of infection and could be diagnostic in some infections.
Bronchoscopy with BAL for CMV, PCP, Tb, ASPERIGELLUS, is diagnostic however, in the context of severe hypoxia, bronchoscopy cannot be performed.
Empirical treatment should cover both viral and bacterial infection:
IV ganciclovir or oral valganciclovir is the first-line treatment for CMV disease.Immunosuppression doses should be decreased: reduce MMF/MPA by 50%, prednisolone is continued with the same dose and can be increased if hypotension occurs, keep CNI within therapeutic levels, reduce dose if in the upper limit of normal or if level is high.Anti-CMV medication should be continued for two weeks following CMV viremia clearance.In addition to anti-CMV therapy, we should initiate PCP medication while awaiting blood and sputum cultures and PCR results.
TMP/SMX is administered as follows: 20mg/kg/day in 4 doses or (TMP/SMX) 5mg/kg/day in 3 doses plus oral Dapson 100 mg qd.
Subsequent treatment is etiology oriented.
Yes, I appreciate that antimetabolites need to be stopped.
1-What is your differential diagnosis?
-CMV Pneumonitis (most likely)
-Pulmonary Fungal Infection;
(Pneumocystis jirovecii (formerly P. carinii) pneumonia)
(Pulmonary aspergillosis)
-Respiratory viruses;
Respiratory syncytial virus, adenoviruses, and human metapneumovirus
COVID-19 – ARDS
-Idiopathic Pneumonia Syndrome
-Tuberculous pneumonia (M. haemophilum and M. avium complex)
-Drug-induced interstitial pneumonitis( mTOR)
2-How do you manage this case?
-Maintain the O2 above 94% by giving High flow O2 & Request ABG,
-Check Vital signs, to evaluate the need for ICU or high dependency unit.
-Multidisciplinary Teams (Nephrology / ICU / Pulmonology / ID)
–Further Investigations;
CBC (search for leukopenia and thrombocytopenia)
CRP (often normal)
Liver function tests, and Renal function tests.
(CMV PCR) – As the patient is at high risk for CMV.
BAL and send for respiratory panel (Influenza type A,B, Adenovirus ,covid-19 , etc) & BAL staining for PCP.
Full septic screen (including sputum C/S)
-Management;
If proven to be a CMV tissue invasive disease (cmv pneumonitis);
–Consider decreasing the IS; (stop the antiproliferative medication, and decrease the CNI by 50%, with monitoring Graft Functions.
-IV ganciclovir (5 mg/kg every 12 hours) for 2-3 weeks; should be used in place of valganciclovir. (after ID recommendations)
-IV ganciclovir can be transitioned to oral valganciclovir once the patient has demonstrated clear clinical improvement, viral loads are down-trending, and the patient can tolerate/absorb oral medications.
-While treating with either ganciclovir or valganciclovir, we monitor the serum creatinine at regular intervals in case dose adjustment is needed.
-The addition of cytomegalovirus immune globulin (CytoGam) to antiviral therapy might theoretically improve treatment response.
-Monitoring on therapy; Viral load / Renal functions / Blood cell counts.
-Gancyclovir ( intolerant or resistant);
-Resistance to ganciclovir should be considered in recipients who fail to improve clinically and/or virologically after two weeks of adequate doses of antiviral therapy or who have recurrent relapses following treatment.
-Factors that raise the likelihood of ganciclovir resistance include prolonged antiviral use, lack of prior CMV immunity (CMV D+/R-), and inadequate antiviral drug selection or dosing (eg, treatment with oral ganciclovir or subtherapeutic dosing of IV ganciclovir.
-Resistance testing ;Genotypic resistance testing should be performed in patients with suspected ganciclovir resistance (UL97 mutation & UL54 mutations).
-Switching the immunosuppressive regimen to one that includes an mTOR inhibitor (eg, sirolimus, everolimus)
–Foscarnet 60 mg/kg IV every 8 hours (or 90 mg/kg IV every 12 hours), with adjustment for renal dysfunction.
-It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet.
-An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity.
-References;
-UP TO DATE,
-Oxford Specialist Handbooks of Renal Transplantation,
I appreciate your comprehensive approach
What is your differential diagnosis?
How do you manage this case?
required admission in HDU +\- ICU , co-ordination between nephrologist and pulmonologist..
Not considering PCP?
I appreciate your comprehensive approach
This is a patient who has a pneumonia based on the symptoms of cough, fevers and hypoxia four months after transplant
It would be important to get a further history about
Pneumocystis prophylaxis and CMV prophylaxis
The CXR is showing increased bronchopulmonary lung markings and ground glass opacities
The differential diagnosis includes:
PJP pneumonia
Viral pneumonias:
Bacterial pneumonitis
Tuberculosis
Management
The patient will need further work up:
Treatment
I appreciate your comprehensive approach
Dear All
Congratulations. You killed the patient. This is a case of PCP. PCP could present in a similar picture in a CMV+ve/CMV-ve scenario.
Why do I strongly think it is a PCP, or at least PCP should be excluded?
One symptom in the scenario may direct your attention to PCP. What is it?
There is a reward for the correct answer.
Hypoxia is the directed symptoms to PCP
You are right hypoxia and dry cough increase the index of suspicion of PCP in solid organ transplant
The CXR changes are not significantly affected in comparison to the symptoms and desaturation.
Usually bilateral hilar shadowing and lung infiltrate but not typical like the x-ray of this case
Thanks alot Prof.Halawa
It’s usually a complication of a serious existing health condition PCP —-HYPOXIA
(ARDS).
Thank you Prof. Halaw
i totally agree it is high in DDx so i mentioned it clearly and how to manage it
Hypoxemia — The presence or absence of hypoxemia can assist in the differential diagnosis of pulmonary infiltrates in immunocompromised patients. Hypoxemia with an elevation in lactic dehydrogenase or beta-1,3-glucan and minimal radiographic findings are common in Pneumocystis pneumonia (PCP), whereas the absence of hypoxemia with pulmonary consolidation is more common in nocardiosis, tuberculosis, and fungal infections until later in the course.
Combination of both dry cough and dyspnea on minimal exertion raise the index of suspicion of PCP and require further investigation to confirm the diagnosis
You are right but do you think CMV pneumonitis can not cause hypoxaemia?
The bottom line is to expand our thoughts in managing these patients. This case is a high risk of CMV infection/disease because D+/R- but the overall picture should be put in mind including immunological evaluation whether the case received any depleting agents for induction, rejection episodes, biochemical results and microbial diagnosis to reach the correct diagnosis.
non productive cough
Why do I strongly think it is a PCP, or at least PCP should be excluded?
The presence of hypoxia and dry cough in at risk patient (immunocompromised) with CXR showing diffuse, bilateral, interstitial infiltrates is typical for PSC infection
The presence of discrepancy between CXR finding (mild infitrates) and clinical situation (severe hypoxemia) is one of the criteria suggestive of PSCOne symptom in the scenario may direct your attention to PCP. What is it?
Dry cough and fever are common also in CMV pneumonitis, but the presence of hypoxemia is highly suggestive of PSC as it presents as interstitial infiltrates like interstitial lung disease
PCP and CMV pneumonitis can be threatening together
Why do I strongly think it is a PCP, or at least PCP should be excluded?
PCP should be ruled out as the patient is immunocompromised with fever , dry cough and hypoxia with diffuse infiltrate in CXR.
One symptom in the scenario may direct your attention to PCP. What is it?
The presence of hypoxia at rest with chest infiltrate
Hypoxia without chest infiltrates would make one suspect PCP
1-pneumonia plus hypoxia are diagnostic feature of PCP
2- CXR .changed not matching with patient symptoms .
Short and sweet
Why do I strongly think it is a PCP, or at least PCP should be excluded?
In a recently transplanted (4 months back) patient (higher levels of immunosuppression) presenting with fever, non-productive cough and hypoxia (oxygen saturation 82% on room air) and chest x-ray showing diffusely reticulo-nodular shadows, pneumocystis pneumonia (PCP) should be excluded.
Hence PCP should be thought in such a patient.
I agree
may be hypoxia
Thank you , Prof, at least we covered him with PCP treatment while waiting for the results as highlighted in number 5 regarding management of this case
How do you manage this case?Management is MDT; nephrologist, intensivist, pulmonologist, virologist, pharmacist, social worker & counsler. The steps are ;
1.Admission to ICU
2 Stop immune suppression e.g., stop anti-metabolites (MPA or AZA), keep CNI and steroids
3.Oxygen support 15l/min non re-breather mask
4.Broad specturm antibiotics, cover the atypical pneumoinas
5.Increase the dose of co-trimoxazole (CTX) porphylaxis to therapeutic dose until the diagnosis is cleared
6.IV fluids and nutrition
7.IV PPI cover against stress ulcers
8.Confirmation of the diagnosis;
9.Other complimentary tests ; sputum, FBC, UECs (eGFR), LFT, blood sugars, blood cultures, urine cuturea and the inflammatory makers
10.Tacrolimus level
11.Allograft U/S including doppler in case of AKI
12.Anti-viral therapy in case of confirmed CMV:
13.Discuss the risk of acute rejection after reduction of immune suppression
PCP should be excluded because ;
One symptom in the scenario may direct your attention to PCP. What is it?
Note :
I am not sure if ‘umbrella approach’ holds any scientific basis. BAL holds the key.
I appreciate your thought process
Thnx prof
Too short a reply, and with spelling error
Hypoxia, that can gradually progress into respiratory failure along with
it’s association with fever ,dry cough In D+/R- for CMV renders PCP more likely
Yes, I agree
Trouble breathing get worse with activity and dry cough
Why do I strongly think it is a PCP, or at least PCP should be excluded?
One symptom in the scenario may direct your attention to PCP. What is it?
sever hypoxia at presentation
-Pneumocystis pneumonia (PCP;); is a potentially life-threatening infection that occurs in immunocompromised individuals.
-So, it is very important to exclude it in this case.
The clinical manifestations of PCP are most commonly gradual in onset, and are characterized by fever (80 to 100 percent), cough (95 percent), and dyspnea (95 percent) progressing over days to weeks.
-Approximately 5 to 10 percent of patients are asymptomatic.
-The cough is generally nonproductive.
-The average patient has pulmonary symptoms for about 3 weeks before presentation.
-Oxygen desaturation can occur with exercise and is highly suggestive of a diagnosis of PCP.
Chest radiographs–
-Chest x-rays are initially normal in up to one-fourth of patients with PCP.
-The most common radiographic abnormalities are diffuse, bilateral, interstitial, or alveolar infiltrates.
-Upper lobe infiltrates and pneumothoraces can also be seen.
PJP C/P :
► Exercise induced Hypoxaemia, often severe and out of proportion to clinical findings
-Dry cough
-Dyspnea
-Fever—often low grade
-Chest examination often normal. Crepitations may be present on auscultation, but clinical features of consolidation are unusual
Yes, I agree
Hypoxia is the directed sign of PCP in immuncompromised patient .
Hypoxia specially with mild activity.
Dry cough
Hypoxia
non-productive cough
hypoxia and dry cough in immunocompromised patient
One symptom in the scenario may direct your attention to PCP.
What is it? Hypoxia
– PCP patients present with severe hypoxia, cough and dyspnoea without major physical findings.
– Chest radiographs are significant for diffuse bilateral perihilar interstitial opacities.
– HRCT has a high sensitivity and specificity for the diagnosis of PCP.
– The hallmark findings on CT include perihilar ground glass opacities. (1)
References
1. Roux A, Gonzalez F, Roux M, Mehrad M, Menotti J, Zahar JR, et al. Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Medecine et maladies infectieuses. 2014 May;44(5):185-98. PubMed PMID: 24630595. Epub 2014/03/19. eng.
Hypoxemia
Symptoms directing towards PCP:
Dry cough and Oxygen saturation on air was reported at 82%.
Other symptoms are:
► Exercise induced Hypoxaemia, often severe and out of proportion to clinical findings
-Dry cough
-Dyspnea
-Fever—often low grade
-Chest examination often normal. Crepitations may be present on auscultation, but clinical features of consolidation are unusual
NON-Productive cough
dry cough , hypoxia
· What is your differential diagnosis?
Symmetrical infiltration is the chest radiographic
· How do you manage this case?
CBC.
RFT.
Sputum smear for AFB, CBNAAT, and COVID-19 RTPCR.
CT chest.
Flexible bronchoscopy:
Bronchial washings:
For Gram stain, bacterial culture, AFB smear, CBNAAT, AFB culture, fungal smear,
fungal Culture, cytology, Galactomannan assay, Nocardia stain, Pneumocystis
jirovecii stain, And Cytomegalovirus (CMV) quantitative PCR.
Plasma CMV quantitative PCR.
Treatment:
Oxygen.
Admission.
Immunosuppressive drugs reduction.
IV ganciclovir.
References:
1-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS
(CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN
TRANSPLANTATION. July 2022.
I appreciate your comprehensive approach
History
==================================================================
====================================================================
What is your differential diagnosis?
Other CMV pnemonic changes which preferred seen by High resolution CT include:-
D.D: Is broad but in the immunocompromised patients consider:-
D.D of this chest xray include:
====================================================================
How do you manage this case?
1- General health of the patient’s condition stabilizing(improve O2 by high flowoO2 and administer an antipyretic ).
2- Consultation with Plumologist and if need too with ICU team.
3- CMV pneumonitis can be accurately diagnosed by quantitative PCR performed in the plasma combined with a lung specimen (biopsy/bronchial wash/bronchoalveolar lavage).
Investigation :-
Treatment
Ganciclovir Resistance
1-Exclude other causes of symptoms
Switch to second line
2- Foscarnet (nephrotoxic; it can result in metabolic changes as well as cardiac arrhythmias and genital ulcerations).
3- Cidovir (nephrotoxic and causes neutropenia, metabolic acidosis and ocular hypotony).
4- Letermovir is a newly approved anti-CMV antiviral which inhibits the viral terminase complex.
5- It interacts with immunosuppression, requires dose adjustment in renal and hepatic impairment and can be used with other anti-CMV medications.
6- Maribavir is a promising new antiviral against the viral UL97 kinase.
7- Co-administration of with GCV is not advised as Maribavir is an inhibitor of the UL97 enzyme required for anabolism of the latter.
Prophylaxis
====================================================================
Reference
1- Cunha BA Cytomegalovirus pneumonia:Community-acquired pneumonia in immunocompetent hosts Infect Dis Clin North Am 2010 24 147 58
2- The immune response to human CMV. Corinna La Rosa and Don J Diamond* Future Virol. 2012 Mar 1; 7(3): 279–293.doi: 10.2217/fvl.12.8
3- Cytomegalovirus Infection in Kidney Transplant patientsSiddiqu, Wasim A1; Al Salmi, Issa1; Jha, Amitabh1; Pakkyara, Abbas1; Yasir, Mohammad1; Shaheen, Faisal A2
4- Radtke J, Dietze N, Spetzler VN, et al. Fewer cytomegalovirus complications after kidney transplantation by de novo use of mTOR inhibitors in comparison to mycophenolic acid. Transpl Infect Dis. 2016;18:79–88.
5- Paya C et al. Am J Transplant 2004; 4:611-620
6- Limaye et al. Transplantation 2004 78(9):139
7- Humar et al. Am J Transplant 2010; 10: 1228-1237
8- UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
Yes, I appreciate that antimetabolites need to be reduced or stopped.
A kidney biopsy shows interstitial infalamation with owel’s eye appearance, the golerulus shows mesangial hypercellularity and a thickened GBM.
What is your differential diagnosis?
CMV disease – owl’s eye
The risk factors in our case are old age of the recipient, received ATG after evident ACR.
Cellular rejection
Diabetic nephropathy
Light chain disease
How do you manage this case?
Investigations:
CBC, Kidney function test (BUN, creat, Na, K, Cl), Liver function test, LDH, serum calcium, total protein and albumin, urinalysis, CRP, ESR, RF.
Serology and viral PCR
Treatment:
Reduce immunosuppressive medications: MMF by 50%, keep lower therapeutic CNI level, continue on steroid, with careful follow up of kidney function.
Anti CMV viral therapy iv ganciclovir till the viral load undetectable then oral valgancyclovir for at least 6 months with continued monitoring of viral load.
IVIG/MCVIG is a good option to treat CMV, and may reduce the inflammation.
The use of m-TOR inhibitor might be of value.
The pathologist queried grade 1 ACR. Would your management differ?
No, as the patient is known to had steroid resistant ACR, and had received ATG lastly. I would not give him another shot of ATG.
However; the prognosis is poor with this old age recipient, and impaired graft function.
What is the association between this condition and ACR?
It was thought that patients with CMV experience more ACR episodes, but lately this was eliminated by a systemic analysis of the CMV associated ACR, that showed slight non-significant increased ACR with CMV infection either by protocol biopsy or indicated biopsies.
The etiology of CMV induced rejection are:
– Production of interferon-ϒ during the inflammatory process increases the expression of major histocompatibility (MHC) class I and II molecules on both vascular endothelial and tubular epithelial cells.
– CMV may express molecules similar to MHC class I and II antigens priming the immune response against the allograft.
– the alloantigen independent pathway of rejection by increasing co[1]stimulatory molecules on APCs, vascular endothelial cells, tubular epithelial cells and T-lymphocytes.
– Elevated anti- endothelial cell antibodies have been reported in a small group of renal and cardiac allograft recipients coincident with CMV infection. This may indicate an increased risk of humoral response.
References:
(1) CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023.
(2) Erdbruegger U, Scheffner I, Mengel M, Schwarz A, Verhagen W, Haller H, Gwinner W. Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant. 2012 Jan;27(1):435-43. doi: 10.1093/ndt/gfr306. Epub 2011 Jun 28. PMID: 21712490.
Sorry, this is the answer of case scenario 4
Well done for your decisions ,but if you have doubts for paraproteinemia the you should ask for protein electrophoresis as well.
Thank you Prof. Dawlat
Differntial diagnosis
A- Infection
1- Viral pneumonitis
– CMV pneumonitis
– HSV pnemonitis
– RSV
– Covid-19
2- Fungal pneumonitis : Pneumocystitis jirivi
3- Bacterial pnoumonia
B-ARDS
C-Diffuse alveolar hge
d- Drug induced pnoumonitis .
Management :
1- Further invstigations :
2- CBC : leucopenia , thrombocytopenia supporting the diagnosis of CMV pneumonitis .
3- Sputum culture and sensitivity. BAL for CMV PCR
4- CMV PCR in sputum and blood.
5- High resolution CT chest
6- Monitoring of graft function for detection of early graft rejection .
7- ICU admition , IV fluid , fluid balance , broad spectrum antibiotics
8- Decrease the dose of IS drugs and stop antiproliferative drugs as MMF
9- Its mostly a case of CMV pneumonitis ( as CXR show diffuse ground glass opacities and CMV R-D+ status).Start treatment with IV gancyclovir 5 mg /kg bdIV for14-21 days followed by oral valgancyclovir with monitoring of CMV PCR . Treatment should continue for at least 2 weeks after obtaining 2 negative CMV PCR results.
-For Pneumocystitis jerovi with TMPSMX 80/400 PO for 3 months.
Ref
1- CMV in kidney transplantation . prof. Ahmed Halawa.
Thankyou
What is your differential diagnosis?
Early post cadaveric renal transplant, with cough for the last 4 months , and O2 desaturation 82% on RA.
Description of the CXR: diffuse alveolar infiltrates. Early post cadaveric renal transplant.
Given that the donor was IgG + ve and the recipient IgG –ve for CMV with high chance of transmission top on the list would be MCV pneumonitis/ pneumonia.
Other differential diagnosis:
Pneumocystis carinii pneumonia (PCP).
Miliary Tuberculosis.
Viral Pneumonitis – Corona viruses, HZV,
Fungal infections- Aspergillus, Cryptococcus, Histoplasma capsulatum, and Coccidioides
Nocardia spp.
Malignancy – lymphoma, PTLD.
Pulmonary edema.
How do you manage this case?
First, rescue his oxygen saturation, antipyretic, hydration, bronchodilators.
Investigations:
Laboratory:
CBC, Kidney function test (BUN, creat, Na, K, Cl), Liver function test, LDH, serum calcium, total protein and albumin, urinalysis, CRP, ESR, RF.
Sputum culture and AFB, and blood cultures,
Arterial blood gases.
Imaging: CT chest abdomen and pelvis.
Pulmonary consultation– bronchoscopy for Broncho-alveolar lavage analysis gram stain and culture and biopsy.
Skin and CNS sampling skin lesions or cerebrospinal fluid (CSF) may demonstrate Cryptococcus spp or mycobacterial infection before microbiologic data from sputum or lung biopsy specimens are available.
viral load and monitoring
Treatment:
(1) Decrease immunosuppressive medications if hemodynamically stable- decrease MMF by 50-75% of the dose, keep the CNI at lower therapeutic level required, and stress dose steroid. If hemodynamically unstable I would stop MMF.
(2) Antibiotics: IV anti staph –vancomycin + wide spectrum covereage Piperacillin-tazobactams, or carbamenems and anti viral therapy (corona virus).
It is proposed that the patient would be on CMV and PCP prophylaxis at this time as in our center the patient continued on CMV prophylaxis in this high risk (D+/R-) CMV for 6 months, and PCP prophylaxis for 6 months.
If it is CMV then I would consider IV ganciclovir for 10-14 days then shift to oral with frequent monitoring of the viral load, if continued to be detectable >/= 1 log copies, or no clinical improvement,then ganciclovir resistant species is considered for this therapeutic measures would be:
– Foscarnet , Cidovir, Letermovir, or Maribavir.
– CMV IG – particularly in this case (pneumonitis).
– Request genotypic resistance.
– Adoptive immunotherapy.
If it is PCP Cotrimethixazole (TMP-SMX)20mg/kg/day in 4 divided doses, or (TMP-SMX) 5mg/kg/day in 3 divided doses + oral Dapson 100 mg qd.
If allergic to TMP-SMX : Primaquine: 30 mg (base) orally once per day+ Clindamycin: 900 mg IV every eight hours, or Atovaquone 750 mg orally twice daily (must be taken with food), or Pentamidine 4 mg/kg IV once daily.
All with oral prednisolone 40 mg x2 for 5 days followed by 40 mg x1 for 5 days then 20 mg x1 for 11 days then tapper down.
If miliary TB isoniazide, rifampin, pyrazinamide, and ethambutol for two months then isoniazid and rifampin for 4 months (total 6 months).
Or Rifapentine-moxifloxacin four-month regimen.
If PTLD Stop one of the immunosuppressive medications used MMF, CNI and reduce the other, or switching to m-TOR inhibitor.
Based on the biopsy histopathology result and extent of involvement – to be discussed with hemato-oncologist.
Rituximab could be the only treatment required.
Radiotherapy is another treatment option.
R-CHOP/ABVD can be a treatment option base on the pathology result.
Adoptive immunotherapy may be usefull but might increase the risk of rejection.
However; PTLD’s carry a poor prognosis with 50% mortality.
References:
(1) UpToDate- Approach to the immunocompromised patient with fever and pulmonary infiltrates.
(2) Shah N, Eyre TA, Tucker D, Kassam S, Parmar J, Featherstone C, Andrews P, Asgari E, Chaganti S, Menne TF, Fox CP, Pettit S, Suddle A, Bowles KM; Haemato-Oncology Task Force of the British Society for Haematology and the British Transplantation Society. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol. 2021 May;193(4):727-740. doi: 10.1111/bjh.17421. Epub 2021 Apr 20. PMID: 33877688.
(3) UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION.
Well done.
Thank you Prof. Dawlat
What is your differential diagnosis?
How do you manage this case?
Therapy??
For CMV, IV ganciclovir or Foscarnet.
For PJP, Pentamidine or Dapsone.
For Aspergellosis, IV liposomal Amphotericin.
DEAR All
Do not assume one diagnosis, but put treatment plans for the most likely diagnoses.
In a patient with a kidney transplant who has had a seropositive donor for 4 months, a CXR reveals bilateral large lung infiltrates.
The differentials are;
Viral infections.( CMV,HSV,VZV, EBV) covid-19
Bacterial infections, T.B, Nocardia
Fungal infections and opportunistic infections; Listeria, Aspergillus, Pneumocystis jiroveci
How to manage the case;
As this patient is very high risk D+/R- he was supposed to be CMV prophylaxis .
He needs to be investigated for ganciclolvir resistant.
Investigations are including;
CBC, CRP, CMV PCR, BAL, Blood culture, T.B DOT. ABGs. And testing for COVID-19 also renal function
CT chest,
TREATMENT
Reduction of immunosuppresion by decreasing the dose of CNI and stopping the anti metabolite but this method apply case to case and patient and his family should be aware of graft detoriation.
Anti-viral therapy ganciclovir 5mg/kg
CMV viral loads weekly or biweekly while on therapy, minimum duration of therapy is two weeks
Follow up investigation CBC for neutropenia, RFT for graft function.
Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:93.
Lecture of pro. Ahmed Halawa
For how long will you use Valgancyclovir after the improvement phase.?
200 days
An further course of suppressive therapy, consisting of valganciclovir 900 mg once daily, may be continued for an additional 1 to 3 months, or longer if necessary, following the successful suppression of viral replication.
Renal insufficiency calls for dose modifications.
What is your differential diagnosis?
Chest x-ray showing bilateral multiple small nodules scattered in the lung fields with pulmonary infiltrates with free costophrenic angles. With these symptoms, high risk of CMV infection (D+/R-) and radiological signs, I will put CMV pneumonitis (tissue invasive) in the top of differential diagnoses
*CMV is the most frequent organism infecting the SOT
*CMV pneumonitis commonly manifests as diffuse interstitial infiltrates, but focal and even nodular infiltrates are described in up to one-third of patients
*CMV may cause severe pneumonia with ARDS requiring ICU admission
*The main risk factor is primary infection
Other differential diagnoses: opportunistic infections
1. Pneumocystis jiroveci pneumonia (PCP)
2. Pulmonary tuberculosis (military)
3. Other viral infections (VZV)
4. Fungal infections (Candida species, Cryptococcus)
5. malignancy
How do you manage this case?
*MD approach and a pulmonologist involvement
*Full history and examinations
*Lab: CBC, RFT and electrolytes, LFT, RBS, urine analysis, ESR, CRP, blood culture, and ABG
*Imaging: HRCT chest
*CMV viral load (a negative plasma or whole-blood does not exclude tissue-invasive disease)
*Induced sputum or bronchoscopy for BAL for inclusion bodies, and CMV viral load and culture (demonstrate organism in lung tissue). Stain for AFP and PCP
ICU admission and O2 therapy
Treatment:
Immunosuppressions:
*Reduce (by 50%) or stop azathioprine/MMF/myofortic (discontinue CNI only if there is evidence of life-threatening infection). Continue steroids
*Monitor graft function closely and discuss the risk of acute rejection with the patient
*Review the dosing of immunosuppression following resolution of CMV disease
Antiviral:
*Treatment is mandatory regardless to viral load if confirmed to be CMV-tissue invasive pneumonitis
*Give intravenous GCV (bioavailability, 5mg/kg bd) for a minimum of of 14 days and for 2 weeks and continue until resolution of symptoms and two tests of CMV DNA by PCR are negative. Do viral load first after 2 weeks and then weekly. Reduce the dose in renal impairment
*Do CBC twice weekly (neutropenia)
*CMV immunoglobulins
1. *Be aware of ganciclovir resistance if there is no clinical improvement despite treatment or CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks. If confirmed, stop ganciclovir and give Intravenous Foscarnet for at least 3 weeks after virology advice (newer agents Letermovir and Maribavir may be an alternative)
Reference
1. Patricia Muñoz et al. Fever in Organ Transplant Recipients. Antimicrobe.
2. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
3. Basinger J, Kapp ME. Cytomegalovirus pneumonia as pulmonary nodules. Autops Case Rep. 2022
4. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
Thankyou for mentioning Gancyclovir resistance ,definition and treatment.
1- CXR showing bilateral massive lung infiltrate suspected CMV disease in renal transplanted patient since 4 months from seropositive donor.
can be differentiated from other viral infections as well as fungal infection or bacterial infection …it is pneumonitis
2-management:
references: lecture of prof. Ahmed Halawa
For how long do you continue oral antiviral in this case,is the IV gancyclovir enough.?
oral can be initiated after finishing iv ganciclovir for 2 weeks , and can be continued until symptoms disappeared and CXR become clean and CMV cleared from blood
-What is your differential diagnosis?
This a post-transplant patient 4 months now with suspected suspected lung infection based on the physical findings and the CXR (bilateral pulmonary infiltrates). He was CMV negative and the donor was positive which put him at high risk for CMV infection and disease. CMV pneumonitis is a serious disease with high mortality. This situation could have been avoided by the use of CMV prophylaxis in this high risk patient. It is important to keep in mind the time line after transplantation for better formulation of the differential diagnosis. This man now in his 4th months and the differential diagnosis from after one months to 6 months are:
-How do you manage this case?
Management is MDT; nephrologist, intensivist, pulmonologist, virologist, pharmacist, social worker & counsler. The steps are ;
1.Admission to ICU
2 Stop immune suppression e.g., stop anti-metabolites (MPA or AZA), keep CNI and steroids
3.Oxygen support 15l/min non re-breather mask
4.Broad specturm antibiotics, cover the atypical pneumoinas
5.Increase the dose of co-trimoxazole (CTX) porphylaxis to therapeutic dose until the diagnosis is clearfied
6.IV fluids and nutrition
7.IV PPI cover against stress ulcers
8.Confirmation of the diagnosis;
9.Other complimentary tests ; sputum, FBC, UECs (eGFR), LFT, blood sugars, blood cultures, urine cuturea and the inflammatory makers
10.Tacrolimus level
11.Allograft U/S including doppler in case of AKI
12.Anti-viral therapy in case of confirmed CMV:
13.Discuss the risk of acute rejection after reduction of immune suppression
14.Review immune-suppression after resolution of CMV
Source;
Thankyou for mentioning the role of PROPHYLAXIS in this case R-,D+.
Or ATG induction
Yes, prof
Most welcome
1-CMV pneumonitis
2-Bacterial pneumonia
3-Pneumocystis Pneumonia (PCP, or Pneumocystis Jirovecii) PJP).
4-Fungal pneumonia
5-Pulmonary Tuberculosis.
To confirm the diagnosis, we need to take details history of presenting illness, its duration and any contact with sick person recently.
Detailed history of immunosuppression, induction, prophylactic medications specifically for CMV and PCP. Weather he is still on prophylaxis or stopped( many centers give prophylactic valgancicolovir for 6months for high risk patients like this case) which will make CMV pneumonia less likely.
Any previous infection, or rejection.
Donor history, any diagnosed infection, like TB.
Routine investigations, CBC,Renal and liver panel. Septic workup, including blood culture, sputum, urine, and broncho alveolar lavage (BAL), specially if no sputum or patient is intubated, if possible and to send it for CMV, PCP, culture and TB
Serum CMV PCR ( but can be negative in almost 50% of cases).
If confirmed CMV pneumonia, management includes:
Reduction of immunosuppression, starting anti metabolite, then CNI if no improvement.
Anti viral treatment with IV ganciclovir 5mg/kg bid, then oral 900mg bid, when tolerated adjusted for renal function. For 3-4 weeks, till negative CMV result for 2consequative weeks, then prophylactic dose 2-3 months.
Involvement of Infectious disease, pulmonology and ICU consultant.
If other bacterial, fungal or PCP to be treated accordingly with the help of ID consultant interested in transplantation.
Gradually resuming his immunosuppression to their pre-morbid levels (after improvement). Some experts may keep anti metabolite on a lower level specially if no history of rejection and standard immunological risk.
References;
1-A retrospective study of cytomegalovirus pneumonia in renal transplant patients
BIAO DONG,* YUANTAO WANG,* GANG WANG, WEIGANG WANG, HONGLAN ZHOU, and YAOWEN FU Exp Ther Med. 2014 May; 7(5): 1111–1115.
Thankyou
It could be:
· CMV pneumonitis
· Miliary TB
· Pneumocystis carinii
Other tests required:
· CMV PCR
· Sputum culture
· AFB smear and culture
· Respiratory viral screening
· Might need bronchoalveolar lavage if all negative
Rx:
Based on laboratory findings, the cause can be identified and treatment can be initiated.
What is your differential diagnosis?
How do you manage this case?
Diagnosis
In case of CMV pneumonitis
Treatment in case of CMV pneumonitis
Together with circulatory support and ventilator support ranging from nasal O2 up to mechanical ventilation, 3 main lines of treatment available for treatment of CMV infection and disease
A- Reduction of immunosuppression
B- Antiviral therapy
Indications of antiviral therapy includes :
So in the current case just detectable CMV either in blood or in BAL is an indication for treatment
Medications used for treatment of CMV infection
1- Oral valgancyclovir
2- IV gancyclovir
3- CMV immunoglobulin or IVIG
When to stop treatment (3 prerequisites required)
C- Prevention of recurrence
So … in the current patient
References
1- Uptodate
Thankyou ,exellent.
What is your differential diagnosis?
Pneumocystosis, miliary-type pulmonary tuberculosis, invasive fungal disease, respiratory viral diseases (COVID-19, Influenza), bacterial pneumonia (including atypical agents).
However, the patient is at high risk for developing CMV pneumonitis due to the epidemiological context, there is no description of prophylaxis or preemptive treatment in this case.
How do you manage this case?
Admission to intensive care for monitoring and adequate respiratory support.
Respiratory isolation in negative pressure (risk of tuberculosis, COVID-19, and Influenza).
Non-invasive methods for diagnosis (urinary antigen for Histoplasmosis, IGRAs for Tuberculosis, PCR detection for CMV, Influenza, COVID-19). Request laboratory routine, arterial blood gases, and procalcitonin.
Consider diagnostic bronchoscopy (depending on clinical conditions) for lavage viral load count, AFB, Ziehl Neelsen, PCP for PCP, galactomannan, biopsy, and immunohistochemistry.
Decrease immunosuppression.
Start Ganciclovir 5mg/kg/dose every twelve hours (depending on renal function) due to high-risk CMV epidemiological link (Positive donor/Negative recipient). Evaluate enriched immunoglobulin for CMV in this case.
Due to the high risk of tuberculosis in Brazil, evaluate the household epidemiological issue and the history of relatives or people living with the patient who may be undergoing treatment.
Look for findings compatible with the established disease (cytopenia, malaise, jaundice, changes in liver enzymes, etc.).
Well done but how are you going to manage after thh IV gancylovir?
Here in Brazil, we do not have Valganciclovir, so for these patients with high-risk we start venous, and after we change to oral Ganciclovir.
Differential diagnosis
Most likely diagnosis is CMV pneumonitis.
Others: PCP
Military TB
ARDS after pneumonitis
Covid 19 pneumonia
Management
Admit in ICU and start on oxygen to maintain saturation above 94%.
Blood works: Complete blood count looking for anaemia, neutropenia and thrombocytopenia
Renal function test for renal dosing of the drugs
Liver function test
Covid 19 PCR
CRP, PCT
BAL for gram staining and culture
CMV PCR in blood/plasma
CXR is suggestive of CMV pneumonitis but not diagnostic requires a BAL histology looking for inclusion bodies.
Reduce by 50% or withdraw the antimetabolites(MMF/AZA)
Maintain the CNI and steroids.
Initiate IV ganciclovir 5mg/kg renal dose can switch to per oral valaganciclovir when clinically possible. Treat for at least 2 weeks.
Monitor CMV DNA every week until not detectable or resolution of symptoms.
Well done.
What is your differential diagnosis ?
A 65-year man, with cadaveric transplantation, CMV D +/R _ , having fever (38 °C) and non-productive cough with oxygen saturation on air to be 82%, and bilateral infiltrates on XRAY chest. Likely possibility in the above case will be CMV pneumonia, however, other differentials which can be considered include: PCP ,other viral pneumonias like( COVID-19,Influenza),fungal infection, bacterial pneumonia ,drug induced interstitial pneumonias or Miliary tuberculosis.
How do you manage this case?
Admission in ITC –Applying oxygen to keep O2 above 94% .Detailed history and examination followed by thorough evaluation to find the cause :Complete blood picture( leukopenia , lymphopenia and thrombocytopenia in viral pneumonia)ESR,CRP , pro-calcitonin level,Blood Culture and Sputum for Gram stain ,AFB, Genexpert and culture and DIC profile including D-Dimers and fibrinogen.ABGs to check for type II Resp.Failure and hypoxia. HRCT Chest to see the extent of involvement .Other specific tests include :PCR for CMV in blood, Sputum for PCP, COVID-19, EBV and HIV,b-galactomannan. BAL if there is no sputum production or above sputum test inconclusive and should be sent for PCP(methamine silver staining ),PCR for CMV DNA.
First thing in the management will be to reduction in immunosuppressant especially anti-metabolite –MMF or azathioprine that is to be reduced or sometimes stopped, while CNIs to be halved .However, steroids can be increased r continued at the same dose. Then specific treatment is according to the cause. As in the above case likely diagnosis is CMV pneumonia so IV Ganciclovir in a dose of 5 mg/kg per day for minimum 02 weeks or until two consecutive viral loads are undetectable. Patient can be switched to oral valganciclovir once the patient start tolerating oral intake. Sometimes Cytogam (CMV Immunoglobulin)may be needed if no response.Frequent monitoring of drug levels to detect rejection early and weekly levels of PCR for CMV DNA needed . In resistant cases, other antivirals like Cidofvir or foscarnet may be needed.
REFERENCES:
1-Professor Ahmed Halawa Lecture.
2-Requião-Moura LR, deMatos AC, Pacheco-Silva A. Cytomegalovirus infection in renal transplantation: clinical aspects, management and the perspectives. Einstein (Sao Paulo). 2015 Jan-Mar;13(1):142-8.
Well done
Thank You
You mentioned sputum for PCP. How would you do it? What is the treatment if proven to be PCP?
sputum induction with hypertonic saline and treatment for PCP is TMP-SMX (15-20MG/KG IN 3-4 divided doses.Other alternatives include TMP plus dapsone,inhaled pentamidine ,Atovaquone suspension.
Steroids if hypoxemia PaO2 <60mmHg or R.R >25/min
Differential Diagnosis
The diagnosis be considered based on the following o
CMV disease
Other differentials
Management
Investigations
Treatment
This is a tissue invasion, hence treatment is needed and a consultation will be sent to the pulmonologist for joint care
References
Thank You
You mentioned sputum for PJP. How would you exclude PCP (PJP)? What is the treatment if proven to be PCP?
Thank you prof Halawa for the response.
A negative sputum test for beta – D- Glucan (BDG) will rule out PJP
Treatment if PJP
A 65-year-old man was admitted with a fever (38 °C) and non-productive cough 4 months after cadaveric transplantation. CMV positive to CMV negative recipient Oxygen saturation on air was reported at 82%.
CXR: shown mixed alveolar-interstitial infiltrative opacification(ground-glass appearance).
What is your differential diagnosis?
CMV pneumonitis /ARDS.
Pneumocystis jirovecii pneumonia.
Other viral pneumonitis.
How do you manage this case?
To send basic investigations (CBC, CRP, RFT, LFT, Blood C/S).
To check immunosuppression level such as tacrolimus level .
To send Respiratory viral panel.
To send CMV PCR.
Imaging :
CT chest is important.
Broncho alveolar lavage (BAL) result that is CMV positive is a common method for diagnosis which shown Owle eyes CMV inclusion bodies.
If CMV pneumonitis(tissue invasive CMV) is confirmed, we should start our treatment irrespective to CMV viral load :
1-ABC support.
2-Respiratory clinician should be involved.
3-Stop anti-proliferative medications and stop CNI if condition worsening.
4-We should start IV GCV till critical status pass after that continue oral GCV for 14 days, till complete resolution of clinical manifestation and CMV DNA not more be detected.
5-PJP should follow the general rule of RI with sulphamethoxazole.
References:-
1- Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients, Up To Date 2023.
2- CMV in Kidney Transplantation Lecture By: professor Ahmed Halawa.
How long do you use the oral regimen after the 3 weeks?
which oral antiviral?
We are starting Ganciclovir IV (Cymeven in hospitalized cases and after improving, the role of oral Valganciclovir (Valcyet ) started.
ARDS post Pneumonitis
Infection ( CMV, COVID-19, Bacterial infection, Pnumocystic carini , TB)
Drug induced pneumonitis
History and examination for vital state to role out septic shock
CBC for evidence of leukopenia and lymphpenia, ESR, PLT count, CRP, pro calcitonin level , serum lactate and ABG, INR and fibrinogen level, Renal function and PBF and blood cultures.
Serology for CMV IgM, IgG and DNA PCR, test for COVID-19, EBV and HIV, HCV and HsAg
CT chest and high resolution CT for chest, Pulmonary function test
Maintain airways and circulation, good IVF and input/ output chart
serial drug level and DSA level
Reduce immunosuppressive therapy to 50% and shift steroid to Dexamethasone
Consider antiviral therapy and antibiotics
Also Liver function test and consider immunoglobulin therapy
??? specific antivirals.
Intravenous ganciclovir
1- CMV pneumonitis
2- miliary TB
3- PCj pneumonitis
4- Covid 19 infection(pneumonia )
5- a fungal, viral, or bacterial infection
6- Drug-induced interstitial pneumonitis( mTOR)
1- maintain the O2 above 94% by giving High flow O2.
2- Do an ABG to check the degree of respiratory acidosis.
3- check the vital signs, to evaluate the need for ICU or high dependency unit
4- consultations for the ID and chest teams
5-full CBC (search for leukopenia and thrombocytopenia, which support the diagnosis of CMV disease), CRP (often normal), liver function tests, and renal function tests.
6- As the patient is at high risk for CMV, send an urgent CMV PCR that, if negative, does not exclude tissue-invasive CMV.
7- BAL and send for respiratory panel(Influenza type A,B, HHV, Adenovirus,etc)
Management:
If proven to be a CMV tissue invasive disease:
Oxford Specialist Handbooks of Renal Transplantation
Exellent why not after control of the viremia shift to Valgancyclovir .
Foscarnet has documented side effects.
I agree to shift to valganciclovir after controlling viremia.
bilateral involvement of both lungs in this pattern in a kidney transplant patient with immunosuppression would pertain the following differential diagnosis:
1] bacterial broncho pneumonia.
2]CMV pneumonia.
3] PCJ pneumonia
4]Malignant infiltration.
5]Tuberculous pneumonia
6] pulmonary hemorrhage .
7] respiratory distress syndrome.
8]Vasculitis process.
9]pulmonary thromboembolism.
presence is fever and desaturation are not specific for any diagnosis.
How to approach:
First of all, the patient has to be admitted to intensive care unit as he is featuring O2 desaturation. Full blood gas analysis has to be performed to highlight respiratory failure type.
Complete blood count, CRP and pro-calcitonin. blood culture
Sputum for gram stain, Culture and sensitivity. sputum for AFB.
sputum for PCR for CMV and PCJ and TB.
Blood for PCR for CMV , PCJ and TB.
blood for PP65 which is specific for CMV infection.
immunological tests for cANCA, pANCA, ABM antibodies. ANA, Complement C3, C4
Doppler of lower limbs veins and CT angiography and CT thorax.
Treatment of CMV pneumonia:
Ganciclovir intravenous. is the treatment of choice.
5 mg/kg per day for 2-3 weeks.
follow up of PCR for CMV DNA .
Immunosuppressants:
During acute infection, Mycophenolate has to be stopped temporarily, CNi halved and continue with same or even larger doses of corticosteroid.
References:
1]Luiz Sergio Azevedo et al.Cytomegalovirus infection in transplant recipients.Clinics (Sao Paulo). 2015 Jul; 70(7): 515–523.
Well done.
· What is your differential diagnosis?
Pneumonia/ bacterial or viral
Bacterial including TB
Viral including CMV
Pneumonitis
Secondary metastasis from other primary site malignancies
· How do you manage this case?
· Maintain him on oxygen and if requires intubation.
· Confirm the diagnosis by sputum culture, Bronchoalveolar lavage
· Reduction of immunosuppression
· Stopping MMF
· Reducing tacrolimus/cyclosporin
· If life threatening all immunosuppressant should be stopped.
Initiation of antiviral therapy
1. Intravenous ganciclovir
2. Very high doses of intravenous hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with ganciclovir for the treatment of pneumonitis
check PCR of CMV DNA it helps in identifying the degree of viraemia and may help to decide the duration of treatment. CMV viral load after to be checked 2 weeks of treatment and repeat at a minimum interval of 7 days
In practice the duration of therapy is decided by:
· The clinical response.
· PCR measurements, at least two weeks full dose treatment is recommended, with a longer duration of treatment if there is not a prompt fall in viral load.
relapse is common in approximately 1/3rd of patients after treatment with ganciclovir .
hence Secondary prophylaxis after treatment of disease is usual practice. but deciding the duration of treatment is controversial some prescribe it for 1 month others for 3 months. there are no randomized trials to inform this strategy.
References:
KDIGO guidlines
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION 2020
Well done but:
metastasis has a .very diff XRA picture.
Differential diagnosis
1) CMV pneumonitis
2) Pneumocystis carinii pneumonia
3) Miliary tuberculosis
4) Bacterial pneumoniae
How do you manage this case?
1) Oksigen supplementation and support the airways
2) Immunosuppression reduction- withholding mycophenolate, lower target tacrolimus
3) Blood culture, sputum culture, sputum for PCP and sputum for AFB
4) To start this patient on IVI Ganciclovir (as evidence of tissue invasive disease)
Thankyou but:
PCJ can show a reletavely clear CXR with severe hypoxia.
BAL will be helpfull.