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3. A 39-year-old CKD 5 secondary to HIV associated nephropathy had a deceased donor kidney transplantation. CD4 count is 250/ml and receiving HAART. Currently she is on Tacrolimus-based triple immunosuppression. Her kidney function has improved and started to pass more urine. She presented with 2 weeks history of non-productive cough, low grade temperature (37.5 °C). She has dyspnoea on excretion (respiratory rate at rest is 20/min) but chest X-Ray reported normal. Clinically there were few physical findings only few scattered wheezes. Sat 100% on air and desaturates to 95% on exertion.
- What is the differential diagnosis?
- How do you manage this case?
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m-tor induced interstitial pneumonitis
-history of using Mtor and clinical features improve after discontinuing the drug
Aspergillosis:
Differential diagnosis includes:
-PCP infection
-viral pneumonia
-bacterial Pneumonia
-TB pneumonia
Management includes:
-labs including : CBC with differential ,CRP with titer , sputum bio fire , culture and sensitivity,CMV PCR quantitative analysis
– CT chest .
Treatment of the cause as given , reduction of MMF as a start and follow up accordingly.
Differential diagnosis of a known case of HIV renal transplant on HAART therapy with dry cough, low grade fever, with heavy immunosuppression is PCP.
Other differential diagnoses include CMV pneumonia, ARDS, bacterial infections, fungal infections, other viral infections as influenza, SARS COV 19 viral infections, and military TB.
Management of this case is searching for viral serology by PCR technique, Bronchoalveolar lavage for PCP or TB, tissue biopsy for detection of microbial related cytopathic changes.
Broad spectrum antibiotics (avoidance of nephrotoxic medications is better)
Oxygen supplementation according to need.
Reduction of immunosuppression doses (keeping drug levels at low doses as well as holding the antimetabolites as MMF).
Use of IV Trimethoprim sulfamethoxazole renally adjusted doses according to disease severity. Second lines as Dapsone in case of bad response to TMS or allergy.
Initiation of dialytic support upon demand.
Supportive care by proper fluids and nutritional support.
Antiviral therapy if proved to be of viral origin.
IVIG can be administered being an immunomodulator.
As the patient is under immunosuppression with positive HIV besides the dry cough and low grade fever the first diagnosis will be : PCP .
Other differential diagnosis include:
☆ Bacterial pneumonia
☆ CMV pneumonia
☆ Fungal pneumonia
☆ Drugs related interstitial pneumonia
☆ TB
☆ Covid 19 pneumonia
● How do you manage this case?
☆ BAL fluid sample or induced sputum.
☆ Detection of the β-d-glucan antigen in blood samples
☆ Bronchoalveolar lavage and transbronchial biopsy
☆ Real time PCR
☆ Anti-Pneumocystis Agents (TMP-SMX)
The recommended daily dose is TMP 15–20 mg/kg plus SMX 75–100 mg/kg, preferably by IV administration for severe PCP. the optimal duration has not been fully studied but is generally 14 days . This duration of therapy can be extended to 21 days in severe infections or when clinical improvement is prolonged
☆ Intravenous pentamidine is the best second-line agent after TMP-SMX
☆ The clindamycin-primaquine combination seems to be the most effective regimen, particularly in cases where TMP-SMX has failed
☆ KDIGO and the American Society of Transplantation guidelines recommend treatment with adjunctive corticosteroids for SOT recipients with moderate to severe PCP (as defined by PaO2 <70 mmHg in room air)
☆ The National Kidney Foundation recommends reducing immunosuppressive medications for kidney-transplant recipients who develop PCP
● Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
☆ Incidence is 3-15%
☆ The severity of respiratory toxicity ranges from very subtle to severe respiratory failure
☆ Most patients are asymptomatic despite the high incidence of interstitial shadows on chest CT
☆ Differentiation of drug-induced ILD and PCP is extremely difficult as they share several of the clinical findings .
☆ The radiographic manifestations of
m-TOR ILD by can be divided into 4 groups: A (nonspecific areas of ground-glass attenuation)
B (multifocal areas of airspace consolidation)
C (patchy distribution of ground-glass attenuation accompanied by interlobular septal thickening)
D (extensive bilateral ground-glass attenuation or airspace consolidation with traction bronchiectasis)
☆ The A, B, and C patterns are not specific to ILD but are often seen in patients with PCP
☆ pattern D is difficult to distinguish from PCP
☆ BAL finding
The cellular pattern of BALF in drug-induced lung toxicity is classified into 5 groups: cellular pneumonitis, eosinophilic pneumonia, organizing pneumonia, cytotoxic reaction, and diffuse alveolar damage
There is no significant difference in cell count or differential count in BALF between PCP and non-PCP patients.
☆ PCR and β-D glucan is a credible marker for PCP, with a sensitivity of 92% and specificity of 86%
● What is the clinical picture of aspergillosis?
☆ Fever, cough, and dyspnea are frequent, although non-specific, findings of pulmonary aspergillosis, Vascular invasion may manifest as pleuritic chest pain due to pulmonary infarction or hemoptysis.
Saprophytic aspergillosis (aspergilloma) in CT is characterized by a mass with soft-tissue attenuation within a lung cavity. The mass is typically separated from the cavity wall by an airspace (“air crescent” sign) and is often associated with thickening of the wall and adjacent pleura
References:
● Toshio Suzuki, Yuji Tada, Kenji Tsushima, Jiro Terada, Takayuki Sakurai, Akira Watanabe, Yasunori Kasahara, Nobuhiro Tanabe, and Koichiro Tatsumia .
Pneumocystis pneumonia in everolimus therapy: An indistinguishable case from drug induced interstitial lung disease . Respir Med Case Rep. 2013; 10: 27–30.
● Xavier Iriart, Marine Le Bouar,Nassim Kamar, and Antoine Berry .
Pneumocystis Pneumonia in Solid-Organ Transplant Recipients . J Fungi (Basel) . 2015 Dec; 1(3): 293–331.
What is the differential diagnosis?
· This index transplant case with back ground of HIV associated nephropathy on HAART and triple immunosuppression presented currently with non-productive cough, fever and hypoxia. PCP is on the top of the list of the DD. A chest CT would be helpful in this scenario.
· Other DD:
· Viral: influenza, para-influenza and CMV
· Bacterial: community acquired bacterial causes including atypical forms and mycobacteria TB
· Fungal infection
· Parasitic infections.
· How do you manage this case?
Diagnosis:
o MDT approach involving pulmonologist, ICU and Nephrologist
o ITU admission and ventilatory 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, serum beta D Glucan, Serum LDH. Check for Tacrolinus trough level transplant and 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.
o Sputum sample examination for microscopy, staining and cultures for CMV, PJP and aspergillus (It may be difficult to obtain a sample as the patient has dry cough); hypertonic saline can be used to induce sputum(sensitivity of induced sputum is only 30%‐55%).
o Bronchoscopy & BAL for stain (Gomori methenamine‐silver stain) and culture, as well as PCR for respiratory viruses like pneumocystis and CMV.
Treatment:
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 PJP:
o TMP-SMX:
o First drug of choice
o Given IV or oral
o Given initially IV at a high dose of (TMP 15 to 20 mg/kg and SMX 75-100 mg/kg) or oral 2 DS tablets TDS.
o Duration: Given for 3 weeks followed by a lower dose for prophylaxis extended to 6-12 months
o Side effects: rash, fever, neutropenia, hepatitis, nephritis, and hyperkalemia, pancreatitis, renal calculi, and anaphylactoid reaction.
o In case of allergy or contraindication to use TMP-SMX then the second line drugs like Pentamidine, Atovaquone, Dapsone, Primaquine with clindamycin can be used.
o Early initiation(within the first 3 days) of adjuvant steroid doses was found to reduce mortality in moderate to severe disease
o Steroids can reduce inflammation, reduces the need for mechanical ventilation and ITU admission in those already on mechanical ventilation.
o Indications: resting PaO2 of <70 mmHg, oxygen saturation <92 % or alveolar-arterial (A-a) oxygen gradient of ≥35 mmHg
o Dose: 40mg BD prednisone (or equivalent) from day 1 to 5, then 40mg OD from day 6 to 11then tapered to 20mg OD up to 3 weeks.
o In case of CMV:
o IV gancicolvir 5mg/kg BD for 5 days followed by oral valganciclovir 900 mg OD until resolution of clinical symptoms and radiological findings with clearance of CMV in blood(2 X PCR are negative). If no response in 2 weeks, assess for ganciclovir resistance and shift to Foscarnet and additional CMV IVIG. Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse.
o Monitor graft function during treatment.
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
· Radiological presents with bilateral lower-lobe interstitial pneumonia while PCP is para-hilar or mid-zonal shadowing.
What is the clinical picture of aspergillosis?
· It is clinically significant only in immunocompromised cases may present as pulmonary disease or tissue invasive disease.
· Radiological: upper lobe single or multiple nodules or cavities together with patchy consolidation and Halo sign that describe hemorrhage in the area surrounding the fungus.
· Treatment is long periods of Voriconazole monotherapy or Voriconazole combined with Echinocandin therapy in invasive disease.
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. Martin SI, Fishman JA, Practice ASTIDCo. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:272-9.
4. Ding L, Huang H, Wang H, He H. Adjunctive corticosteroids may be associated with better outcome for non-HIV Pneumocystis pneumonia with respiratory failure: a systemic review and meta-analysis of observational studies. Ann Intensive Care 2020; 10:34.
5. Weiner SM, Sellin L, Vonend O, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome–a single-centre experience and review of the literature. Nephrol Dial Transplant 2007; 22:3631.
6. Kanj A, Abdallah N, Soubani AO. The spectrum of pulmonary aspergillosis. Respir Med. 2018 Aug;141:121-131.
HIV positive patient post transplantation with CD4 count 250/ml and having desaturation on mild exertion and normal X-Ray Chest–following differentials should be considered: Pneumocystis jirovecii , Viral ,bacterial and fungal pneumonia. First, we will get basic investigations like CBC, CRP, LDH , RFT, LFT followed by Blood C/S, Sputum C/S, ABG/ COVID PCR/serum beta-D-glucan assay. HRCT chest for para hilar shadows with sub pleural sparing , and ground glass appearance for PCP. Diagnosis is confirmed via staining of induced sputum sample or BAL sample with special stains or getting PCR done on respiratory samples. If CP is the likely diagnosis ,then modification of immunosuppression i.e., withholding MMF and achieving lower target of tacrolimus and then starting IV TMP-SMX in a dose of 15 to 20 mg/kg/day (based upon the TMP component) in three or four divided doses, later on switching to oral when tolerating for a duration of 21 days. Steroids in the form of oral prednisolone 40 mg twice a day for 6-10 days then 40 mg once daily for 11-21 days for severe disease and having PaO2 <70 mmHg on room air, A-a oxygen gradient ≥35 mmHg,or SpO2 <92%..Other drugs which can be used include Atovaquone,Clindamycin plus primaquine,TMP plus dapsone,Clindamycin plus primaquine,or Intravenous pentamidine in case if patient not tolerating co-trimoxazole. Choice of alternative drug will also depend on severity of drug. After treatment, patient should be placed on prophylaxis with drugs like TMP-SMX , Dapsone , Dapsone plus pyrimethamine, Atovaquone plus pyrimethamine for a duration 01 year-02 year.
mTORi-induced pneumonitis usually presents within 6 months after start of treatment, no elevation of LDH and diagnosis via BAL with biopsy showing lymphocytic alveolitis. Resolution of symptoms after stopping offending drug with short course steroids as treatment.
ABPA is characterized by asthma and recurrent exacerbations, fever, malaise, expectoration of brownish mucus plugs, elevated serum eosinophils> 500/microL and IgE level >1000 IU/mL. Pulmonary aspergillosis being the most common site of invasive aspergillosis. Clinical spectrum ranges from simple bronchitis, to ulcerative tracheobronchitis or necrotizing pseudomembranous TBA with bronchopleural fistulae.Patient may present with fever, cough, and dyspnoea or pleuritic chest pain, or hemoptysis.One of the lethal complication of invasive aspergillosis is involvement of CNS .
REFERENCES:
1-Orlando G, Tariciotti L, Manzia TM, et al. Ab initio calcineurin inhibitor-based monotherapy immunosuppression after liver transplantation reduces the risk for Pneumocystis jirovecii pneumonia. Transpl Infect Dis. 2010;12(1):11–5
2-Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1-155
3-Lecture: Prof Gamal Saadi Pneumocystis Pneumonia in SOT
This is most probably a case of PCP infection.Chest radiographs are initially normal in up to one-fourth of patients with PJP. PJP associated with HIV is more gradual in nature than PJP associated with Transplant setting.
What is the 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.
immunocompromised patient, HIV positive with CD4 count 250 on HAART presenting after kidney transplantation with fever, dry cough, and dyspnea on exertion.
1-What is the differential diagnosis?
–Pneumocystis Pneumonia.
-CMV Pneumonitis, also CMV as a clear risk factor for PCP .
-bacterial Pneumonitis but less possible (low grade fever).
-Respiratory viruses, as Influenza virus ,COVID-19 .
– Fungal as aspargellosis.
-Drug-induced interstitial pneumonitis (mTOR).
Presence of fever, dyspnea , desaturation, dry cough, few clinica findings and nonspecific imaging finding in transplanted patient PCP comes first in DD
2-How do you manage this case?
Investigations;
-CBC ,CRP.
-graft function.
-sputum culture
-BAL staining for PCP.
-Serum 1-3 beta-D-glucan assay which is highly sensitive but not specific.
-BALF and culture
– CMV PCR
-Blood culture.
-Tacrolimus level.
-ABG
Treatment
first supportive treatment to Maintain the sufficient O2 saturation MORE THAN 95% with follow up of the ABG and the alkalosis.
Antipyretics for fever.
Keep good hydration with fluid chart to keep fluid balance.
Pulmonology consultation is important.
Broad spectrum antibiotics against secondary bacterial infection
Treatment of PJP;
-reduce MMF or even discontinue
-Reducing CNI dose but keep steroid as it is, for fear of rejection .
–In case of PCP, treatment with TMP-SMX is considered as a first-line therapy with 15 to 20 mg/kg IV, switching to oral after clinical improvement with dose adjustment according to graft function .
Second-line therapy for severe cases would be pentamide 4 mg/kg IV o.d., and better to be used as inhaled though with comparable efficacy but worse safety profile.
Primaquine plus Clindamycin for severe cases and 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.
PCP prophylaxis Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend TMP-SMX as a first-line therapy for 3–6 months after KTx and at least 6 weeks during and after treatment for acute rejection. Alternative therapies with dapsone, aerosolized pentamidine or atovaquon should be considered in the event of allergic reactions or severe side effects
–References;
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.
Up To Date; Over view of Pneumocystis jirovecii pneumonia in patients without HIV: Aug 02, 2022.
What is the differential diagnosis?
The differential diagnosis is of CMV pneumonia, Pneumocystis pneumonia, TB infection
How do you manage this case?
Tests for CBC, ABG, Sputum test, BAL, HRCT of chest, Bronchoscopy, lung biopsy, cytology and immunophenotyping analysis
Reducing the Tacrolimus dosage, Antibiotic treatment and steroids
Q1: differential diagnosis:
1.
PJP pneumonia
2.
CMV pneumonia
3.
Covid-19
4.
Bacterial of fungal pneumonia
Q2:
1.
ICU admission
2.
O2 saturation monitoring
3.
Lab test: CBL, ESR, CRP, Biochemistry, LDH, B/C, and sepsis
workup, induced sputum or BAL fluid test for staining, culture, and PCR
4.
Treatment with (TMP-SMX) 15-20 mg/kg/day divided every 6-8
hours for 21 days.
5.
Wide-spectrum antibiotics
6.
Alternative treatment for TMR-SMMX includes Atovaquone for
mild disease, clindamycin, and primaquine, TMP, and dapsone.
The images suggest a picture of mild bilateral interstitial and perihilar infiltrate, with dry cough and low-grade dysthermia, just 15 days after the transplant.
Possible differential diagnoses would be:
– Hospital pneumonia
– Congestion, associated with infection at another site;
– drug-related pneumonitis
I would perform more accurate tests:
– Chest CT: for a better evaluation of the alterations present on the chest X-ray, with a view to excluding any of the suspected infectious pulmonary conditions.
– Bronchoscopy with bronchoalveolar lavage: CT scan of the chest would not exclude all etiologies, so a bronchoscopy with bronchoalveolar lavage would also be necessary with collection of:
– PCR for Pneumocystis
– PCR for Tuberculosis
– Pyogenic germ cultures
– Galactomana
Initiate ATB scheme for coverage of care-related pathogens (coverage for ESBL and MRSA resistance), as a result of the other tests.
I would undergo cardiological investigation with natriuretic peptide to assess the possibility of cardiac decompensation and troponin and also a transthoracic echocardiogram.
For the diagnosis of drug-related pneumonitis, it will be necessary to perform a biopsy with histopathological evaluation, associated with tests that exclude other causes, making it almost a diagnosis of exclusion.
What is the differential diagnosis?
· 1-Bacterial infection ;
· Typical and atypical pneumonia .
· 2-Viral infection ;
· CMV ,EBV , adenovirus ,Covid .
· 3-Fungal infection ;
· Pneumocyst carinii
· Spergellous .
· 4-drug induced pneumonitis
How do you manage this case?
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 .
Therapeutic approach ;
1. Hospital admission to guard against severe hypoxia as a cascade of exertional dyspnoea. He needs bed rest and oxygen support.
2- Respiratory support with oxygen supply.
3- Reduction and adjustment of immunosuppression.
4-Patient should be started on IV antibiotics like broad spectrum antibiotics and they should be continued till the cultures report.
5- Antimetabolites should be stopped and Patient should be managed with CNI based on trough levels and increased dose of steroids.
6-IV TMP SMX or 160/800mg 2 tablets twice daily should be given for 21 days and then followed by low dose prophylaxis for 6 months .
7-Steroids in PCP are indicated if there is hypoxia.
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 .
The patient is immunocompromized with CD4 count 250 on HAART presenting with fever, dry cough. No expectations and desaturation on exertion
DD include
1. Viral infections including respiratory virusrs, CMV and other herpes viruses
2. Bacterial infections less possibility
3. Fungal as PCP, histoplasmosis, cryptococcosis
And even parasites
In such patient with CMV positive recipient, desaturation, dry cough and fever most probably PCP
Management include
1 complete history and clinical examination including immunosuppression protocols and induction history
2. Lab tests including routine tests, inflammatory markers, virology, cultures, and immunosuppression trough levels
3. Imaging after CXR we should perform HRCT
4. In case of sputum we shall perform cytology and culture even BAL with virology markers
5. Being CMV positive recipient so risk of reactivation is high and CMV PCR
Regarding treatment
ICU administration owing to hypoxia
Empirical antibiotics should be started including beta lactame antibiotics
Pcp empirical treatment including Trimethoprin sulphamethoxazole
If confirmed continue for 3 weeks if allergic or CI give pentamidine
If negative stop the drug
If CMV manage for CMV treatment
Regarding immunosuppression
Stop MMF and adjust CNI according to trough level
Plus continue supportive care
39 years HIV-positive on HAART, renal transplant recipient; having low grade fever, dyspnoea and non-productive cough, normal Chest X ray –
Differential Diagnosis:
Viral pneumonitis – CMV, Influenza, Parainfluenza
Pneumocystis jerovecii Pneumonia
Atypical Tuberculosis
Atypical Bacterial pneumonitis
Fungal pneumonitis – Aspergillus, Cryptococcus, Histoplasma, Mucormycosis
Non‐infectious – PTLD, mTORi‐induced pneumonitis
clinical features (non-productive cough, fever) and radiographical picture indicates, more towards Pneumocystis jerovecii Pneumonia – early cases may not have findings on X ray.
Management of the case:
Admission and monitoring in HDU
Oxygen supplement by mask, Nebulisation
HRCT Chest
Lab investigations – CBC, RFT, LFT,
Ser LDH – elevated; is prognostic marker
serum β-d-glucan assay
Sputum (induced) for – AFB, PJP
– If sputum not yielding, BAL fluid – staining – look for CMV / PJP
– If BAL negative transbronchial lung biopsy
Treatment:
1. Trimethoprim-sulfamethoxazole (TMP-SMX):
2 double strength (160 + 800) Tab thrice daily
If no improvement in a week, Injection (TMP 15-20 mg + SMX 75-100mg) /kg/day IV in divided doses Q8H till symptoms resolve, then switch to oral 2tab tid
Duration of therapy – 21 days is preferred to avoid disease progression and relapse
2. Then secondary PJP prophylaxis (TMP-SMX) single strength 1 tab daily
3. Adjunctive steroids: if hypoxemia develops (pAO2 < 70 mm Hg on room air)
Early administration of corticosteroid therapy gives maximum benefit – ideally <72 hours of initiating antimicrobial therapy; Optimal dose 40-60 mg of prednisone (or equivalent) in adults 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.
4. Reduction of immunosuppression – MMF to be reduced by 50%, CNI to minimal Tac dose
If CMV infection – Valgancyclovir 900mg twice daily till symptoms resolve and viral DNA becomes undetectable.
Fungal infection – IV antifungal therapy with Amphotericin B, later switch to Voriconazole, along with steroid and reduction / discontinuation of immunosuppression.
Discussion: Reply to Question by Prof Ahmed Halawa
Q1- Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PJP?
mTORi-induced interstitial pneumonitis presents with cough, dyspnoea on exertion or hypoxemia preceded by history of mTORi use, especially late switch rather than de novo use.
– Low grade fever, progressive dyspnoea, dry cough, occasional haemoptysis.
– Common radiological findings are bilateral patchy, interstitial opacities.
– BAL – usually lymphocytosis
– The Lung biopsy – histopathological features include organizing pneumonia, interstitial pneumonitis, focal fibrosis, non-necrotizing granulomas with macrophages and pulmonary haemorrhage
– It is difficult to distinguish from PJP and is mostly a diagnosis of exclusion (after excluding infective causes).
Rapid clinical response after discontinuation of mTORi makes the diagnosis
Q2- What is the clinical picture of aspergillosis?
Clinical Manifestations of Aspergillus Pneumonia
Aspergillosis involves mainly sinopulmonary tract; pulmonary aspergillosis being the most common site of invasive aspergillosis.
Presentation ranges from simple bronchitis, bronchial obstruction by fungal balls, ulcerative tracheobronchitis to necrotizing pseudomembranous TBA with bronchopleural fistulae.
– Fever, cough, and dyspnoea are frequent, although non-specific findings may be there.
– Vascular invasion may manifest as pleuritic chest pain, pulmonary infarction or haemoptysis.
– Sometimes CNS involvement may be associated, manifest with seizures or focal
neurological signs from mass effect or stroke – sometimes devastating.
Radiographic imaging (CT scan) and bronchoscopy with culture remain the cornerstone of diagnosis.
Demonstration of invasive hyphae on histology or positive culture from a normally sterile environment (e.g., pleural fluid) is equated as proven invasive fungal disease.
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. Ussavarungsi K, Elsanjak A, Laski M, Raj R, Nugent K. Sirolimus induced granulomatous interstitial pneumonitis. Respir Med Case Rep. 2012 Nov 7;7:8-11. doi: 10.1016/j.rmcr.2012.09.002. PMID: 26029599; PMCID: PMC3920426.
4. Husain, S, Camargo, JF, on behalf of the AST Infectious Diseases Community of Practice. Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33:e13544
Differential diagnosis:
Management:
– Oxygen inhalation, when needed
– Anti-pyretic for fever.
– I/V fluid if necessary.
– CBC, CRP
– Blood culture, urine culture, sputum culture
– CD4 cell count: values below 200cells or low CD4/CD8 ratio suggest reactivation of PCP
– PCR for CMV, PCP
– Serum beta D-glucan: is non-specific but if positive it supports diagnosis of fungal infection.
– LDH for the assessment of severity of PCP and prognosis
– BAL should be checked for gram stains, silver stain or IF for PCJ, ZN stain, and sent for microbial cultures including fungus.
– CT scan of Chest
– Sputum for GeneXpert TB test
– Following confirm diagnosis, treatment of PCP drug of choice is TMP SMX we need to give at least for 3 weeks at a dose of 15-20 mg/ kg IV of TMP
– Close monitoring for side effects of drugs is important as may need to decrease the dose.
– Alternative agents are less effective such as IV pentamidine, Dapsone with Pyrimethamine plus Leucovorin, aerosolized Pentamidine and Atovaquone.
– Modification of immunosuppressive medications:
Hold MMF or Azathioprine.
Reduce the dose of CNIs, aiming at lower target level.
Increase the dose of steroid
– Secondary prophylaxis for life.
– Anti-HIV HAART and monitoring specially with possible drug interaction with other IS medications
References:
(i) UpTodate
(ii) Lecture: Prof. Gamal Saadi on Pneumocystis Pneumonia in SOT
From the given scenerio & CXR i have following differentials-
– Early PCP
– Other viral pneumonia
– Atypical bacterial pneumonia
a) Investigations-
– CBC, CRP, ABG
– Renal function test, LFT
– LDH
– HRCT of chest( subpleural spearing, honey combing, ground glass opacity, reticulation, stripes)
– Diagnostic specimen – BAL, Transbronchial biopsy, open lung biopsy/ VATS, induced sputum.
– Diagnostic technique- immunofluorescence assay, real time PCR, nucleic acid testing, silver staining.
– Lung biopsy specimen -lymphocytic infiltration, Gonori methenamine silver staining ( dark brown oval or cup shaped organism in alveolar spaces)
d)Trealment-
1. TMP (15 – 20 mg/ kg)- SMX (75 – 100mg/kg)- IV or p o divided into 3 – 4 doses.
2. Continue HAART in moderate to severe infection.
3. APAs ( pentamidine, atovaquone, dapsone)
4. Long term seconday prophylaxis.
Differential diagnosis:
PCP
CMV pneumonia
COVID pneumonia
Bacterial pneumonia.
Mycobacterium TB
Management:
ICU admission
Oxygen therapy for hypoxia
CD4 cell count: values below 200cells or low CD4/CD8 ratio suggest reactivation of PJP
BAL for PCP diagnosis
HRCT
Reduction of immunosuppression, Stop MMF/AZA, CNI levels
Monitoring for rejection
Consider increasing steroids especially if hypoxic.
TMP-SMX 15-20 mg/kg for 21days
If patient is allergic to TMP/SMX, alternatives include Atovaquone, Dapson, or Primaquine, or IV pentamidine.
corticosteroids in patients with moderate or severe disease.
(PaOs < 70 mmhg)
1- CMV Pneumonitis
2- PJP Pneumonia
3- TB infection
4- Aspergillosis
5- Atypical Bacterial infection
6- Drug induced interstitial pneumonitis
1- Oxygen support to optimize saturation to above 92%
2- Serum LDH – and B D glucan usually elevated in PCP
3- Induced sputum For culture , gram stain and analysis
4- Bronchoalveolar lavage sample microscopy for cyst identification , PCR for CMV and other virus , AFP for TB , looking for malignant cells etc
5- serum CMV PCR
6- HRCT
7- Lung biopsy for definite diagnosis
1- PJP – High dose trimethoprim/sulfamethoxazole for 21 days then prolonged prophylaxis. If the patient is allergic to septrin: clindamycin/primaquine, atovaquone, trimethoprim/dapsone or iV pentamidine can be used
2- Pulmonary TB – Rifafor plus pyridoxine – Have to monitor the tacrolimus levels closely
3- CMV pneumonitis – IV ganciclovir for at least five days, then valganciclovir once stable to complete 21 days.
What are your differential diagnosis?
PCP is very rare in first month post-transplantation, but there risk factors strong immunosuppression tacrolimus, diabetes, slow graft function.
According to the history, clinical presentation and radiological finding the provisional diagnosis is PCP.
Other differentials could be,
. CMV pneumonitis,
. Bacterial infection,
. Viral pneumonia,
. Atypical pneumonia.
. Other fungal infection,
. COVID-19.
How do you manage this case?
According to history the patient is immunocompromissed, diabetic, slow graft function all these make prone the recipient vulnerable for opportunistic infections, and there is high risk of opportunistic infection (with no history of prophylaxes), symptoms dry cough, hypoxemia, and radiological finding suggest PCP pneumonitis, but further to confirm the diagnosis needed.
Baseline investigations, galactomenone, CMV PCR, BAL, for biopsy, microscopy, gram stain, cytology, blood C/S, procalcitonine, CRP.
General management;
Keep well hydrated,
Keep Fio2 >90, otherwise give maximum O2, arrange and put on CPAP, if not responding and persistently hypoxemic need to discuss with family for intubation.
Empirical broad spectrum antibiotic.
Start corticosteroids.
Specific management;
Trimethoprim-sulphamethoxazole 20mg/kg split dose /day, according to eGFR.
If not responsive or allergic to sulfa group switch to second line agent, clindamycin 600mg bid plus primaquine 30mg tid.
Then secondary prophylaxes for next six months.
Reference;
1. https://pubmed.ncbi.nlm.nih.gov/10530464/.
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734213/
3. https://www.uptodate.com/contents/treatment-and-prevention-of-pneumocystis-pneumonia-in-patients-without-hiv?search=Role%20of%20corticosteroids%20in%20treatment%20of%20PCP&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H6.
4. https://www.uptodate.com/contents/treatment-and-prevention-of-pneumocystis-pneumonia-in-patients-without-hiv/abstract/11.
5. https://journals.scholarsportal.info/details/21938229/v10i0003/1733_mnsftdinpars.xml&sub=all.
6. https://www.sciencedirect.com/science/article/abs/pii/S1341321X07708802.
7. https://www.uptodate.com/contents/search?search=pcp%20prophylaxis%20adult&sp=0&searchType=PLAIN_TEXT&source=USER_INPUT&searchControl=TOP_PULLDOWN&searchOffset=1&autoComplete=true&language=&max=0&index=5~10&autoCompleteTerm=pcp&rawSentence.
The given patient is a 39 year old female patient with Basic disease of HIV associated nephropathy and has had a renal transplant from a cadaveric donor…Her CD4 counts are normal and is on HAART therapy…. Patient currently has improving renal functions and has normal urine output… She has history of non productive cough, dyspnea on exertion and fever 2 weeks after transplant…Chest Xray is normal….Clinical features are suggestive of post transplant pneumonia…
Differential diagnosis are viral (influenza, RSV, COVID 19, pneumo virus), bacterial – Tuberculosis and streptococcal, Fungal – PCP and histoplasmosis and Cyrptococcus…
In view of exertional hypoxia and non productive cough in an immunocompromised individual with HIV early onset PCP can be expected …Although the traditional PCP occurs after 3 to 6 months of renal transplant, this patient has other risk factors like HIV in which PCP should be kept in mind as the first DD….
CMV pneumonia is rare.. The donor and recipient status are not included in this patient…
Detailed history and physical examination needs to be included as induction agent, details of rejection if any, details of previous opportunistic infection in HIV, history of tuberculosis in the past… Laboratory testing including CBC, RFT, LFT, LDH, Blood culture, Sputum testing after saline induction, Rapid biofare throat swab, COVID 19 testing, Swine flu throat swab, serum LDH, Procalcitonin and Blood culture, Tacrolimus level, Serum beta D glucan has to be done… Induced sputum examination should be stained for gram stain, bacterial culture, AFB stain, Gene Xpert MTB, Giemsa or toulidien blue stain for PCP should be included… ABG should be done to assess the hypoxia and ALV-Art gradient…
CT chest should be done…. CMV PCR should be done although it is unlikely in thissetting… If not significantly hypoxic patient should undergo bronchoscopy and BAL has a better yield for all as compared to sputum examination….
Empirical treatment should be started with antibiotics, oseltamavir for influenza if there is an epidemic… empirical treatment for PCP in the form of Cotrimoxazole 15-20 mg/kg/day for 21 days…. Steroid for PCP have to be decided based on hypoxic status and ABG on a day to day basis…early steroid therapy is always beneficial as compared to late therapy in PCP….
antimetabolites should be stopped and CNI should be managed based on trough levels…
Second line of PCP treatment includes Dapsone Plus TMP – can be used as an alternative but may cause nausea, fever, vomiting, hepatotoxicity and hemolysis in G6PD deficiency… Clindamycin(600-900mg 6 to 8th hourly) plus primaquine (15-30mg/day) is another alternative… Pentamidine and Atovoquone are other alternatives
mTOR induced interstitial pneumonitis presents with cough and dyspnea, there maybe hypoxia on exertion..A delayed type hyersensitivity reaction or a direct alveloar cytotoxicity is reported with mTOr inhibitors….. CT chest shows inflammatory infiltrates in the lungs which are interstitial in nature…Cryptogenic organizing pneumonia like picture is common and they are involving predominant lower lobes and pleural locations..NSIP is a common finding by CT scan… PCP on the other had are predominantly involving perihilar locations initially… The picture of mTOR inhibitor pneumonitis are diffcult to distinguish from PCP, but a recent conversion within 6 months and graft dysfunction with negative BAL for PCP or CMV may give a clue…
Aspergillosis can be present as a fungal infection in the post transplant patients… Fever, pleuritic chest pain and hemoptysis are found… CT chest shows cavity with halo sign with nodulo- cavitatory features… they also can have non resolving fungal sinusitis and Allergic bronchopulmonary aspergillosis is common in asthmatics and will have elevated levels of IgE….
Q1- What is the differential diagnosis?
Differential diagnosis include
a- Pneumocystis jirvocii pneumonia
b- Covid 19 infection
c- CMV
d- TB
e- In early post-transplant period (1 month )- hospital acquired infection – nosocomial infection .
f- Other viral infection EBV, HSV ….
Q2- How do you manage this case?
1- Admition to hospital and multi-disciplinary team management .
2- Monitoring of the vital signs , O2 saturation .
3- O2 therapy – if indicated
4- IV hydration .
5- WORK UP to prove the most probable diagnosis (PCP ) .
Note : Chest x RAY and computed-tomography scans (HRCT) are both are suggestive of pneumocystis jirovocii pneumonia.
This case need further test for diagnosis which include
1- Microbiological diagnosis: sputum sensitivity for diagnosis is differ
Routine sputum has poor outcome and Induced sputum has about 30–55%. Bronchoalveolar lavage increase the sensitivity to 80–95% but the most sensitive way are Bronchoalveolar lavage and transbronchial biopsy, Open-lung biopsy with sensitivity of >95%.
Note: Pneumocystis remains a non-cultivable microorganism.
2 – Polymerase Chain Reaction:
PCR is a highly effective at diagnosing . the negative predictive value of this method, close to 100%, allows PCP to be excluded .
5-5- Plasmatic Markers
– the level of serum LDH is elevated (>300 IU) in most patients with PCP .
– serum levels of β-d-glucan (BDG), with sensitivities ranging from 90% to 100% and specificities of 88% – 96% .
Other tests
1- SPUTUM for covid 19 PCR and chest ct scan .
2- CMV PCR.
3- T B – sputum for AFB, IgRA , Gen Expert .
4- PCR for EBV , SHV ..
TREATMENT :
When the PCP is diagnosed this case should be treated
Manipulation of immunsupresant : stopping MMF and Azathioprine.
Reduce the CNI dose to half .
Increase the steroid dose .
Maintaining Anti HIV HAART treatment with close monitoring for drug- drug interaction.
Trimethoprim-Sulfamethoxazole (TMP-SMX) TMP-SMX is the first-line agent for the treatment of mild to severe PCP . The recommended daily dose is TMP 15–20 mg/kg plus SMX 75–100 mg/kg, preferably by IV administration for severe PCP. Recommended duration of treatment is 21 days.
Intravenous pentamidine is about as effective as TMP-SMX and it is the best second-line agent after TMP-SMX for SOT recipients .
second-line treatment
Atovaquone, clindamycin-primaquine, or dapsone-TMP have only been evaluated in mild to moderate PCP. The clindamycin-primaquine combination seems to be the most effective regimen, particularly in cases where TMP-SMX has failed .
patients with moderate-to-severe PCP, the use of adjunctive glucocorticoids remains questionable and is highly controversial. KDIGO and the American Society of Transplantation guidelines recommend treatment with adjunctive corticosteroids for SOT recipients with moderate to severe PCP (as defined by PaO2 <70 mmHg in room air). American Society of Transplantation guidelines suggest that 40–60 mg of prednisone is administered per os twice daily and tapered after 5–7 days over a period of 1–2 weeks
after treatment and recovery it is important to keep patient on TMP-SMX secondary prophylaxis.
references
1- Sunsane B, etL: Prophylaxis and Treatment of Pneumocystis Jeroveci Pneumonia after Solid Organ Transplantation, Pharmacological Research Volume 134, August 2018, 61-67
2- Jay A, ETAL: Pneumocystis Jiroveci in solid Organ Transplantation: Guidelines from the American Society of Infectious Disease Community of Practice, Clinical Transplantation volume 33.
1- Patient admission in hospital
2- Computed tomography of the chest
2- O2 supplement is not needed in this period with excellent saturation at rest and exertion.
3- lab test
CBC – LDH (non specific)- CRP- procalcitonin-
BAL analysis and culture
PCR (CMV)
PCR(PCP)
β-d-Glucan antigen
4- re-evaluate the HIV status in this patient
5- immunosuppression reducing
6- in the case of PCP thd best treatment is TMP-SMX 15- 20 mg /kg Tmp intravenous for 14 to 21 days
7- alternative therapy for PCP
pentamidine for SOT recipient
Atovaquone
lindamycin+ primaquine
dapsone- Tmp
For patients Who do not tolerate
TMP-SMX aerosolized pentamidine is the alternative Treatment
8- corticosteroid may be indicated is some serious cases but in this case in not indicated
Patients with a PaO2 of <70 mmhg initially .
9- – treatment for CMV is indicated
Clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP (1-3)
– mTORi-induced interstitial lung disease (ILD) is a clinical diagnosis made by scrutinizing the signs and symptoms, the radiographic changes, pulmonary function tests and after excluding other possible causes of parenchymal lung disease
– the time to onset of interstitial pneumonitits is short with most being diagnosed within 6 months after starting treatment
– patients present with non-specific symptoms i.e., dry cough, progressive dyspnoea, fever, hypoxia, fatigue, occasionally hemoptysis hence making it difficult to distinguish it from other opportunistic pulmonary infections (e.g., PCP) or pulmonary events (e.g., PE)
– radiological features include bilateral patchy, interstitial opacities; less commonly consolidation or nodular opacities
– mTORi-induced interstitial pneumonitis appears to be clinically similar to PCP
– features that favour a diagnosis of mTORi-induced interstitial
pneumonitis include resolution of symptoms upon discontinuation of the drug and a negative PCP PCR test
Clinical picture of aspergillosis (4)
– cough, dyspnoea, fever, pleuritic chest pain, hemoptysis
– a classic triad has been described in neutropenic patients i.e., fever, pleuritc chest pain, hemoptysis
– CXR is insensitive in the early stages of pulmonary disease
– Chest CT scan findings vary i.e., patchy or segmental consolidation, single or multiple nodules with or without cavitation, peri-bronchial infiltrates with or without tree-in-bud patterns
References
1. Willemsen AE, Grutters JC, Gerritsen WR, van Erp NP, van Herpen CM, Tol J. mTOR inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm. International journal of cancer. 2016 May 15;138(10):2312-21. PubMed PMID: 26452336. Epub 2015/10/11. eng.
2. Ussavarungsi K, Elsanjak A, Laski M, Raj R, Nugent K. Sirolimus induced granulomatous interstitial pneumonitis. Respiratory medicine case reports. 2012;7:8-11. PubMed PMID: 26029599. Pubmed Central PMCID: PMC3920426. Epub 2012/01/01. eng.
3. Suzuki T, Tada Y, Tsushima K, Terada J, Sakurai T, Watanabe A, et al. Pneumocystis pneumonia in everolimus therapy: An indistinguishable case from drug induced interstitial lung disease. Respiratory medicine case reports. 2013 08/08;10:27–30.
4. Horger M, Hebart H, Einsele H, Lengerke C, Claussen CD, Vonthein R, et al. Initial CT manifestations of invasive pulmonary aspergillosis in 45 non-HIV immunocompromised patients: association with patient outcome? European journal of radiology. 2005 Sep;55(3):437-44. PubMed PMID: 16129254. Epub 2005/09/01. eng.
Differential diagnosis:
Management:
– Oxygen inhalation, when needed
– Anti-pyretic for fever.
– I/V fluid if necessary.
– CBC, CRP
– Blood culture, urine culture, sputum culture
– CD4 cell count: values below 200cells or low CD4/CD8 ratio suggest reactivation of PCP
– PCR for CMV, PCP
– Serum beta D-glucan: is non-specific but if positive it supports diagnosis of fungal infection.
– LDH for the assessment of severity of PCP and prognosis
– BAL should be checked for gram stains, silver stain or IF for PCJ, ZN stain, and sent for microbial cultures including fungus.
– CT scan of Chest
– Sputum for GeneXpert TB test
– Following confirm diagnosis, treatment of PCP drug of choice is TMP SMX we need to give at least for 3 weeks at a dose of 15-20 mg/ kg IV of TMP
– Close monitoring for side effects of drugs is important as may need to decrease the dose.
– Alternative agents are less effective such as IV pentamidine, Dapsone with Pyrimethamine plus Leucovorin, aerosolized Pentamidine and Atovaquone.
– Modification of immunosuppressive medications:
Hold MMF or Azathioprine.
Reduce the dose of CNIs, aiming at lower target level.
Increase the dose of steroid
– Secondary prophylaxis for life.
– Anti-HIV HAART and monitoring specially with possible drug interaction with other IS medications
References:
(i) UpTodate
(ii) Lecture: Prof. Gamal Saadi on Pneumocystis Pneumonia in SOT
Differential Diagnosis
How do you manage this case?
Treatment:
I would start broad spectrum antibiotics.
PCP treatment
References
1. Jay A, ETAL: Pneumocystis Jiroveci in solid Organ Transplantation: Guidelines from the American Society of Infectious Disease Community of Practice, Clinical Transplantation volume 33, 9
2. Sunsane B, etL: Prophylaxis and Treatment of Pneumocystis Jeroveci Pneumonia after Solid Organ Transplantation, Pharmacological Research Volume 134, August 2018, 61-6
Differential diagnosis of this patient
hypoxia in post op period with low CD4 count and immunosuppression
non infective -atelectasis, pulmonary edema , capillary leak , emboli, pulmonary haemorrhage
INFECTIVE- bacterial , viral pneumonitis , PJP pneumonia , CMV pneumonitis
treatment
multidisciplinary
ICU care
reduction of immunosuppression
microscopy of sputum, BAL, biopsy through bronchosocpy
nasal O2
antibacterial volume control
graft monitoring
CLINICAL PICTURE OF MTOR INDUCED PENUMONITIS
not specific to the diagnosis
dry cough
dyspnoea
hypoxia
non productive cough
fever and fatigue
HRCT findings
GG opacities
inter or intra lobal septal thickening
in advance cases consolidation at bases and periphery , often B/L
rarely pleural effusion
common when secondary treatment with mTOR rather than de novo
discontinuation is safest option
ASPERGILOSIS
symptoms are dyspnoea , cough, chest pain and fever and wheezing
weight loss and fatigue in chronic cases
organ specific symptoms like eye , sinus and CNS
CXR – may show fungus ball
HRCT- halo sign , nodule with surrounding attenuation, fungus ball
CT SCAN may show associated sinus and CNS lesions
The pt symptoms are mostly due to Pneumocystis pneumonia and differential diagnosis will include ;
CMV pneumonitis
Tuberculous pneumonia
aspergillosis
bacterial pneumonia
Atypical pneumonia
influenza – COVID
workup
septic screen ,ESR, CRP, procalcitonin
CBC, AST ALT
cultures from blood, sputum if cough turns productive, urine
BAL then specimen stained, cultured, PCR
HRCT
BD glucan blood levels
LDH is more prognostic rather than diagnostic
treatment
oxygen therapy adequate hydration -antipyretics
TMP 15-20 mg/kg -SMX 57-100 mg/ kg is given IV or p.o divided into 3 or 4 doses daily for 21-30 days, in mild cases, 2 double-strength tablets are given p.o tid
steroids are added in severe cases
deterioration of the patient necessitates the reduction of immunosuppression
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
mTORi-induced interstitial pneumonitis tends to occur within 6 months of medication initiation and resolves within 3 months of mTORi discontinuation or dose reduction.the condition is not associated with LDH elevation
the radiological lesion in PCP tends to spare the pleura and para-pleural space. and tends to occur after prophylaxis discontinuation
BAL can discriminate PCP from mTORi-induced pneumonitis
Aspergillosis is usually associated with eosinophilia,fever, asthma
radiological finding characteristically shows Perihilar opacities, Ring shadows,, Gloved finger shadows, tram lines and Toothpaste shadows
Early infection post transplantation is common and increase the mortality and morbidity.
Differential Diagnosis include:
1-Pneumocystic Jerovecii Pneumonia
2-CMV pneumonitis
3-Fungal infection like Aspergillus
4-Bacterial Pneumonia
History of presenting complaints and Immunosuppresion ,deplition of CD4,rejection,treatment option
. In addition to donor CMV status, donor history of recent infection.
Investigations including CBC differential, Chemistry, septic workup, sputum culture, BAL for PJP, CMV, TB and fungal culture.
Normal chest xray doesn’t exclude PJP, we need to do CT scan of the chest which is more sensitive.
Treatment
Admission to ICU,
oxygen Supplementation
Reduction of immunosuppression
Broad spectrum antibiotics, anti PJP and CMV
PCP
Trimethoprim 15 mg/kg
Sulphamethoxazole 75 mg/kg in 3-4 divided dosesThe treatment should be continued for long period (months –yearsAtavaquone 750 mg, orally twice daily for 21 day
.
OUR CASE;
RISKS;
DIFFERENTIAL DIAGNOSIS.
MANAGEMENT.
REFERENCES.
Uptodate – Treatment and prevention of PCP in patients with HIV.
Differential Diagnosis
· Acute Respiratory Distress Syndrome
· Cytomegalovirus
· Lymphocytic Interstitial Pneumonia
· Mycoplasma Infections
· Viral Pneumonia
· Pneumocystis jiroveci Pneumonia
· Pulmonary Embolism
· Legionellosis
· Tuberculosis
· Mycobacterium avium Complex (MAC) Infection
PJP should be excluded as this patient has high risk to develop PJP
· The most common manifestations of PJP in HIV recipients are: subacute onset of progressive dyspnea, fever, non-productive cough, and chest discomfort that worsens within days to weeks.
· Fulminant pneumonia is less common among patients with HIV.
· In mild cases, pulmonary examination while the patient is at rest usually is normal.
· Oxygen desaturation with exercise is often abnormal but is non-specific
· In patients with early disease, a chest radiograph may be normal
· About 13% to 18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction, such as tuberculosis (TB), Kaposi sarcoma, or bacterial pneumonia.
· Thin-section CT is useful for diagnosis, since even in patients with mild-to-moderate symptoms and a normal CXR, a CT scan may reveal “ground-glass” attenuation that may be patchy
· Normal CT has a high negative predictive value.
· The sensitivity for diagnostic tools: <50% to >90% for induced sputum, 90% to 99% for bronchoscopy with BAL, 95% to 100% for transbronchial biopsy, and 95% to 100% for open lung biopsy
· 1,3 β-D-glucan, is often elevated in patients with PCP but not specific.
Treating Disease
· Outpatient therapy with oral TMP-SMX is highly effective in patients with the mild-to-moderate disease (AI)
· lower doses (than standard) may also be effective, potentially with less toxicity
· Patients who have PCP despite TMP-SMX prophylaxis usually can be treated effectively with standard doses of TMP-SMX
· No need for corticosteroid in this patient with mild disease, and should be given for patients with moderate-to-severe disease(room air PO2 <70 mm Hg) as soon as possible and within 72 hours after starting specific PCP therapy
· Alternative therapeutic regimens for mild-to-moderate disease include: dapsone and TMP (BI)
· Alternative therapeutic regimens for patients with moderate-to-severe disease include clindamycin-primaquine or IV pentamidine (AI)
· The recommended duration of therapy for PCP is 21 days.
· As PCP occurred in this patient at a CD4 count >200 cells/mm3 while she is on ART, PCP prophylaxis should be continued for life, regardless of how high the CD4 cell count rises as a consequence of ART
https://www.idsociety.org/practice-guideline/prevention-and-treatment-of-opportunistic-infections-among-adults-and-adolescents/#:~:text=Recommendations-,Guidelines%20for%20the%20Prevention%20and%20Treatment%20of%20Opportunistic%20Infections%20in%20Adults%20and%20Adolescents%20with%20HIV,-Published%20NEW%20JOURNAL
3. A 39-year-old CKD 5 secondary to HIV associated nephropathy had a deceased donor kidney transplantation. CD4 count is 250/ml and receiving HAART. Currently she is on Tacrolimus-based triple immunosuppression. Her kidney function has improved and started to pass more urine. She presented with 2 weeks history of non-productive cough, low grade temperature (37.5 °C). She has dyspnoea on exertion (respiratory rate at rest is 20/min) but chest X-Ray reported normal. Clinically there were few physical findings only few scattered wheezes. Sat 100% on air and desaturates to 95% on exertion.
issues/ concerns
– 39yo, CKD5, HIVAN, deceased donor kidney transplantation
– CD4 is 250/ml, on HAART
– Tacrolimus-based triple immunosuppression therapy
– good kidney function
– 2/52 hx nonproductive cough, low grade fever, dyspnoea on exertion, RR 20, SPO2 95% on exertion, scattered rhonchi
– CXR normal
What is the differential diagnosis?
– Pneumocystis pneumonia
– Bacterial pneumonia – Community acquired
– Viral pneumonia – CMV, SARSCOV2, Kaposi
– Atypical pneumonia
– Other fungal infection – Aspergillus, Candida
– Pulmonary tuberculosis
– Mycobacterium avium complex (MAC) infection
– Acute respiratory distress syndrome (ARDS)
– Metastatic disease
How do you manage this case?
– multidisciplinary approach i.e., engage an infectious disease specialist, microbiologist, pulmonologist
– comprehensive history i.e., history of opportunistic infections, viral suppression, prophylactic antibiotics, night sweats, weight loss, smoking history
– thorough physical examination i.e., oral thrush, lymphadenopathy
– baseline investigations: – (1-3)
– imaging: – (4)
– therapeutic options: – (5)
– TMP-SMX is given at a dose of 1920mg TID for 21 days
– Other options available if the patient is unable to use TMP-SMX
– Corticosteroids are used as adjunctive initial treatment in patients with severe disease – best given within 72hours of initiating antibiotics in states of hypoxia i.e., pAO2 < 70 mmHg on room air
– duration of antibiotics should be 21days
References
1. Grover SA, Coupal L, Suissa S, Szentveri T, Falutz J, Tsoukas C, et al. The clinical utility of serum lactate dehydrogenase in diagnosing pneumocystis carinii pneumonia among hospitalized AIDS patients. Clinical and investigative medicine Medecine clinique et experimentale. 1992 Aug;15(4):309-17. PubMed PMID: 1516288. Epub 1992/08/01. eng.
2. Fauchier T, Hasseine L, Gari-Toussaint M, Casanova V, Marty PM, Pomares C. Detection of Pneumocystis jirovecii by Quantitative PCR To Differentiate Colonization and Pneumonia in Immunocompromised HIV-Positive and HIV-Negative Patients. Journal of clinical microbiology. 2016 Jun;54(6):1487-95. PubMed PMID: 27008872. Pubmed Central PMCID: PMC4879311. Epub 2016/03/25. eng.
3. Alanio A, Hauser PM, Lagrou K, Melchers WJ, Helweg-Larsen J, Matos O, et al. ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. The Journal of antimicrobial chemotherapy. 2016 Sep;71(9):2386-96. PubMed PMID: 27550991. Epub 2016/08/24. eng.
4. Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2007 Feb;13(1):1-7. PubMed PMID: 17334722. Epub 2007/03/06. eng.
5. Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Mar;13 Suppl 4:272-9. PubMed PMID: 23465020. Epub 2013/03/08. eng.
Covid19
PCP
Pneumonia
CMV
mTORi induced interstitial pneumonitis:
In the early clinical trials of sirolimus, several cases of fatal Pneumocystis pneumonia were described in patients who did not receive prophylactic Bactrim.
noninfectious interstitial pneumonia has also been described, typically presenting as bilateral lower-lobe interstitial pneumonia. Pathologic features are similar to bronchiolitis obliterans organizing pneumonia with alveolar hemorrhage and lymphocytic infiltration. The diagnosis is one of exclusion, and the pneumonia
typically resolves within 2 to 3 weeks of drug discontinuation.
Presentation , fever, chest pain, cough
In patient with HIV , the risk of pneumonia due to TB , PJP and other opportunistic and bacterial infections is increased. As she suffers from fever , dry cough , desaturation with exersion and had normal CXR , PJP is the most probable diagnosis.
Management :
1- Lab : CBC with differntial , procalcitonin , CRP .
2- Bronchoscopy , BAL for C&S as well as PCR for TB and PJP.
3- PCR for Covid and CMV .
Treatment :
1- Decrease IS doses specially MMF .
2- Monitoring of graft function.
3- For PJP : TM – SMX , alternatively Dapsone if the patient is allergic to sulfa.
4- For CMV : CMV pneumonia : 5 mg /kg IV gancyclovir for 5 days followed by oral vlgancyclovir.
5- For TB : INH+ rifambicin .
6- For other bacterial infection : based on culture and sensitivity.
· Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
Introduction
The mammalian target of rapamycin inhibitor (mTORi) sirolimus was introduced into clinical transplantation in 1999. It is frequently used either in the induction phase or for maintenance immunosuppression to prevent acute and chronic rejection. Sirolimus is often used to achieve adequate immunosuppression while decreasing the dose and possible toxicity of primary agents, such as calcineurin inhibitors. Dose related myelosuppression and hyperlipidemia are the most common side effects. Pulmonary toxicity had been reported since 2004 and can cause interstitial pneumonitis, organizing pneumonia, and alveolar hemorrhage
The mechanism of sirolimus induced interstitial pneumonitis is still unclear.
A cell-medicated autoimmune response may have a role when cryptic pulmonary antigens are exposed, and this causes lymphocytic alveolitis and interstitial pneumonitis. T-cell mediated, delayed type hypersensitivity may be another pathogenic mechanism
The common radiological findings are bilateral patchy, interstitial opacities. Consolidation or nodular opacities are less commonly seen. BAL lymphocytosis is usually associated with drug induced pneumonitis. The histopathological features from biopsies include organizing pneumonia, interstitial pneumonitis, focal fibrosis, non-necrotizing macrophagocytic granulomas, and pulmonary hemorrhage
Risk factors of sirolimus induced pulmonary pneumonitis are not completely understood.
Previous studies have reported that male gender, high dose sirolimus, and exposure to sirolimus after toxicity to other drugs may increase the risk of pulmonary toxicity
Drugs induced pneumonitis should always be considered in transplant patients after infectious or other etiologies have been excluded. Sirolimus can cause granulomatous infiltrates in the lung possibly secondary to T-cell mediated hypersensitivity
Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds:
(a) occurrence of pneumonitis during sirolimus therapy.
(b) absence of any other causes.
(c) resolution within 3 months of sirolimus discontinuation or dose reduction. Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.
References –1S. Garrean, M.G. Massad, M. Tshibaka, Z. Hanhan, A.E. Caines, E. Benedetti
Sirolimus associated interstitial pneumonitis in solid organ transplant recipients
Clin Transplant, 19 (2005), pp. 698-703 View article CrossRefView in ScopusGoogle Scholar
2-E. Morelon, M. Stern, D. Israeal-Biet, J.M. Correas, C. Danel, M.F. Mamzer-Bruneel, et al.
Characteristics of sirolimus associated interstitial pneumonitis in renal transplant patients
Transplantation, 72 (2001), p. 787
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· What is the clinical picture of aspergillosis?
There are five major clinical forms of aspergillosis, of which rhinocerebral (sinuses and brain) and pulmonary (lung) infections are the most common. The clinical hallmark of aspergillosis is the rapid onset of tissue necrosis (tissue death) with or without fever. Necrosis is the result of invasion of blood vessels and subsequent thrombosis (blood clotting).
• Rhinocerebral aspergillosis is most commonly seen in neutropenic (low white blood cell counts) cancer patients, hematopoietic stem cell transplant (HSCT) recipients, and patients with diabetic ketoacidosis. Symptoms may include unilateral (one-sided) facial swelling, headaches, nasal or sinus congestion or pain, serosanguinous (bloody) nasal discharge, and fever. As the infection spreads, ptosis (“drooping eyelid”), proptosis (eye dislocation), loss of extraocular muscle function, and vision disturbance may occur. Necrotic black lesions on the hard palate (upper inside of mouth) or nasal turbinate (nasal cavities) and drainage of black pus from eyes are useful diagnostic signs.
• Pulmonary (lung) aspergillosis generally occurs in patients with hematologic malignancy (blood cancers) or profound neutropenia and in those who have been on steroid therapy. The symptoms include fever, cough, chest pain, and dyspnea (shortness of breath). Angioinvasion results in necrosis of tissue, which may ultimately lead to cavitation (formation of empty spaces) and/or hemoptysis (coughing up blood).
• Gastrointestinal aspergillosis is rare and is thought to result from ingestion of microorganisms and occurs in severely malnourished patients and transplant recipients. The stomach, colon, and ileum are most commonly affected. Symptoms depend on which area is affected, but the most common symptoms are nonspecific abdominal pain and bloating with nausea and vomiting. Gastrointestinal basidiomycosis, a rare type of infection, has been reported in Arizona. Symptoms such as fever, abdominal pain, diarrhea, and constipation are nonspecific, and masses in the gastrointestinal tract may appear on abdominal images. Diagnosis requires microscopic examination and biopsy culture.
• Cutaneous (cutaneous) aspergillosis can be primary or secondary. Primary infection usually results from direct inoculation of the fungus into damaged skin and is most commonly seen in patients with burns or other forms of localized skin damage. Primary infection causes an acute inflammatory response with pus, abscess formation, tissue swelling, and necrosis. Lesions may be red and hardened (hardened) and often develop as black scabs (dead tissue). Secondary cutaneous infection is generally seen when the pathogen spreads hematogenously (in the blood). In hematogenously disseminated infection, the lesions typically begin as an erythematous (reddened), indurated, and painful cellulitis (skin inflammation) and then progress to an ulcer covered with a black eschar.
• Disseminated aspergillosis may follow any of the four forms of aspergillosis described above but is usually seen in neutropenic patients with a pulmonary infection. The most common site of spread is the brain, but metastatic necrotic lesions have also been found in the spleen, heart, and other organs. Clinical manifestations include lethargy, changes in mental status, or obtundation (reduction in mental status) with or without a sudden onset of focal neurological signs.
Reference:
CDC
Infection depends on the timing of transplantation. This patient’s dyspnea on exertion with non-significant findings on CXR entails further evaluation with chest CT. If the patient is on prophylaxis, we do not expect CMV and PJP. This patient’s ddx should include viral infections, including influenza, RSV, CMV etc.
Interstitial pneumonia can rarely occur due to mTOR inhibitors. Bronchiolitis obliterans can evolve as well. Although it is a class side effect, shifting from sirolimus to everolimus resolved pneumonia in some cases.
D/D: PJP, viral pneumonia ( CMV, Covid -19, RSV, infuenza), atypical bacterial pneumonia, oppurtunistic fungal pneumonia (e.g. Aspergillosis).
Mx: Do all necessary test ( CBC, LFT, RFT, all possible culture, HRCR chest, S. LDH, induced sputum /BAL for staining of PJP, CMV PCR)
Modification of IS agent, start TMP/ SMX.
PCP is the most common opportunistic respiratory infection in patients with (AIDS). It typically occurs in patients with (HIV) with a CD4 count <200 cells/microL who are not receiving antiretroviral therapy or appropriate prophylaxis
What is the differential diagnosis?
acute bronchitis, pneumonia due to bacteria, fungi, viruses and mycobacteria, neoplasm, drug hypersensitivity, pulmonary hypertension, and cardiomyopathy.
Pulmonary infections with specific organisms are a significant concern in patients with HIV and CD4 counts less than 200 cells/microL.
These include tuberculosis, nontuberculous mycobacteria, several different fungi, toxoplasma, cytomegalovirus, and influenza. Kaposi’s sarcoma involving the lung is also a concern, particularly in patients with CD4 counts less than 100 cells/microL.
Compared with PCP, tuberculosis is associated with more severe constitutional symptoms. The incidence of TB in individuals with HIV varies markedly depending on epidemiology. Most cases in the United States now occur in individuals originally from countries where TB is highly endemic, or in those with risk factors for exposure (eg, prisoners, injection drug users, household contacts of active TB cases).
Nontuberculous mycobacteria
There are a variety of nontuberculous mycobacteria (NTM) that can cause disease in patients with HIV, especially in those with CD4 cell counts less than 50 cells/microL. Most disease in HIV secondary to NTM presents as disseminated disease, without respiratory symptoms or pulmonary involvement; this is particularly the case for Mycobacterium avium complex (MAC). This manifestation of MAC is different from the multifocal nodular disease (with “tree in bud” radiographic opacities) seen in immunocompetent hosts, such as those with bronchiectasis. However, on rare occasions disease due to M. kansasii and M. xenopi can present with localized pulmonary findings.
Fungi — Patients with HIV who are from regions known to have endemic fungal infections can present with disseminated diseases that may mimic PCP. The most important of these is disseminated histoplasmosis. Both diagnoses should be considered in a patient with fever, cough, and diffuse interstitial infiltrates who is from a histoplasmosis-endemic area. Elevated beta-glucan levels are observed in both PCP and histoplasmosis. Findings suggestive of histoplasmosis include adenopathy, hepatosplenomegaly, and/or the presence of oral or other mucosal ulcerations. The diagnosis is confirmed with histoplasmosis antigen testing. Other fungi, including cryptococcus and coccidioides, can also mimic PCP.
Toxoplasma — Pneumonitis, as an extracerebral manifestation of toxoplasmosis, presents with fever, dyspnea and non-productive cough
Cytomegalovirus — Pneumonitis due to Cytomegalovirus (CMV) typically occurs in patients with HIV and CD4 cell counts less than 50 cells/microL. CMV pneumonitis and PCP have similar clinical presentations, but CMV pneumonitis is much less common in patients with HIV. A definitive diagnosis of CMV pneumonitis requires observing CMV inclusion bodies on biopsy.
Influenza — Individuals with HIV are considered at high risk for complications of influenza, one of which is primary influenza pneumonia. This presents with the acute onset of a severe viral syndrome (fever, myalgias, headache) followed by progressive respiratory symptoms such as dyspnea and possibly cyanosis. Typical radiographic manifestations include bilateral reticular or reticulonodular opacities with or without superimposed consolidation. High-resolution computed tomography (CT) may show multifocal peribronchovascular or subpleural consolidation and/or ground glass opacities. Unlike the acute onset of influenza pneumonia, symptoms associated with PCP occur in a subacute fashion.
COVID-19 and Pneumocystis pneumonia can present with dry cough and oxygen desaturation with ambulation. In addition, both can have ground-glass opacities on chest CT. Given these similarities, the diagnosis of Pneumocystis may not be considered, especially when COVID-19 incidence is high Although chest CT findings are more likely to involve the upper lobes in patients with Pneumocystis pneumonia, whereas chest CT abnormalities often have a peripheral distribution and involve the lower lobes in patients with COVID-19, there are no pathognomonic radiographic findings that would lead to the exclusion of either diagnosis without further testing. In some patients, concurrent COVID-19 and Pneumocystis pneumonia have been reported
The diagnosis of COVID-19 is typically based on the results of polymerase chain reaction (PCR) testing from a nasopharyngeal swab.
Kaposi sarcoma may cause a multifocal nodular disease in individuals with HIV and CD4 counts less than 100 cells/microL. Although most patients with pulmonary symptoms have skin findings, up to 20 percent have no evidence of cutaneous disease. Direct visualization of characteristic lesions on bronchoscopy remains the gold standard for diagnosis; if bronchoscopy cannot be performed, findings with nuclear scans can help differentiate KS from PCP.
How do you manage this case?
ADMISSION ICU ISOLATION ROOM
ABG
SEPTIC SCREEN (BLOOD -URINE -SPUTUM CULTURES -CRP -LDH )
Patients who show progressive respiratory failure (eg, increased respiratory rate, worsening oxygen saturation) may require mechanical ventilatory support. For such patients, low tidal volumes and plateau pressures should be used given the potential presence of pneumatoceles, which increase the risk of pneumothorax
Antimicrobial therapy directed against P. jirovecii is the mainstay of treatment for (PCP). some patients will require adjunctive corticosteroids. Antiretroviral therapy (ART) should be initiated to restore immune function. Although PCP is uncommon in those on ART, for those patients already receiving it, continue their ART regimen while they are being treated for PCP.
Empiric therapy for PCP should be initiated pending the results of the diagnostic evaluation if there is a high clinical suspicion for PCP (eg, CD4 count <200 cells/microL, hypoxemia, interstitial infiltrates). In certain situations, it is not possible to confirm the diagnosis, and patients are treated and monitored for clinical response
After patients complete their initial treatment regimen, antimicrobial therapy should be continued at lower doses to prevent recurrent infection (ie, secondary prophylaxis). This preventive therapy can be discontinued after immune recovery has been achieved for a prolonged period of time
(TMP-SMX), a sulfa-containing regimen, is the preferred treatment for PCP.
standard dose of TMP-SMX is 15 to 20 mg/kg/day orally or intravenously in three or four divided doses.
For patients with mild to moderate disease, we prefer oral therapy since TMP-SMX has excellent oral absorption. For most patients, this turns out to be two double-strength tablets given every six or eight hours, depending upon body weight.
For patients with severe disease, administer IV therapy.
Alternative regimens For those who are unable to take TMP-SMX
Alternative regimens for mild to moderate disease
The following oral regimens should be administered for 21 days
●Trimethoprim-dapsone – Oral trimethoprim is administered at a dose of 5 mg/kg (typically rounded to the nearest 100 milligrams) three times per day with dapsone 100 mg per day.
●Clindamycin-primaquine – Oral clindamycin-primaquine is administered as clindamycin (450 mg every six hours or 600 mg every eight hours) along with primaquine base 30 mg per day.
●Atovaquone – Atovaquone suspension can be used for the treatment of mild PCP . The dose is 750 mg twice daily and should be taken with food
Alternative regimens for severe disease
clindamycin-primaquine for patients with severe disease who cannot take TMP-SMX. However, primaquine must be administered orally; thus, IV pentamidine must be used for patients with severe PCP who have a life-threatening sulfonamide allergy and cannot take oral medications.
We prefer clindamycin-primaquine rather than IV pentamidine based upon the lower rate of severe side effects.
Corticosteroid regimen — Corticosteroids should be initiated concurrently with anti-Pneumocystis therapy. we administer the following 21-day oral regimen
●Prednisone 40 mg twice daily for 5 days
followed by
●Prednisone 40 mg daily for 5 days
followed by
●Prednisone 20 mg daily for 11 days
Intravenous methylprednisolone can be substituted for oral prednisone at 75 percent of the prednisone dose if IV therapy is necessary
.Aerosolized pentamidine – administer AP for PCP prophylaxis only when other therapies cannot be used. The recommended dose of AP is 300 mg monthly via a nebulizer. AP is generally administered with two puffs of albuterol to reduce cough and bronchospasm.
Screening for active tuberculosis including a baseline chest x-ray, should be performed before AP is administered since there is a concern about transmission of tuberculosis to health care workers and other patients through pentamidine-induced bronchospasm
. In addition, AP should be administered in a negative pressure room in order to contain both aerosolized particles of the drug and any microbes that may be expectorated.
When AP needs to be administered in an individual patient’s hospital room
, a HEPA-filtered containment tent should be used and the airflow into this room should be temporarily altered to negative pressure, if possible.
The major side effects of AP are cough and bronchospasm. The use of AP is also a risk factor for developing a pneumothorax
Early infection post transplantation is common, and it is one of the main causes of morbidity and mortality.
Presentation with 2 weeks dry cough, low grade fever with desaturation on exertion on the background of HIV AIDS on HAARTs in addition to recent kidney transplant on immunosuppression is highly suggestive of opportunistic infection like PJP, CMV and fungal infection.
So, my differential includes:
1-Pneumocystic Jerovecii Pneumonia
2-CMV pneumonitis
3-Fungal infection like Aspergillus
4-Bacterial Pneumonia
Management starts with detailed history of presenting complaints and target history if risk factors for opportunistic infections. Like type of immunosuppression, any lymphocyte depleting agents, recent rejection and its treatment, WBC counts and its differential including CD4 count, PJP and CMV prophylaxis. In addition to donor CMV status, donor history of recent infection.
We need to do routine initial investigations including CBC differential, Chemistry, septic workup, sputum culture, BAL for PJP, CMV, TB and fungal culture.
Normal chest xray doesn’t exclude PJP, we need to do CT scan of the chest which is more sensitive.
General treatment of such case, including admission to HDU, support with oxygen as needed, reduction of immunosuppression such 50% reduction MMF and FK to lower end of target putting in mind risk of rejection. Broad spectrum antibiotics, anti PJP and CMV.
Treatment of PJP:
First line cotrimoxazole 5mg( trimethoprim /kg 8-12 hourly IV for 14-21 days, alternatives are:
Clindamycin, Pentamidine IV at 4mg/kg/day or atovaquone PO 750 mg BID.
References;
1-Medescape, PJP treatment
2- Prophylaxis and treatment of Pneumocystis Jirovecii pneumonia after solid organ transplantation Pharmacological Research Volume 134, August 2018, Pages 61-67
What is the differential diagnosis?
This will include-
· PCP pneumonia
· CMV pneumonitis
· COVID 19
· Bacterial pneumonia
· Tuberculosis
· Aspergillosis
How do you manage this case?
The will include investigations-
· Blood tests like Blood CP/ESR, renal and liver functions, CRP , Clotting profile
· ABGs
· CMV PCR
· LDH
· Beta D Glucan
· BAL for staining , culture , PCP PCR
· HRCT Chest
Treatment
Patient will require admission, oxygen supplementation and optimization.
Adopting a multimodality approach
For PCP
Trimethoprim 15 mg/kg
Sulphamethoxazole 75 mg/kg
in 3-4 divided doses
In case of allergy to sulpha drugs-
Atavaquone 750 mg, orally twice daily for 21 days
Trimethoprim 15 mg/kg/day by mouth twice daily plus dapsone 100 mg by mouth every day,
Primaquine 30 mg daily, plus clindamycin by mouth 450 mg every 6 hours or 600 mg every 8 hours.
Modification by immune suppression- Reduce Tac by 50%, stop antimetabolites
Adjuvant steroids will be given
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.
– clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
>c/p:
nonspecific symptoms (fever, fatigue, tiredness, cough & dyspnsea)
CXR may be normal
CT chest findings: ground glass opacities, fibrosis, bronchiolitis obliterans & perihilar infiltrations
Lung biopsy show lymphocytic infiltration which favour direct toxicity as the pathophysiology
Incidence is more if sirolimus level is higher than therapeutic levels but within target sirolimus level can not rule out the diagnosis
Clinical improvement on discontinuation of the drug
>treatment:
– stop sirolimus
– shift of everolimus may be tried (incidence is low compared to sirolimus)
– high dose steroid in serious cases
(Interstitial pneumonitis as an adverse reaction to mTOR inhibitors Gloria Molas-Ferrer, Dolors Soy-Muner, Helena Anglada-Martínez, Gisela Riu-Viladoms,Anna Estefanell-Tejero, Josep Ribas-Sala Servicio de Farmacia Hospitalaria. Hospital Clínic de Barcelona (Spain),Nefrologia 2013;33(3):297-300)
– What is the clinical picture of aspergillosis?
Guidelines on the management of aspergillosis by the Infectious Diseases Society of America are as follows:
– high level of suspicion in immunocompromised patient
– sputum culture &cytology
– DNA sequencing
– x ray findings of well demarcated cavity
– ct chest showing halo sign
– Bronchoscopy with bronchoalveolar lavage.
-Detection of galactomannan (a component of the Aspergillus cell wall) in serum or bronchoalveolar lavage fluid is recommended as an accurate marker for the diagnosis of invasive aspergillosis in adults and children.
Scenario 3
Young female withHIV associated nephropathy had a DD kidney transplantation.
CD4 count is 250/ml and receiving HAART.
She presented with 2 weeks history of non-productive cough, low grade temperature (37.5 °C) and dyspnoea on excretion.
chest X-Ray reported normal.
few scattered wheezes.
Sat 100% on air and desaturates to 95% on exertion.
Based on the data above the PCP pneumonitis is the most probable diagnosis .
Viral infection influenza ,COVID 19, CMV pneumonitis ….
Bacterial pneumonia
TB pneumonia
Fungal infection PJP,Aspergillosis
Pneumocystis pneumonia can be life threatening. It can cause respiratory failure that can lead to death. People with this condition need early and effective treatment. Giving history of HIV on HAART making this patient in a high risk , MDT is mandatory in management.
Hx and clinical examination is clue in any management
Routine labs CBC,KFT ,LFT ,CRP ,LDH ,Serum electrolytes,urine analysis and culture
Blood culture
Induced sputum culture
All respiratory secretions should be stained using antibodies for PCP (immunoflourescent, immunoperoxidase, or similar) as well as routine stains for Pneumocystis and other organisms (Giemsa, Silver, and others) . Use of PCR-based diagnostics on respiratory secretions can be considered .Samples should also be assayed for routine bacterial, fungal, mycobacterial, and other organisms to rule out concomitant infections. Evaluation for CMV or other respiratory viral coinfection, in particular, should be considered .
bronchoscopy with BAL to obtain diagnostic samples .This may have the dual advantage of increasing the yield and helping expedite the diagnosis of other and/or concomitant infections.
bronchoscopy should be considered for transbronchial biopsies. Increased yield is likely obtained by multiple samples .
Measurement of plasma (1→3) β-d-glucan levels can be considered and may suggest the diagnosis .This assay lacks specificity for Pneumocystis, however, and can be positive in the setting of other invasive fungal infections.
Open lung biopsies can be obtained when other diagnostic approaches have been unrevealing or where other concomitant diseases may be a concern .Video-assisted thoracoscopic (VATS) biopsies may be appropriate for some patients in this regard.
First line treatment is with TMP-SMX 15 to 20 mg/kg for 21 days.
Treatment of severe disease should include adjunctive steroids as for HIV-infected persons with PJP (60 mg/day initially, then taper).
Second line agents include intravenous pentamidine (4 mg/kg/day), dapsone-trimethoprim (100 mg dapsone daily with trimethoprim 100 mg twice daily), or clindamycin plus primaquine (600 mg 4 times daily clindamycin with 30 mg base daily primaquine).
Mild-to-moderate PJP can be treated with atovaquone (750 mg orally twice daily for 21 days) in patients allergic to TMP-SMX.
Prophylactic agents, in order of efficacy, include TMP-SMX (single-strength tablet 3 times weekly), monthly aerosolized pentamidine, daily dapsone, and daily atovaquone.
Prophylaxis against disease should be reinstituted following augmentation of immunosuppression, such as steroid bolus or ATG administration for acute rejection.
Patients reporting sulfa allergies should be questioned regarding the nature of their reaction; desensitization may be possible with mild reactions. For those with severe allergies, dapsone should also be avoided, and PJP prophylaxis provided using atovaquone.
Reference
Pneumocystis Pneumonia in Solid Organ Transplantation
S. I. Martin, J. A. Fishman, the AST Infectious Diseases Community of Practice
SIXTH EDITION Handbook of Kidney Transplantation ,Edited by Gabriel M. Danovitch, MD
Medical Director, Kidney and Pancreas Transplant Program Ronald Reagan Medical Center at UCLA John J. Kuiper Chair of Nephrology and Renal Transplantation Distinguished Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
Mammalian target of rapamycin inhibitors (mTORi) have clinically significant activity against various malignancies, such as renal cell carcinoma and breast cancer, but their use can be complicated by several toxicities.
-Interstitial lung disease (ILD) is an adverse event of particular importance.
Mostly, mTORi-induced ILD remains asymptomatic or mildly symptomatic, but it can also lead to severe morbidity and even mortality.
-Because of the nonspecific clinical features and non specific laboratory findings , a broad differential diagnosis that includes (opportunistic) infections should be considered in case of suspicion of mTORi-induced ILD.
The radio-graphic manifestations of drug-induced ILD by mTORi change over time.
In general, CT patterns can be divided into 4 groups pattern :
A: (nonspecific areas of ground-glass attenuation);
B: (multifocal areas of airspace consolidation);
C: (patchy distribution of ground-glass attenuation accompanied by inter-lobular septal thickening); and
D: (extensive bilateral ground-glass attenuation or airspace consolidation with traction bronchiectasis) .
The A, B, and C patterns are not specific to ILD but are often seen in patients with PCP .
A, B, and C patterns are not specific but pattern D is difficult to distinguish from PCP, particularly in patients with underlying pulmonary diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, and pulmonary fibrosis.
What is the clinical picture of aspergillosis?
-Rhinocerebral aspergillosis is most common in neutropenic, hematopoietic stem cell transplant (HSCT) recipients, and diabetic ketoacidosis, with symptoms such as facial swelling, headaches, nasal congestion, and fever.
-Gastrointestinal aspergillosis is less common, is thought to arise from ingestion of the organism, and occurs in patients who are severely malnourished and in transplant recipients.
-Gastrointestinal basidiobolomycosis, a rare type of infection, has been reported in Arizona.Its symptoms are non-specific, including fever, abdominal pain, diarrhea, and constipation, and abdominal imaging will reveal masses in the gastrointestinal tract.
-Cutaneous (skin) aspergillosis may be primary or secondary.
-Disseminated aspergillosis: is usually seen in neutropenic patients with a pulmonary infection, with the most common site of spread being the brain.
Referrence :
3.CDC Clinical Features of aspergillosis
39-year-old CKD 5 secondary to HIV associated nephropathy had a deceased donor kidney transplantation. CD4 count is 250/ml and receiving HAART. Currently she is on Tacrolimus-based triple immunosuppression. Her kidney function has improved and started to pass more urine. She presented with 2 weeks history of non-productive cough, low grade temperature (37.5 °C). She has dyspnoea on excretion (respiratory rate at rest is 20/min) but chest X-Ray reported normal. Clinically there were few physical findings only few scattered wheezes. Sat 100% on air and desaturates to 95% on exertion.
– this patient with history of HIV associated nephropathy while CD4 is more than 200/ (250/ml) with HAART means decreased viral load.
– developed dry cough, desaturated and dyspnea on exercise
The differential diagnosis
1- PCP.
2-CMV pneumonitis .
3-Covid-19 pneumonia
4-TB
How to mange :.
Respiratory support with target SPO2 > 92%
Pan culture ( blood culture aerobic, anaerobic and urine culture)CMV PCR
Blood chemistry :- CBC, D-dimer, renal panel, liver panel
LDH : it more than 495 denotes very bad survival outcomes.
***As regard to immunosuppression
– Glucocorticoid: If used alone no risk for PCP but it used with other immunosuppressive medication can be predisposed for PCP e.g: mTOR inhibitors
-Mucophenolate mofetil increased risk for PCP while mycophenolate sodium is not proved to cause that.
– sirolemus, studies showed that it considered risk factor for PCP.
for management of PCP :
1- first line of therapy : TMP-SMX 15-20mg/kg for 21 days , if disease associated with HIV , we give steroid gong then titrated.
2- second line of therapy intravenous pentamidine 4 mg/kg/d, dapsone-trimethoprim 100 mg dapsone daily + trimethoprim 100 mg twice daily) or clindamycin + primaquine (600 mg/6H daily + clindamycin 30mg with base daily primaquine
For HIV:
Continue antiretroviral therapy with follow up for proteinuria and consider ACEI or ARBS if present
References:
uptodate
week 5 lecture
Thank you all
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
What is the clinical picture of aspergillosis?
Clinical picture of mTORi induced interstitial pneumonitis mimics quite a lot with opportunistic lung infections like PJP. Its quite difficult to differentiate between two on basis on x ray. But History of recent conversion from CNI to mTORi, absence of fever, associated renal dysfunction favours more towards mTORi induced pneumonitis.
Exclusion of other infections and response in symptoms after reduction in mTORi confirms the diagnosis.
Clinical features of aspergillosis includes:
Pleuritic chest pain and hemoptysis is differentiating feature of pulmonary aspergillosis from PJP
REF:
https://www.revistanefrologia.com/index.php?p=revista&tipo=pdf-simple&pii=X2013251413003279&r=498
👉 mTORi induced interstitial lung disease;
_ Similar in presentation with PCP (marked desaturation, few auscultatory findings and dry cough).
_Use of mTORi is the clue together with improvement of symptoms after it’s discontinuation.
_negative PCP PCR in BAL.
👉clinical picture of aspergillosis;
_ Clinical triad of fever, pleuritic chest pain (increase with respiration and the patient lies on the affected side), and hemoptysis.
_rhiosinusitis commonly coexist with severe pain localized to the sinuses.
_CT chest show localized infiltration or nodular affection (halo sign that represents hemorrhage around the fungus), and some times cavitation called (air crescent sign).
_CBC shows eosinophilia and neutropenia.
_elevated level of IgE
mTOR inhibitors caused non infectious interstitials pneumonia
presented by bilateral lower lobe interstitial pneumonia
Pathological features are the same as bronchiolitis obiltrans organising pneumonia with alveolar haemorrhage and lymphocytic infiltrations
Causes of noninfectious pulmonary infiltrates are common in immunocompromised patients are :
pulmonary embolus
tumour
radiation pneumonitis
cancer
fibrosis
atelectasis with pulmonary oedema
drug allergy or toxicity
pulmonary haemorrhage
where when fever is resolved after antibiotics trial is suggesting that infection was present.
>>>Hypoxemia with high lactic dehydrogenase or beta-1,3-glucan and minimal radiographic findings are common PCP while the absence of hypoxemia with evidence pulmonary consolidation is more common in nocardiosis, tuberculosis, and fungal infections until been later in the course.
Clinical pictures of aspergillosis:
fever
chest pain
shortness of breath
cough
haemoptysis
classic triad has been described in neutropenic patients with pulmonary aspergillosis is fever, pleuritic chest pain and hemoptysis
on other hand, the absence of this triad mustn’t consider diagnosis in the patient with risk factors for disease since neutropenic patients frequently present with fever where localising pulmonary symptoms not present.
such patient , image will often showed pulmonary nodules and/or infiltrates.
References:
Handbook of kidney Transplantation sixth edition Gabriel M. Danovitch
uptodate
mTORi-induced interstitial pneumonitis
-The incidence of this adverse effect was estimated at 4-11%
-Pneumonitis caused by mTOR inhibitors has heterogeneous clinical manifestations
-Nonspecific signs and symptoms, may begin with fever, fatigue, coughing and dyspnea.
– Patients may also exhibit occasional systemic symptoms, such as fever and fatigue, making the distinction from infectious causes more difficult
– It may appear at the beginning or after several years of treatment.
– No pathognomic radiological feature; CXR may be normal, CAT finding includes: ground glass opacities, peripheral infiltrates and patterns of bronchiolitis obliterans have been observed.
– Diagnosis is difficult and tends to be made by excluding other causes, such as infections, autoimmune diseases or toxicity due to other products.
– Clinical improvement upon discontinuation of the drug can confirm the diagnosis
-It has been observed that patients who began post-transplant immunosuppression directly with mTOR inhibitors have a lower incidence of pneumonitis than those who started treatment with calcineurin inhibitors and subsequently changed to sirolimus or everolimus.
– Treatment ; dose reduction or discontinue mTOR and high doses of corticosteroids.
Pulmonary Aspergillosis:
-Signs and symptoms: fever, chest pain, shortness of breath, cough, and/or hemoptysis.
The classic triad in neutropenic patients is fever, pleuritic chest pain, and hemoptysis.
-Radiologically manifests as single or multiple nodules with or without cavitation, patchy or segmental consolidation, or peribronchial infiltrates with or without tree-in-bud patterns. The initial findings typically include nodules that have surrounding ground-glass infiltrates (the halo sign), reflecting hemorrhage into the area surrounding the fungus the nodule eventually cavitate, producing the air-crescent sign
-Histopathology − Invasive aspergillosis is characterized by progression of the infection across tissue planes. One hallmark of infection is vascular invasion with subsequent infarction and tissue necrosis.
–Diagnosis: is based upon both clinical suspicion and isolating the organism from respiratory specimen (sputum, BAL).
–fungal staining with Gomori methenamine silver or periodic acid-Schiff staining; septated branching hyaline hyphae.
– Fungal culture
– Galactomannan antigen detection in serum or BAL fluid, it can be detected in the serum before the presence of clinical signs or symptoms of invasive aspergillosis. It has low PPV <50% and high NPP >90 %.
– beta-D-glucan assays; not specific for Aspergillus and can be positive in patients with a variety of invasive fungal infections including PCP.
– PCR on serum or BAL
References:
-Molas-Ferrer G, Soy-Muner D, Anglada-Martínez H, Riu-Viladoms G, Estefanell-Tejero A, Ribas-Sala J. Interstitial pneumonitis as an adverse reaction to mTOR inhibitors. Nefrologia. 2013;33(3):297-300. English, Spanish. doi: 10.3265/Nefrologia.pre2013.Jan.11439. PMID: 23712219.
-Husain, S, Camargo, JF, on behalf of the AST Infectious Diseases Community of Practice. Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33:e13544.
Thank you Prof. Ahmad
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
What is the clinical picture of aspergillosis?
ABPA is dominated by asthma and recurrent exacerbations, fever, malaise, expectoration of brownish mucus plugs, elevated serum eosinophils> 500/microL and IgE level >1000 IU/mL.
Chest Xray:
CT chest: widespread proximal cylindrical bronchiectasis with upper lobe predominance and bronchial wall thickening, mucus plugging, tree-in-bud opacities, atelectasis, peripheral airspace consolidation, or ground-glass attenuation, and possibly mosaic perfusion or air trapping, and a fungus ball.
References:
(1) Willemsen AE, Grutters JC, Gerritsen WR, van Erp NP, van Herpen CM, Tol J. mTOR inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm. Int J Cancer. 2016 May 15;138(10):2312-21. doi: 10.1002/ijc.29887. Epub 2015 Oct 27. PMID: 26452336.
(2) Cillóniz C, Dominedò C, Álvarez-Martínez MJ, Moreno A, García F, Torres A, Miro JM. Pneumocystis pneumonia in the twenty-first century: HIV-infected versus HIV-uninfected patients. Expert Rev Anti Infect Ther. 2019 Oct;17(10):787-801. doi: 10.1080/14787210.2019.1671823. Epub 2019 Oct 4. PMID: 31550942.
(3) Bateman M, Oladele R, Kolls JK. Diagnosing Pneumocystis jirovecii pneumonia: A review of current methods and novel approaches. Med Mycol. 2020 Nov 10;58(8):1015-1028. doi: 10.1093/mmy/myaa024. PMID: 32400869; PMCID: PMC7657095.
(4) UpToDate- clinical manifestations of aspergillosis.
– clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
>c/p:
nonspecific symptoms (fever, fatigue, tiredness, cough & dyspnsea)
CXR may be normal
CT chest findings: ground glass opacities, fibrosis, bronchiolitis obliterans & perihilar infiltrations
Lung biopsy show lymphocytic infiltration which favour direct toxicity as the pathophysiology
Incidence is more if sirolimus level is higher than therapeutic levels but within target sirolimus level can not rule out the diagnosis
Clinical improvement on discontinuation of the drug
>treatment:
– stop sirolimus
– shift of everolimus may be tried (incidence is low compared to sirolimus)
– high dose steroid in serious cases
(Interstitial pneumonitis as an adverse reaction to mTOR inhibitors Gloria Molas-Ferrer, Dolors Soy-Muner, Helena Anglada-Martínez, Gisela Riu-Viladoms,Anna Estefanell-Tejero, Josep Ribas-Sala Servicio de Farmacia Hospitalaria. Hospital Clínic de Barcelona (Spain),Nefrologia 2013;33(3):297-300)
– What is the clinical picture of aspergillosis?
Guidelines on the management of aspergillosis by the Infectious Diseases Society of America are as follows:
– high level of suspicion in immunocompromised patient
– sputum culture &cytology
– DNA sequencing
– x ray findings of well demarcated cavity
– ct chest showing halo sign
– Bronchoscopy with bronchoalveolar lavage.
-Detection of galactomannan (a component of the Aspergillus cell wall) in serum or bronchoalveolar lavage fluid is recommended as an accurate marker for the diagnosis of invasive aspergillosis in adults and children.
mTORi associated pneumonitis;
-Is not a rare disease; Pneumonitis was not apparently dependent on the drug dose or the blood levels.
-Increased risk factors for pneumonitis include a late switch to sirolimus and impaired kidney function.
-Forty-three cases of pulmonary toxicity due to Sirolimus (rapamycin) have been reported including cases of interstitial pneumonitis, fibrosing alveolitis, and pulmonary hemorrhages.
-The majority of these cases have occurred in renal transplant recipients within the initial six months of iniciation of the drug and lesions have generally responded to the lowering or withdrawal of the drug dosage.
-The mechanism of pulmonary toxicity of Sirolimus (rapamycin) is not clear; direct toxicity, immunomediated toxicity, or both have been proposed as the mechanism.
-The presence of lymphocytes in lung biopsies suggests an immunomediated mechanism.
-Possibly, some cryptic pulmonary antigens induce an autoimmune response.
-Clinical symptoms consist of dyspnea, dry cough, fever, and fatigue.
-Most of the patients present with progressive breathlessness, weakness, cough, and bilateral lower zone pulmonary opacities, and over half of the cases present with fever.
-However, the rapid clearance of lung lesions with the discontinuation of the drug or dose reduction without steroids, favors direct toxicity.
-Discontinuation of mTORi seems to be the safest treatment option to avoid pulmonary fibrosis or a fatal outcome.
-Complete recovery was observed in all patients within six months of sirolimus withdrawal.
-Administration of mTOR inhibitors is a potential risk factor for late-onset PCP after SOT. Targeted PCP prophylaxis based on recipients’ risk factors rather universal prophylaxis may lessen the risk.
Clinical features of aspergillosis;
-Invasive aspergillosis most frequently occurs in the lungs or sinuses after inhalation of conidia, although, less commonly, disease can spread from the gastrointestinal tract or result from direct inoculation into the skin.
Pulmonary aspergillosis;
-Invasive aspergillosis most commonly involves the lungs.
-Patients can present with a number of signs and symptoms: fever, chest pain, shortness of breath, cough, and/or hemoptysis.
-The classic triad that has been described in neutropenic patients with pulmonary aspergillosis is (fever, pleuritic chest pain, and hemoptysis).
-However, absence of this triad should not discourage consideration of this diagnosis in the patient with risk factors for disease since neutropenic patients frequently present with fever in the absence of localizing pulmonary symptoms.
-In such patients, lung imaging often reveals pulmonary nodules and/or infiltrates.
References;
-Pham PT, Pham PC, Donovitch GM, Ross DJ, Gritsch HA, Kendrick EA, et al. Sirolimus-associated pulmonary toxicity. Transplantation. 2004;77:1215–20.
–European Journal of Clinical Pharmacology; m-TOR inhibitors and risk of Pneumocystis pneumonia after solid organ transplantation: Published: 03 August 2019.
-Up To Date; clinical manifestations of invasive aspergillosis: Aug 08, 2022.
mTORi induced pneumonitis
There will be history of mTORi Use
Presentation is similar to PCP
Negative PCP PCR
Improvement after stopping mTORi
Presentation of Aspergillosis
Fever, haemoptysis, pleuritic chest pain
High IgE, Eosinophilia
CT may show infiltrates or haemorrhage around fungus Halo sign
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
The prevalence of mTOR i-induced interstitial pneumonitis post-SOT was reported in the range of 4-11%, more with sirolimus, have no specific clinical or radiological features, and can’t be differentiated om underlying infections including PJP as the clinical symptoms are very diverse and should be suspected in cases with the new introduction of sirolimus, with abnormal renal function and chronic use of CNI, diagnosis very challenges radiological features by CT shows bilateral lower lobes infiltrations ad BAL fluid assessment shows mainly lymphocytic alveolitis with negative cultures ( 2). and in suspected cases, the best treatment is the discontinuation of m TOR I plus steroids course.
What is the clinical picture of aspergillosis?
Again symptoms are nonspecific similar to bronchopneumonia and cough, sob, and fever usually not responding to antibiotics, sometimes patients presented with pleuritic chest pain due to vascular involvement with small pulmonary infarction, hemoptysis, Aspergillus is introduced to the lower respiratory tract by inhalation of the infectious spores, invasive pulmonary aspergillosis should be suspected in critically ill patients, on steroid > 3 weeks and prolonged neutropenia associated with high mortality and can hematogenous dissemination of IPA to the brain with ring-enhancing cerebral infarction ,carry high mortality if not diagnosed and treated early.
Diagnosis
Aspergillus isolated from the sputum, in immunocompetent patients 92% were consistent with colonization and only 4.5% had IPA, and it’s highly predictive of invasive disease in immunocompromised patients. a positive predictive value of 80–90% in some reports
CXR is nonspecific in early stages but can have nodular lesions, HRCT of more diagnostic value with typical multiple nodules peri bronchial infiltrates, and the halo sign ( which is nonspecific), which is mainly seen in neutropenic patients early in the course of infection (usually in the first week) and appears as a zone of low attenuation due to hemorrhage surrounding the nodule. Another late radiological sign is the air crescent sign, which appears as a crescent-shaped lucency in the region of the original nodule secondary to necrosis. bronchoscopy and BAL still recommended with sensitivity and specificity of a positive result of BAL fluid are about 50% and 97%, respectively.
The gold standard in the diagnosis of IPA is a histopathological examination of lung tissue obtained by thoracoscopic or open-lung biopsy, Grocott Methenamine silver fungus stain
Blood culture rarely positive in IPA
References
1. Molas-Ferrer G, Soy-Muner D, Anglada-Martínez H, Riu-Viladoms G, Estefanell-Tejero A, Ribas-Sala J. Interstitial pneumonitis as an adverse reaction to mTOR inhibitors. Nefrologia. 2013;33(3):297-300.
2. Errasti P, Izquierdo D, Martín P, Errasti M, Slon F, Romero A, Lavilla FJ. Pneumonitis associated with mammalian target of rapamycin inhibitors in renal transplant recipients: a single-center experience. Transplant Proc. 2010 Oct;42(8):3053-4.
3. Kanj A, Abdallah N, Soubani AO. The spectrum of pulmonary aspergillosis. Respir Med. 2018 Aug;141:121-131.
Clinical picture of mTORi interstitial lung diseases is nonspecific, includes dry cough, bronchospasm and desaturation. Pathologically, it consists of bronchiolitis obliterans, organising pneumonia,interstitial pneumonitis and non-necrotizing granuloma. Radiologically, features alveolar space infiltrate and non-homogenous opacities bilaterally involing lower zones in particular. The diagnosis is reported increasingly with Sirolimus and diagnosis is concluded by excluding infective and malignant causes with BAL and lung biopsy. The most important point to prove the diagnosis is reversal of lung disease with switching of Sirolimus to Everolimus.
References:
1]Stefan M Weiner et al.Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome–a single-centre experience and review of the literature.Nephrol Dial Transpl 2007 Dec;22(12):3631-7.
For aspergillosis:
1] Neuricerebral aspergillosis , by spreading from sinusitis in immune compromized to involve oropharynx and CNS.
2]Pulmonary Aspergillosis. Cavitatory lesion is common.
3]Gastroentistinal aspergillosis.
4]Cutaneous .
5] Disseminated aspergillosis.
Herewith I am sharing a case report we published in SJKDT in 2009 for pulmonary aspergillosis in a hemodialysis patient.
references:
1]Clinical Features of aspergillosis. CDC2] Wael L Jabur1, Hareth M Saeed2.Pulmonary aspergilloma in a patient on hemodialysis.Year : 2009 | Volume : 20 | Issue : 1 | Page : 133-134
What is the clinical picture of aspergillosis?
Pulmonary aspergillosis — Invasive aspergillosis most commonly involves the lungs Patients can present with a number of signs and symptoms: fever, chest pain, shortness of breath, cough, and/or hemoptysis. The classic triad that has been described in neutropenic patients with pulmonary aspergillosis is fever, pleuritic chest pain, and hemoptysis. However, absence of this triad should not discourage consideration of this diagnosis in the patient with risk factors for disease since neutropenic patients frequently present with fever in the absence of localizing pulmonary symptoms. In such patients, lung imaging often reveals pulmonary nodules and/or infiltrates.
Tracheobronchitis — Aspergillus tracheobronchitis has been reported most commonly in lung transplant recipients but has also been described in other types of hosts (eg, recipients of other solid organ transplants, patients with hematologic malignancies, patients with HIV infection)
Affected patients typically present with prominent dyspnea, cough, and wheezing; they occasionally expectorate intraluminal mucus plugs. Chest imaging may be normal or reveal areas of airway thickening, patchy infiltrates, consolidation, or centrilobular nodules.
●Obstructive bronchial aspergillosis, a condition in which thick mucus plugs filled with Aspergillus hyphae are found in the airways, with little mucosal inflammation or invasion
●Ulcerative tracheobronchitis, in which there is focal invasion of the tracheobronchial mucosa and/or cartilage by fungal hyphae
●Pseudomembranous tracheobronchitis, which is characterized by extensive inflammation and invasion of the tracheobronchial tree with a pseudomembrane composed of necrotic debris and Aspergillus hyphae overlying the mucosa
Lung transplant recipients can also develop aspergillosis of the bronchial stump.
This complication results from infection of the suture material and its incidence can be reduced with the use of nylon monofilaments rather than silk sutures.
Patients complain of cough and may have hemoptysis.
Chronic necrotizing and chronic cavitary pulmonary aspergillosis — Patients who have underlying chronic lung disease are at risk for indolent forms of pulmonary aspergillosis, characterized by cavities or infiltrates that may or may not demonstrate hyphal invasion of tissue on histopathology. Presumably, the slowly progressive nature of this infection is a function of the host immune response, which is enough to hold the organism in check but not to eliminate it. Cough, weight loss, fatigue, and chest pain are common, and the chest radiograph shows a slowly progressive lesion, which can be better defined by CT scanning.
Disseminated infection — In the presence of angioinvasive disease, Aspergillus spp can disseminate beyond the respiratory tract to multiple different organs, including the skin, brain, eyes, liver, and kidneys. Disseminated infection is associated with a very poor prognosis.
Rhinosinusitis — In the paranasal sinuses, aspergillosis can present in an identical fashion to mucormycosis. However, rhinocerebral aspergillosis is usually seen in neutropenic patients with hematologic malignancy, whereas mucormycosis occurs most commonly in those with diabetes mellitus or hematologic malignancy.
nasal congestion, fever, and pain in the face and around the eye are common presenting features. If the orbit becomes involved, additional symptoms may include blurred vision, proptosis, and chemosis. The infection can also extend locally into the vasculature and the brain, leading to cavernous sinus thrombosis and a variety of central nervous system (CNS) manifestations.
CT findings may be subtle and can include focal soft tissue lesions, subtle focal bony erosions, and focal hypodense areas; magnetic resonance imaging (MRI) may also show soft tissue lesions as well as focal enhancement of the sinus lining
Biopsy is necessary to establish the diagnosis; multiple biopsies are sometimes necessary
Central nervous system infection — CNS aspergillosis may occur in the setting of disseminated infection as well as from local extension from the paranasal sinuses. Patients with CNS involvement with Aspergillus spp may present with seizures or focal neurologic signs
Mycotic aneurysms develop in some cases and can rupture, resulting in a hemorrhagic cerebrovascular accident, subarachnoid hemorrhage, and/or empyema formation .
In a study of the CT and/or MRI findings associated with CNS aspergillosis, three patterns were observed
●Ring-enhancing lesions consistent with brain abscesses
●Cerebral cortical and subcortical infarction with or without superimposed hematomas
●Mucosal thickening of a paranasal sinus with secondary intracranial dural enhancement consistent with direct extension from the sinuses
CNS infection is associated with a very poor prognosis.
Endophthalmitis — Aspergillus endophthalmitis may be a presenting feature of disseminated aspergillosis, in which involvement of the deep structures of the eye results not only from hematogenous spread. In other patients, corneal infection or direct inoculation following trauma is the genesis of infection
Patients present with eye pain and visual changes
Progressive infection is characterized by destruction of multiple components of the eye.
Endocarditis — Aspergillus spp are second only to Candida spp as a cause of fungal endocarditis This infection occurs primarily in patients with prosthetic heart valves. In many patients, infection occurs at the time of surgery, with the fungus contaminating the surgical site. Patients may present at any time postoperatively.
Cutaneous aspergillosis — Cutaneous aspergillosis can be either primary, occurring from direct inoculation, usually in the presence of trauma, or secondary, occurring from contiguous extension or bloodborne spread
Diagnosis can only be verified by skin biopsy, which should be taken from the center of the lesion and reach the subcutaneous fat in order to visualize hyphae invading blood vessels of the dermis and subcutis
Gastrointestinal aspergillosis — Aspergillosis can involve the gastrointestinal (GI) tract, causing focal invasion as a primary site of inoculation and presenting as neutropenic enterocolitis (typhlitis), appendicitis, colonic ulcers, abdominal pain, and/or GI bleeding Direct inoculation from the GI tract is likely, with risk factors including neutropenia, receipt of glucocorticoids, and mucosal breakdown (mucositis).
Q1
Q2
Source; hand book of kidney transplantation 6th edition
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
What is the clinical picture of aspergillosis?
Aspirgillosis is acquired by inhalation and is clinically significant only in immunocompromuied individuals since it become invasive (7)
Risk factors for invasive aspirgillosis includes
Clinically
Diagnosis
Radiological findings of Pulmonary aspergillosis includes the following
Treatment
References
1. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012; 367:329.
2. Washino S, Ando H, Ushijima K, et al. Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice. Am J Physiol Lung Cell Mol Physiol 2014; 306: L1117– L1128.
3. Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation 2004; 77: 1215– 20.
4. Schmitz F, Heit A, Dreher S, et al. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur J Immunol 2008; 38: 2981– 92.
5. Weiner SM, Sellin L, Vonend O, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome–a single-centre experience and review of the literature. Nephrol Dial Transplant 2007; 22:3631.
6. Champion L, Stern M, Israël-Biet D, et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med 2006; 144:505.
7. UPTODATE
mTORi sirolimius more than everolimus can induce interstitial lung disease ILD mimicking pcp , and when the patient shifted to another class, it will be complete resolution even if shifted to everolimus as everolimus is more hydrophilic , it may be dose dependent toxicity, the mechanism of ILD is not fully clarified, dose-dependent toxicity, T cell-mediated delayed-type hypersensitivity reaction, and idiosyncratic cell-mediated autoimmune response have been suggested as potential mechanisms.
can be DD by doing PCR
Patricia Lopez, Sven Kohler, Seema Dimri.Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature. J Transplant. 2014; 2014: 305931.
cp of aspergillosis:
1- invasive pulmonary aspirgillosis can be presented by fever, cough, and dyspnea. the most common site of invasive aspergillosis, Vascular invasion may manifest as pleuritic chest pain due to pulmonary infarction or hemoptysis.
2-Central nervous system involvement is a devastating consequence of disseminated aspergillosis, and may manifest with seizures or focal neurological signs from mass effect or stroke.
Rami Sherif, Brahm H. Segal. Pulmonary Aspergillosis: clinical presentation, diagnostic tests, management and complications. Curr Opin Pulm Med. 2010 May; 16(3): 242–250.
mTORi induced Interstitial pneumonitits
· typically presenting as bilateral lower-lobe interstitial pneumonia.
· Pathologic features are similar to bronchiolitis obliterans organizing pneumonia with alveolar hemorrhage and lymphocytic infiltration.
· The diagnosis is by exclusion of other causes of pneumonia
· the pneumonia typically resolves within 2 to 3 weeks of drug discontinuation.
Invasive aspergillosis
· Typically manifests as fever, cough, dyspnea, pleuritic chest pain, and, sometimes, hemoptysis
· Patients may be tachypneic and have rapidly progressive hypoxemia
· Risk factors include organ transplantation, especially bone marrow but also lung, heart, and other solid organ transplants
1) https://emedicine.medscape.com/article/296052-overview#:~:text=Diseases%20%3E%20Pulmonology-,Aspergillosis,-Updated%3A%20May%2012
2) Handbook of Kidney Transplantation Edited by Gabriel M. Danovitch, MD
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
mTORi-induced interstitial pneumonitis should be kept in differential diagnosis of a solid organ transplant recipient on mTOR inhibitors presenting with pneumonia (1). It is infrequent, but severe side effect of mTOR inhibitors, and subsides on discontinuation of the drug. It may be associated with PCP or other infections (1).
The signs and symptoms of mTORi-induced interstitial pneumonia are similar ot infection associated pneumonias – with shortness of breath being the most common symptom (2). Patients may present with hypoxemia, cough, or dyspnea on exertion (3). Sometimes the patient may remain asymptomatic. Pulmonary function tests reveal a restrictive pattern. Radiology will reveal ground glas opacities and reticular changes especially in lower lobes (3). Usually PCP will have fever and non-productive cough, which might be seen in mTORi-induced interstitial pneumonitis also. mTORi-induced interstitial pneumonitis should be a diagnosis of exclusion once all the investigations have turned out to be negative (3).
What is the clinical picture of aspergillosis?
Aspergillosis presents as fever, cough, pleuritic chest pain, shortness of breath, or hemoptysis (feature of angioinvasion) (3). CT scan may reveal single or multiple nodules with or without cavitation, or patchy consolidation. CT pulmonary angiography can show angioinvasion. BAL galactomannan, and respiratory secretion (sputum, BAL fluid) testing can help in clinching the diagnosis (1,3).
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. Lopez P, Kohler S, Dimri S. Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature. J Transplant. 2014;2014:305931. doi: 10.1155/2014/305931. Epub 2014 Dec 18. PMID: 25580277; PMCID: PMC4281397.
3. Alvarez RH, Bechara RI, Naughton MJ, Adachi JA, Reuben JM. Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer. Oncologist. 2018 Jun;23(6):660-669. doi: 10.1634/theoncologist.2017-0343. Epub 2018 Feb 27. PMID: 29487226; PMCID: PMC6067931.
4. Husain S, Camargo JF. Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13544. doi: 10.1111/ctr.13544. Epub 2019 Apr 23. PMID: 30900296.
This index case of HIV recipient on HAART with low grade fever, dyspnea 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:
clinical picture of mTORi-induced interstitial pneumonitis:
clinical picture of aspergillosis?
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.
Ussavarungsi K, Elsanjak A, Laski M, Raj R, Nugent K. Sirolimus induced granulomatous interstitial pneumonitis. Respir Med Case Rep. 2012 Nov 7;7:8-11. doi: 10.1016/j.rmcr.2012.09.002. PMID: 26029599; PMCID: PMC3920426.
https://www.aspergillus.org.uk/new_treatment/lung-transplantation/
MTORI induced ILD presents with cough, dypnea on exertion or hypoxemia preceded by a hx of tx with MTORI esp late switch compared to denovo use, it is difficult to distinguish from PCP and is mostly a diagnosis made after excluding other infective causes.
Aspergillosis presents with cough, dyspnea, fever, pleuritic chest pain and hemoptysis if invasive in nature.On imaging masses or cavitations might be seen. Histology key in diagnosing it.
REF;
Patricia lopez et al;ILD association with MTORi in SOT recipients; results from a large phase three clinical trial program of everolimus and review of literature.
Remi sherif et al;pulmonary aspergillosis, clinical presentation, diagnostic tests, management and complications.
Q1- Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
CLINICAL PRESENTATION
Pneumonitis caused by mTOR inhibitors has heterogeneous clinical manifestations and may begin with fever, fatigue, coughing and dyspnoea, nonspecific signs and symptoms, which does not facilitate diagnosis.
It may appear at the beginning or after several years of treatment.
The most common RADIOLOGIC are ground glass opacities, although additional
peripheral infiltrates and patterns of bronchiolitis obliterans with organising pneumonia and signs of pulmonary fibrosis.
Diagnosis is difficult and tends to be made by excluding other causes,
Clinical improvement upon discontinuation of the drug can confirm the diagnosis. Which characterized by the rapid response to drug discontinuation .this will differentiate it from Pneumocystis jirvocii pneumonia in adition to absence of
Microbiological plasma marker of PCP .
Q2- What is the clinical picture of aspergillosis?
Clinical Manifestations
Invasive aspergillosis principally involves the sinopulmonary tract.
Fever, cough, and dyspnea are frequent, although non-specific, findings of pulmonary aspergillosis, the most common site of invasive aspergillosis. Vascular invasion may manifest as pleuritic chest pain due to
pulmonary infarction or hemoptysis. Central nervous system involvement is a devastating
consequence of disseminated aspergillosis, and may manifest with seizures or focal
neurological signs from mass effect or stroke.
Diagnosis of invasive aspergillosis is difficult. Demonstration of invasive hyphae histologically or a positive culture from a normally sterile environment (e.g., pleural fluid) is equated as proven invasive fungal disease.
REF:
1- https://www.revistanefrologia.com/index.php?p=revista&tipo=pdf-simple&pii=X2013251413003279&r=498
2- Husain, S, Camargo, JF, on behalf of the AST Infectious Diseases Community of Practice. Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33:e13544
mTORi induced interstitial pneumonitis and how to differentiate from PCP?
. mTORi induced ILD/ pneumonitis remains an important side effect of mTORi, the incidence is 3-13%(RECORD, Global ARCCtrail). Time of onset from start of treatment the median time is up-to 6 months with clinical manifestation..
It may be asymptomatic or with lower respiratory symptoms, and some time with sever disease. It may effect directly toxic effect or immune mediated, although, the exact mechanism is unknown.
The mTORi induced ILD is difficult as its clinical radiological and pathological features are nonspecific.
Radiological features,
Ground glass appearance mostly bilaterally, lower lobes, otherwise same features like PCP
Refreneces;
1. https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.29887.
Clinical picture of mTORi – induced pneumonitis-
-History of recent change from CNI to mTORi, absence of fever & renal dysfunction. Other clinical picture is similar to PCP.
– Marked improvement of symptom after discontinuation of mTORi in mTORi induced pneumonitis.
Clinical picture of aspergillosis-
Fever, pleuritic type of chest pain, haemoptysis are the cardinal clinical picture associated cough, dyspnoea, wheezing, weight loss, anorexia are present.
Clinical picture mTOR induced interstitial pneumonitis-
– H/O current conversion from CNI to mTORi.
– Absence of fever
– Cough, dyspnoea
– Associated renal dysfunction
– Improvement with discontinuation of mTORi.
Clinical picture of PCP-
– Dry cough
– Low grade fever
– Dyspnoea
– Hypoxaemia, desaturation
– Few auscultatory finding
Clinical picture of aspergillosis-
– Fever
– Cough
– Pleuritic type of chest pain
– Haemoptysis
– Anorexia, weight loss
– Chest findings of cavitary lesion
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP:
mTORi-induced interstitial pneumonitis should be kept in differential diagnosis of a solid organ transplant recipient on mTOR inhibitors presenting with pneumonia (1). It is infrequent, but severe side effect of mTOR inhibitors, and subsides on discontinuation of the drug. It may be associated with PCP or other infections (1).
The signs and symptoms of mTORi-induced interstitial pneumonia are similar ot infection associated pneumonias – with shortness of breath being the most common symptom (2). Patients may present with hypoxemia, cough, or dyspnea on exertion (3). Sometimes the patient may remain asymptomatic. Pulmonary function tests reveal a restrictive pattern. Radiology will reveal ground glas opacities and reticular changes especially in lower lobes (3). Usually PCP will have fever and non-productive cough, which might be seen in mTORi-induced interstitial pneumonitis also. mTORi-induced interstitial pneumonitis should be a diagnosis of exclusion once all the investigations have turned out to be negative (3).
What is the clinical picture of aspergillosis:
Aspergillosis presents as fever, cough, pleuritic chest pain, shortness of breath, or hemoptysis (feature of angioinvasion) (3). CT scan may reveal single or multiple nodules with or without cavitation, or patchy consolidation. CT pulmonary angiography can show angioinvasion. BAL galactomannan, and respiratory secretion (sputum, BAL fluid) testing can help in clinching the diagnosis (1,3).
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. Lopez P, Kohler S, Dimri S. Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature. J Transplant. 2014;2014:305931. doi: 10.1155/2014/305931. Epub 2014 Dec 18. PMID: 25580277; PMCID: PMC4281397.
3. Alvarez RH, Bechara RI, Naughton MJ, Adachi JA, Reuben JM. Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer. Oncologist. 2018 Jun;23(6):660-669. doi: 10.1634/theoncologist.2017-0343. Epub 2018 Feb 27. PMID: 29487226; PMCID: PMC6067931.
4. Husain S, Camargo JF. Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13544. doi: 10.1111/ctr.13544. Epub 2019 Apr 23. PMID: 30900296.
Q1: post TX mTOR inhibitor pneumonitis has no specific characteristics which could be differentiated from PIP pneumonia. It should be considered in patients with recent use of sirolimus and abnormal renal function and long-term use for CNIs. they respond well to stopping the sirolimus and steroids.
Q2: Aspergillus’s pneumonia has non-specific manifestations like fever, cough, and pleuritic chest pain or hemoptysis non-responding to wide-spectrum antibiotics.
CXR is non-specific with nodular lesion may be seen. Bronchoscopy and BAL fluid test serum galactomannan and eventually histopathology of lungs.
What is the differential diagnosis?
39 y old female, HIV positive, recent renal Tx, 2wweks post Tx presented with exertional dyspnea, low grade fever, scattered wheezes on chest auscultation and normal chest X-ray.
DD includes:
1- PJP: most likely.
2- Viral Pneumonia: CMV, EBV, Covid-19.
3- Bacterial pneumonia.
4- Mycobacterium TB (less likely).
5- Aspergillosis (less likely)
6- Histoplasmosis.
How do you manage this case?
Confirm diagnosis:
1- ABG.
2- CD4 cell count: values below 200cells or low CD4/CD8 ratio suggest reactivation of PJP.
3- Septic work up: CRP, blood culture, induced sputum culture, CMV PCR, PJP PCR, B-D-Glucan, Covid-19 PCR.
4- Serum and urinary antigens for histoplasmosis.
5- Bronchoscopy and BAL: PJP can be detected using stains like Giemsa, modified Grocott, Weigert-Gram, or methenamic silver.
6- Radiological: CT-chest, looking for PJP CT findings like ground glass opacities and pneumatoceles.
7- Metagenomic next generation sequencing.
Non-specific treatment:
1- Oxygen if Hypoxic.
2- NIV if indicated.
3- Keep ITU in the loop if deteriorated.
4- Anti-pyretic.
Immunosuppression modifications:
1- 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.
4- Choice of Anti-HIV HAART and monitoring especially with possible drug interaction with other IS medications.
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, like ttt of CMV if positive.
Monitor for side effects of medications
Monitor renal functions and electrolytes.
Reference:
Uptodate.
Thank you
Clinical scenarioHIV-associated nephropathy had a deceased donor kidney transplantation. CD4 count is 250/ml and receiving HAART.Presented with non-productive cough, low-grade temperature (37.5 °C) and exertional. dyspnoea Chest radiograph reported normal.
In this case the differential diagnosis
Management
References
1) https://emedicine.medscape.com › 359972-overview
Thank you
As the case with HIV- infection presented with dry cough, low grade fever , exersional dyspnea with normal CXR and minimal physical finding , post KT from cadaveric donor ,this make us to highly suspect PJP putting in our mind that CXR may be normal in up to 30% of cases .
Other DDX include
CMV pneumonitis
Other viral infection like adenovirus , HSV , VZV , Covid 19 and influenza virus.
Bacterial pneumonia and atypical bacterial pneumonia.
Fungal pneumonia, Aspergillosis’
Pulmonary TB.
The management plant start from hospital admission for O2 supplementation and stabilization, HRCT for more appreciation of PJP infection, other investigations include CBC, CRP, ESR, LDH, RFT, LFT,serum electrolytes,TB screen ,PCR for Covid-19 and CMV , sputum for culture and staining, special diagnostic ways for PJP identification like PCR , BAL for secretion staining by GMS stain and IF, serum beta- D glucan .
The drug of Chioce in PJP is TMP-SMX in a dose 15-20/75-100 mg/ kg every 6-8 hrs intravenously for 3 weeks then continue on oral after stabilization of patient condition.
Alternative drugs in case of allergy or intolerance include dapson with trimethoprim , pentamidine spray ,
Atovaquone 750 mg/12 h
primaquine plus clindamycin.
If CMV treated by gancyclovir I.v then valgancyclovir 900 mg for 200 days.
Management of her IS by stopping antimetabolites , reduce the dose of Tac by 50% and adjunctive glucocorticoid should be given
if room air pao2 <70 by increasing the dose of steriod to 20-40 mg dialy.
Regular monitoring of RFT and LFT and drug level.
Prophylaxis continue for 6-12 months by DS TMP/SMX or SS.
The prevelance of PJP infection in HIV infected patients has changed due to the advances in diagnosis and treatment.
The occurrence of PJP in HIV-infected on HAART therapy usually subclinical , while in non-HIV ,PJP infection was rapid and progressive and may increase the mortality rate .
Also attention must be taken to drug-drug interaction between PIs and CNIs .
In case of HAART no need for drug adjustment.
Thank you
Differential diagnosis
39 year old KTX secondary to HIVAN presents with 2 weeks history of low grade fever and a non-productive cough. His chest X-ray is reported to be normal though he is noted to desaturate on exertion.
PCP is a highly likely diagnosis, the fact that he is HIV positive on triple immunotherapy even with a CD4 counts above 200cells/ml.
Other differentials to consider include:
Management
Investigations
Blood works including: CBC,UECS, LFT,CRP,ESR
BAL for microscopy, culture, immunofluorescence and PCR.
Induced sputum for microscopy, culture, PCR, staining.
Imaging: High resolution CT scan chest
Treatment
TMP/SMX drug of choice.
TMP 15 to 20 mg/kg/day and SMX 75 to 100 mg/kg/day, given orally in 3 or 4 divided doses or TMP-SMX DS, two tablets three times per day.
Alternatives in persons with sulpha allergies:
References
Pneumocystis Jirovecii Pneumonia Truong J, Ashurst JV. Publication Details
Impact of Pneumocystis jirovecii pneumonia on kidney transplant outcome
Ji Eun Kim, Ahram Han, Hajeong Lee, Jongwon Ha, Yon Su Kim & Seung Seok Han
Thank you
KTR on HAART therapy for HIV. CD4 count of more than 250 denotes stable issues regarding HIV infection and very unlikely to have HIV related severe complications and AIDS.
Dry cough, dyspnoea on exertion and radiological findings in addition to SOT and history of HIV are highly suggestive of PCP.
The likely differentials are:
· PCP
· CMV Pneumonitis.
· COVID-19 pneumonia.
· Miliary TB.
· Other viral infection e.g. RSV, VZV and HSV.;
· Bacterial infection; Atypical bacterial infection
How do you manage this case?
1. Hospital admission to guard against severe hypoxia as a cascade of exertional dyspnoea. He needs bed rest and oxygen support.
2. Antipyretic to relieve pyrexia ( Paracetamol PO or IV).
3. Laboratory tests:
· CBC, RFT,ABG, LFT, CRP, RBG & LDH.
· Screening for COVID-19.
· Sputum for C&S(looking for concomitant bacterial infection).
· Silver methenamine staining and PCR for PCJ (from sputum, respiratory secretions or BAL).
· CMV IgG & IgM beside PCR for CMV may be needed.
· Screening for TB.
4. PCP is the most likely diagnosis(dry cough, hypoxia and radiological findings) and specific management for PCP is warranted:
a) Respiratory support with oxygen supply.
b) Reduction and adjustment of immunosuppression.
c) TMP-SMX is the first line of therapy; low to intermediate dose of TMP-SMX is preferred as it is effective and associated with low adverse effects(1). The first choice: trimethoprim-sulfamethoxazoleat a dose of 2tablets DS every 8h or IV Trimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 h.
d) Alternatives:
I. Dapsone( 100 mg daily) plus trimethoprim(320 mg every 8 h).
II. Clindamycin(PO 300–450 mg every 6 h) plus primaquine (IV 30 mg daily).
III. Pentamidine IV at 4mg/kg/day.
IV. Atovaquone PO 750 mg BID.
e) Adjunctive therapy: Prednisone in patients with room air pAO2 < 70 mmhg (9.3 kPa)
· 40 mg twice daily for 5 days.
· 40 mg daily; days 6 through 11.
· 20 mg daily, days 12 through 21 while on anti-PCP therapy.
References
1. Haseeb A, Abourehab MAS, Almalki WA, Almontashri AM, Bajawi SA, Aljoaid AM, Alsahabi BM, Algethamy M, AlQarni A, Iqbal MS, Mutlaq A, Alghamdi S, Elrggal ME, Saleem Z, Radwan RM, Mahrous AJ, Faidah HS. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review. Int J Environ Res Public Health. 2022 Feb 28;19(5):2833. doi: 10.3390/ijerph19052833. PMID: 35270525; PMCID: PMC8910260.
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1- DD:
2- Management:
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What is the differential diagnosis?
How do you manage this case?
Treatment:
References:
Thank you
What is the differential diagnosis?
How do you manage this case?
Thank you
The index patient is a 39-year-old female with basic disease HIV associated nephropathy, on Tacrolimus, MMF, steroids and HAART and having CD4 count of 250/ml. She is having good graft function, now presenting with low grade fever, non-productive cough with dyspnea and desaturation on exertion. The chest x ray is normal. The clinical symptoms are suggestive of post-transplant pneumonia. The differential diagnosis in such a scenario would be (1):
· Viral: Respiratory viruses (Influenza, parainfluenza etc), Herpesviruses (cytomegalovirus, CMV etc)
· Fungal: Pneumocystis jirovecii, histoplasma, Cryptococcus
· Bacterial: community acquired like streptococcus, tuberculosis etc.
· Parasitic
In view of hypoxia and non-productive cough in an immunocompromised individual, probability of PCP is high (2). A high resolution computed tomogram (HRCT) of chest would be helpful in this scenario.
Bacterial etiology of the clinical picture is unlikely (low-grade fever, no expectoration).
Although the CMV serostatus of the recipient and the donor has not been given, CMV pneumonia possibility is less likely (it may present with patchy ground glass opacities, small nodules, or consolidation which is not seen on the x ray done) (3,4).
The management of the index case involves:
1. A detailed history and clinical examination including a history of tuberculosis in past and the medications being taken for HIV (as part of HAART) should be taken with emphasis on drug interactions with Tacrolimus.
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 influenza season) and other respiratory viral testing (biofire), serum beta D Glucan, Serum LDH, Tacrolimus trough levels.
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: To rule out CMV infection (although unlikely in this setting).
6. Admission in intensive care unit (ICU): With oxygen therapy in view of hypoxia. May need CPAP or BiPAP or invasive ventilation if worsening takes place.
7. Bronchoscopy with bronchoalveolar lavage (BAL) 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 (1):
1) If influenza season: Antiviral against influenza (Oseltamivir) till the results for respiratory virus panel is available.
2) Empirical antibiotics: Beta lactam agent and agent against intracellular organisms should be started.
3) Considering the clinical status, empirical anti PCP treatment in form of co-trimoxazole (trimethoprim-sulfamethoxazole, TMP-SMX: 15-20 mg/kg/day of TMP with 75-100 mg/kg/day of SMX intravenous) should be started pending the investigation results. Steroids should be added.
9. Immunosuppression: Antimetabolites to be stopped, CNI doses to be adjusted as per trough levels.
10. Further management as per the laboratory reports:
11. If BAL or biopsy shows PCP: Continue TMP-SMX. Treatment should be given for 3 weeks, followed by secondary prophylaxis with low dose of TMP-SMX. If TMP-SMX is contraindicated, or patient is allergic to it, then second line drugs like Pentamidine, Atovaquone, Dapsone, Primaquine with clindamycin can be used.
1) TMP-SMX: It is the drug of choice, and can be used orally or parenterally. It may cause rash, fever, neutropenia, hepatitis, nephritis, and hyperkalemia, pancreatitis, renal calculi, and anaphylactoid reaction.
2) Dapsone (100 mg/day) plus TMP: It can be used as an alternative, but may cause rash, nausea, fever, vomiting, hepatotoxicity, and hemolysis in G6PD deficiency.
3) Clindamycin (600-900 mg 6-8 hourly) plus Primaquine (15-30 mg/day): It may cause diarrhea, nausea, vomiting, hepatitis, and rash. Oral primaquine is not easily available.
4) Pentamidine (4 mg/kg/day): Given as slow intravenous infusion, it is highly effective, but has toxicity including nephrotoxicity, hypoglycemia, pancreatitis, pancytopenia, and Q-T prolongation.
5) Atovaquone (750 mg twice a day): It is expensive, given orally, and is useful only for mild to moderate disease in patients who cannot tolerate TMP-SMX. Hence not useful in the index patient.
6) Adjunctive steroids (Prednisone 40-60 mg twice a day for one week, and then tapered over next 2 weeks): Used in moderate to severe PCP with low pAO2 (<70 mm Hg), although associated with metabolic effects like glucose and electrolyte abnormalities.
12. If BAL 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.
13. Supportive care: Intravenous fluids, nutrition.
References:
Thank you
Diferential diagnosis
The top differential is PJP although happens early as the patient is considered a high risk
Other differentials
Management
The patient as he is a high risk he had to receive PJP prophylaxis, and this can explain an early occurrence of PJP
management include
In case of resistance or AEs another alternative;
In case of concomitant CMV infection
Balanced immunosuppressant reduction, considering the graft function and therapeutic response.
Refferences;
Creemers-Schild, D.; Kroon, F.P.; Kuijper, E.J.; de Boer, M.G.J. Treatment of Pneumocystis pneumonia with intermediate-dose and step-down to low-dose trimethoprim-sulfamethoxazole: Lessons from an observational cohort study. Infection 2016, 44, 291–299. [CrossRef] 14. Sattler, F.R.; Cowan, R.; Nielsen, D.M.; Ruskin, J. Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: A prospective, noncrossover study. Ann. Intern. Med. 1988, 109, 280–287. [CrossRef] [PubMed]
Stringer JR, Walzer PD. Molecular biology and epidemiology of Pneumocystis carinii infection in AIDS. AIDS 1996;10(6):561–571 9. Cushion MT. Pneumocystis: unraveling the cloak of obscurity. Trends Microbiol 2004;12(5):243–249
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Differential diagnosis
– Pneumocystis Jirovecii
–Community Acquired Pneumonia
– Bacterial, Viral, fungal pneumonias
– Mycobacteria (especially Tuberculosis)
– Histoplasmosis
– invasive aspergillosis
– COVID 19
Management
1. Diagnosis
2. Clinical management
3. Post-treatment care
regarding HAART therapy Tenofovir and protease inhibitors carry a high risk of kidney damage and should be avoided if possible.
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HIV associated nephropathy post-KT on triple IS and HAART, with 2 weeks history of dry-cough, dyspnea, with normal CXR is highly suggestive of PCP.
Normal X-ray findings does not exclude the diagnosis. High clinical suspicion is needed for the diagnosis.
CXR showed perihilar infiltrates more obvious in lateral view( could be early findings). However this need to be compared with previous x-rays.
CMV co-infection should be considered as CMV as a clear risk factor for PCP in SOT patients, studies shows that 20%–53% of SOT recipients with PCP had a CMV infection
Differential diagnosis:
– Fungal pneumonia; Pneumocystis pneumonia PCP , aspergillus
– Viral pneumonia: COVID, CMV, Influenzas, HSV, VZV
– Bacterial pneumonia (typical, atypical)
– Drug-induced interstitial pneumonitis.
How do you manage this case?
Management:
General supportive measures:
– Stabilized the patient
– Monitor O2 and respiratory support as needed.
– Manage the fever with antipyretic.
– Patient should be managed empirically till we have the results.
– Fluid management.
Workup required:
– CBC with differential, CRP, and procalcitonin.
– VBG
– RFT, LFT.
– LDH
– Blood culture.
– Respiratory culture and a viral panel (respiratory multiplex)
– COVID PCR
– Viral load; CM PCR, , EBV PCR.
– Sputum sample for; microscopy, staining, CMV, PJP and aspergillus
– BAL for GMS‐stain, PCR, culture.
– Immunosuppression level Tacrolimus level.
– serum beta-D-glucan.
– HRCT chest; detects abnormalities not appreciated on CXR and should be obtained if CXR is normal with a consistent clinical presentation.
– New CD4 level should be obtained.
Antimicrobial management:
Cover for bacterial pneumonitis:
– Generally, start broad-spectrum antibiotics, then guided by culture.
PCP;
-TMP‐SMX ; the drug of choice and the most effective systemic therapy for PJP.
– Duration: for at least 3 weeks.
– 15‐20 mg/kg/day of the TMP component given IV divided every 6‐8 h; lower doses may be sufficient.
– In milder diseases, two double‐strength tablets can be given PO TID.
– If the patient is allergic to sulfa or has intolerance or if there is resistance consider alternative.
– Alternative agents include:
pentamidine, Dapsone plus trimethoprim, atovaquone, primaquine and clindamycin
-In severe infections, IV pentamidine is the second‐line agent after TMP‐SMX; for side effect profile, mainly hypotension should run slow infusion. Aerosolized pentamidine is usually used in prevention not treatment.
Adjunctive corticosteroids:
– In moderate to severe disease should receive corticosteroids; hypoxemia (pAO2 < 70 mm Hg on room air or an alveolar gradient of >35 mm Hg )
-It should be given prior to the first dose of any antibiotic or no later than the first 72 hours after the initiation of therapy
-The optimal dose of corticosteroids has not been established, but 40‐60 mg of prednisone given two to three
times daily for 5‐7 days before gradual tapering over 7‐14 days is recommended to avoid rebound pneumonitis
Secondary prophylaxis:
-TMP‐SMX is the drug of choice for prophylaxis of PJP. then continue on secondary prophylaxis for 6-12 months.
– Dapsone is often used as a second‐line agent for PJP prophylaxis.
– Patients with a history of PCP should have lifelong chemoprophylaxis, if immune reconstitution cannot be achieved.
-If the CD4 count is maintained > 200 cells/mm3 for at least 3 months in response to HAART, then it may be discontinued.
-Secondary prophylaxis should be restarted if the CD4 count declines to < 200 cells/mm3 or if PCP recurred with CD4 counts above 200 cells/mm.
Drug interaction of HAART therapy and IS
Protease inhibitors
– Associated with reduce 3 years patient survival and graft survival.
– PIs with CNIs increase CNI level, when used require significantly decreased CNI doses and prolonged dosing intervals to avoid supratherapeutic trough levels.
-Also, PIs increasing the level or effect of prednisone and mycophenolate.
-Despite appropriate CNI dose adjustments, variations of drug serum levels are difficult to control and have been linked to increased graft rejection in HIV+ KT recipients
Nucleoside reverse transcriptase inhibitor (NRTI)
– the use of NNRTI or tenofovir disoproxil fumarate (TDF) did not influence GS. Tenofovir alafenamide (TAF) is a new formulation of tenofovir associated with less kidney toxicity
Integrase strand transfer inhibitors (INSTIs ) based therapy are the preferred ART in patients with HIV who undergo KT, primarily because of decreased drug–drug interactions with immunosuppressive medications such as CNIs, enabling easier monitoring of immunosuppressive medications and superior graft outcomes
As the patient is at high risk for CMV pneumonitis, if confirmed:
-Treatment is mandatory in all cases of tissue-invasive CMV disease, irrespective of viral load, with IV gancyclovir for 14-21 days followed by oral valganciclovir ( adjust for eGFR)
Management of IS:
– Reduce (by 50%) antimetabolites or discontinue if there is evidence of life-threatening infection
-Reduce CNI to a lower level.
-Corticosteroids are generally continued
– Monitoring graft function closely for any rejection ( kidney function, drug level)
References:
Hsu JM, Hass A, Gingras MA, et al. Radiographic features in investigated for Pneumocystis jirovecii pneumonia: a nested case-control study. BMC Infect Dis. 2020;20(1):492. Published 2020 Jul 10. doi:10.1186/s12879-020-05217-x
Kim JE, Han A, Lee H, Ha J, Kim YS, Han SS. Impact of Pneumocystis jirovecii pneumonia on kidney transplant outcome. BMC Nephrol. 2019;20(1):212. Published 2019 Jun 10. doi:10.1186/s12882-019-1407-x
Fishman, JA, Gans, H; on behalf of the 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; 33:e13587. https://doi.org/10.1111/ctr.13587
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1-155.
Castro JG, Morrison-Bryant M. Management of Pneumocystis Jirovecii pneumonia in HIV infected patients: current options, challenges and future directions. HIV AIDS (Auckl). 2010;2:123-34. doi: 10.2147/hiv.s7720. Epub 2010 Feb 18. PMID: 22096390; PMCID: PMC3218692.
Zheng X, Gong L, Xue W, et al. Kidney transplant outcomes in HIV-positive patients: a systematic review and meta-analysis. AIDS Res Ther. 2019;16(1):37. Published 2019 Nov 20. doi:10.1186/s12981-019-0253-z
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A 39-year-old CKD 5 secondary to HIV associated nephropathy had a deceased donor kidney transplantation.
CD4 count is 250/ml and receiving HAART, on Tacrolimus-based triple immunosuppression and with good RFT.
She presented with 2 weeks history of non-productive cough, low grade temperature (37.5 °C) and dyspnea on excretion (respiratory rate at rest is 20/min).
Chest X-Ray reported normal. Clinically there were few physical findings only few scattered wheezes. Sat 100% on air and desaturases to 95% on exertion.
What is the differential diagnosis?
1-Specially with these few physical findings and dyspnea on exertion PJP is considered our first differential diagnosis, unless PCP is strongly suspected in the patient with HIV and a CD4 cell count less than 200 cells/microL but our patient is also heavily immunosuppressed post KTX.
2-T.B.
3-Viral induced pneumonia (COVID 19 ,Influenza).
4-CMV pneumonitis .
5-aspergillus.
6-Other causes of CAP.
How do you manage this case?
1-Basic investigation (CBC, CRP, LDH, Blood C/S, Sputum C/S, Serial RFT, LFT ).
2-ABG/ serum beta-D-glucan assay.
3-Covid 19 swab.
4-HRCT (looking for par hilar shadows with sub pleural sparing , and ground glass appearance).
5-BAL(The definitive diagnosis of PCP requires identification of the organism either by tinctorial (dye-based) staining, fluorescent antibody staining, or polymerase chain reaction (PCR)-based assays of respiratory specimens.)
Treatment:
=We recommend starting with TMP-SMX (15 to 20 mg/kg/day of the trimethoprim component) orally or IV given in three or four divided doses, after G6PD enzyme activity.
=Corticosteroids given in conjunction with anti-Pneumocystis therapy can decrease the incidence of mortality and respiratory failure associated with PCP but only in moderate to sever cases.
= Alternative agents when TMP-SMX sensitivity is present such as
For mild disease, options include:
•Atovaquone.
•Clindamycin plus primaquine.
•TMP plus dapsone.
For moderate disease, options include:
•Clindamycin plus primaquine.
•TMP plus dapsone.
For severe disease, options include:
•Clindamycin plus primaquine.
•Intravenous pentamidine.
=Stopping MMF at tine being and continue steroid and CNI with low trough level.
=After complete recovery, we can extend prophylaxis Septrin dose up to 2 years.
References:
1- Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med. 2004;350(24):2487-2498. doi:10.1056/NEJMra032588.
2- Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med. 1984;100(5):663-671. doi:10.7326/0003-4819-100-5-663.
3- Wilson JW, Limper AH, Grys TE, Karre T, Wengenack NL, Binnicker MJ. Pneumocystis jirovecii testing by real-time polymerase chain reaction and direct examination among immunocompetent and immunosuppressed patient groups and correlation to disease specificity. Diagn Microbiol Infect Dis. 2011;69(2):145-152. doi:10.1016/j.diagmicrobio.2010.10.021.
4- Hughes WT, Feldman S, Sanyal SK. Treatment of Pneumocystis carinii pneumonitis with trimethoprim-sulfamethoxazole. Can Med Assoc J. 1975;112(13 Spec No):47-50.
5- Ewald H, Raatz H, Boscacci R, Furrer H, Bucher HC, Briel M. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection. Cochrane Database Syst Rev. 2015;2015(4):CD006150. Published 2015 Apr 2. doi:10.1002/14651858.CD006150.pub2.
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What is the differential diagnosis?
The patient under discussion is HIV positive patient on HAART. With 2 weeks history of low grade fever, cough, chest x ray is normal with scattered wheeze.
1. Reactivation of tuberculosis
2. Invasive aspergillosis
3. Cryptosporidiosis
4. PJP
There are few key points which might help in planning treatment.
1. 2 weeks of fever and no x ray findings, PJP is unlikely
2. Reactivation of tuberculosis is most probable ( low grade fever, cough)
3. Fungal infection should be kept on very high index of suspicion in these patients as they respond well to early treatment but delayed treatment can be fatal.
Urgent diagnostics and interventions:
1. Sputum for AFB
2. CBNAAT
3. Sputum fungal KOH mount
4. Beta D glucan
A. Needs nebulisation and bronchodilator support to manage wheeze
B. A broad spectrum antibiotics till definite diagnosis is available
C. CNI levels as they are significantly modified by HAART
D. MMF should be lowered down.
REF:
1Elmi Muller, MD PhD,1 Francois C. J. Botha, MBChB,2 Zunaid A. Barday, MBChB,3 Kathryn Manning, MPH,1 Peter Chin-Hong, MD PhD,4 and Peter Stock, MD PhD5 Kidney Transplantation in HIV Positive Patients: Current Practice and Management Strategies. Transplantation. 2021 Jul 1; 105(7): 1492–1501.
doi: 10.1097/TP.0000000000003485
Thank you
-What is the differential diagnosis?
-The most likely diagnosis is PCP
-Other differential diagnosis are
-Bacterial pneumonia
-CMV ,covid 19 or other viral pneumonitis
-How do you manage this case?
– Maintain oxygen saturation and hemodynamic stabilization while taking complete history and examination .
Investigations :
– ABG ,full blood count , graft function and liver function test .PCR for CMV .
-BAL ( which is the gold standard ,) sputum sample for gram stain culture and PCR for PCP . ( The trophozoite life-form can be detected with Giemsa, Diff-Quik, Wright-Giemsa stains, modified Papanicolaou, or Gram-Weigert stains. However, due to its small size and nonspecific staining pattern, this is not the life-form typically used in diagnosis. )
-Serum beta-D-glucagon and LDH may be elevated and are non specific for PCP.
– CMV PCR
– Complete other septic screen urine and blood cultures for other bacterial infection.
Imaging ;
HRCT of the chest looking for ground glass appearance bilateral hilar reticular shadowing despite normal CXR .
Treatment :
In patients who are allergic to sulfa and have mild to moderate disease :
Alternative treatments for moderate to severe cases :
Reduction of immunosuppression :
-Stop antimetabolite and optimize the CNI level plus increase the dose of steroid prednisolone tablets 40 mg by mouth twice per day from day 1 to day 5, 40 mg by mouth daily from day 6 to day 10, and 20 mg orally daily on days 11 through 21.
Prophylaxis :
HIV-infected individuals should receive prophylaxis with the same medications
Reference ;
Thank you
1-What is the differential diagnosis?
-Pneumocystis Jirovecii Pneumonia (most likely).
-CMV tissue invasive disease (cmv pneumonitis).
-Pulmonary aspergillosis.
-Drug-induced interstitial pneumonitis( mTOR).
2-How do you manage this case?
-Maintain the O2 above 94% by giving High flow O2 (BIPAP vs 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 – CRP – LDH.
-Liver function tests & Renal function tests.
-BAL staining for PCP (Gomori methenamine silver (GMS) staining).
-Serum 1-3 beta-D-glucan assay.
-BAL and send for respiratory panel (Influenza type A,B, Adenovirus , covid-19 , etc).
-Virology (including HIV) , (CMV PCR).
-Full septic screen (including sputum C/S).
Treatment;
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.
Regarding I.S. ;
-Holding antimetabolites until this patient is in ICU.
-Reducing CNI dose with steroid cover.
-HAART should be reviewed in this patient. Tenofovir and protease inhibitors should be avoided as high risk for AKI & for drug interactions with CNI.
–In this case, the appropriate regimen should be (Abacavir , emtricitabine, and dolutegravir).
-Monitoring CNI trough (high risk of interaction, increasing risk of rejection due to insufficient doses of immunosuppression).
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 for six to twelve months.
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; Treatment and prevention of Pneumocystis infection in patients with HIV; Sep 12, 2022.
Thank you
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis?
Thank you so much; our Prof.
mTORi associated pneumonitis;
-Increased risk factors for pneumonitis include a late switch to sirolimus and impaired kidney function.
-The majority of these cases have occurred in renal transplant recipients within the initial six months of iniciation of the drug and lesions have generally responded to the lowering or withdrawal of the drug dosage.
-The mechanism of pulmonary toxicity of Sirolimus (rapamycin) is not clear; direct toxicity, immunomediated toxicity, or both have been proposed as the mechanism.
-The presence of lymphocytes in lung biopsies suggests an immunomediated mechanism.
-Possibly, some cryptic pulmonary antigens induce an autoimmune response.
-Clinical symptoms consist of dyspnea, dry cough, fever, and fatigue.
-Most of the patients present with progressive breathlessness, weakness, cough, and bilateral lower zone pulmonary opacities, and over half of the cases present with fever.
-Discontinuation of mTORi seems to be the safest treatment option to avoid pulmonary fibrosis or a fatal outcome.
-Complete recovery was observed in all patients within six months of sirolimus withdrawal.
-Administration of mTOR inhibitors is a potential risk factor for late-onset PCP after SOT. Targeted PCP prophylaxis based on recipients’ risk factors rather universal prophylaxis may lessen the risk.
Differential diagnosis
likely diagnosis:
PCP– patient is at high risk of PCP being a recipient from cadaveric donor and HIV. Clinical scenario likely as an early presentation of the disease
Aspergillus tracheobronchitis– although reported most commonly in lung transplant recipients, but also described in other solid organ transplant recipients. Typically present with dyspnea, cough and wheezing, and CXR may be normal or reveal areas of airway thickening.
CMV pneumonia
Less likely
Viral pneumonia in particular influenza and COVID-19
Pulmonary Tuberculosis
Mycobacterium avium Complex (MAC) Infection
Atypical pneumonia including Legionella pneumonia and Mycoplasma pneumonia
How to manage this case?
As the patient has nonproductive cough, sputum study is not an option
CXR is reported as normal, so HRCT is the next step
Complete blood test for renal profile, liver function test, inflammatory markers, Serum Galactomannam, Swab for COVID-19 and influenza A and B
Confirmation of offending cause is achieved by studies on BAL-bronchoscopy- sample should be sent for culture, Galactomannan, PCR TB, CMV, PCP, MAC.
Empirical treatment should be started with antibiotic to cover typical and typical bacteria, influenza, PCP and CMV, awaiting for requested tests results. Immunosuppressive drugs should be adjusted to minimize the risk of infection and infection progression. Tacrolimus level should be optimized to lower trough levels. MMF dose should be reduced by 50 %.
If the investigations are compatible with PCP, then the duration of treatment is 21 days.
– TMP-SMX – 15 to 20 mg/kg/day orally or intravenously in 3 to 4 doses
Alternatively, or in cases of TMP-SMX allergy the following regimens are recommended.
TMP plus dapsone – TMP: 5 mg/kg orally three times per day and Dapsone, 100 mg orally once per day
Primaquine plus clindamycin – Primaquine, 30 mg orally daily, and clindamycin, 900 mg IV 8-hourly, or 600 mg three times daily.
Atovaquone 750 mg twice daily orally
Nebulized pentamidine
Thank you
What is the differential diagnosis?PJP Pneumonia(likely)
Atypical pneumonia(mycoplasma/legionella)
CMV pneumonia
Pulmonary TB
Hospital acquired pneumonia.
COVID-19
How do you manage this case?Diagnosis
Sputum /induce sputum or BAL- gram stain, culture, AFB, immunofluorescence, if not conclusive qPCR or mNGS
Serum
CBC, RFT, LFT, LDH (prognosis), G6PD, CRP, Beta D Glucan
Imaging
High resolution CT chest
Treatment
Trimethoprim-sulfamethoxazole (TMP-SMX) ds 3 2 tab thrice a day orally for 21 days
Alternative when TMP/sulfamethoxazole sensitive or resistant
Dapsone +TMP
Clindamycin +primaquine
atovaquone
IV or Aerosole pentamidine
Caspofungine
Seconday prophylaxis
TMP/SMX daily or TMP/SMX ds 3/7
Reference
Lecture: Prof Gamal Saadi Pneumocystis Pneumonia in SOT
Salzer H, J, F, Schäfer G, Hoenigl M, Günther G, Hoffmann C, Kalsdorf B, Alanio A, Lange C: Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia. Respiration 2018;96:52-65. doi: 10.1159/000487713
Thank you
-differential diagnosis
Pneumocytitis pneumonia is the most possible diagnosis for this cadaveric renal tarns plant recipient presented with dry cough and exertional dyspnea with history of HIV associated nephropathy having low CD4 count is 250/ml receiving HAART and on Tacrolimus-based triple immunosuppression.
Other Differential diagnosis
Viral or bacterial pneumonia
Pulmonary Tuberculosis
Mycobacterium avium Complex (MAC) Infection
Legionella pneumonia
Mycoplasma infections
COVID-19 pneumonia
other specific respiratory disorders HIV-associated
-Management
Patient need to do urgent investigations and start therapy for PCP at the same time without delay
Investigation
CBC , Serum beta-D-glucagon, LDH ,kidney function tests ,liver function test
ABG ,an elevated Alveolar-arterial (A-a) oxygen gradient can be the finding .
Asessing HIV status ,CD4 count has to be monitored
CMV testing
Gammainterferon test for TB
Induced sputum analysis
CXR was reported normal and it is non sensitive test can be normal in early disease
Pulmonary HRCT is highly sensitive for P jiroveci pneumonia (PJP) in patients with HIV infection.
PCP typically appears as patchy areas of ground-glass attenuation with a background of interlobular septal thickening meanwhile if CT scan findings are negative ,this alone do not rule out PJP.
Pulmonary function test is needed and , if added to normal HRCT findings, pulmonary function tests can identify patients unlikely to have PJP
Bronchoscopy and BAL specially induced sputum sample findings are negative after pulomonolgist consultation
BAL respiratory secretions are used for analysis of respiratory secretions by special stain including Crystal violet, Giemsa, Diff-Quik, Wright stain ,Methenamine silver, toluidine blue, and Gram-Weigert or direct immunofluorescence using monoclonal antibodies to detect Pneumocystis organisms as it is more sensitive or metagenomic next generation sequencing analysis ,quantitative Pneumocystitis PCR
Open lung biopsy for rare cases when bronchoscopy findings are nondiagnostic.
Treatment
the first-line treatment choice for HIV-infected cases is 21 days of trimethoprim-sulfamethoxazole (TMP-SMX).TMP 15 to 20 mg/kg/day and SMX 75 to 100 mg/kg/day, given orally in 3 or 4 divided doses or TMP-SMX DS, two tablets three times per day.
For cases with mild allergy to TMP-SMX desensitization should be attempted but with severe allergy no need.
Alternatives include Atavaquone 750 mg, orally twice daily for 21 days (must be taken with food).
Trimethoprim 15 mg/kg/day by mouth twice daily plus dapsone 100 mg by mouth every day
Primaquine 30 mg daily, plus clindamycin by mouth 450 mg every 6 hours or 600 mg every 8 hours.
Addition of glucocorticoids can improve outcome and mortality.
HAART therapy has to be continued when patient is stabilised
Tacrolimus dose has to be reduced as it represent a risk factor for PCP
Prophylaxis with TMP-SMX is needed when a CD4+ count is below 200 cells/microL or CD4+ less than 14%, the presence of oropharyngeal candidiasis, and a CD4+ of 200-250 cells/microL when ART cannot be started or if monitoring of CD4+ count every three months is not possible.
Reference
-Gilroy S A. Pneumocystis jiroveci Pneumonia (PJP) Overview of Pneumocystis jiroveci Pneumonia.Medscape, 2022
-Truong J , Ashurst J V . Pneumocystis Jirovecii Pneumonia. [Updated 2022 Nov 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.
Thank you
·DD
– PJP early presentation
– Other viral (CMV) or atypical bacterial infection like mycoplasma.
Diagnosis:
– repeating CXR; if normal, CT chest.
-BAL with Gomori silver staining for PJP and PCR.
-CMV PCR
– Mycoplasma pneumoniae infections :culture, serology, or PCR.
Treatment
-O2 therapy with SMZ -TMP ;the first line therapy; IV for 2-3 weeks foe severe infections or orally in mild to moderate conditions.
Concurrent CMV infection if present must be treated with IV ganciclovir or oral valganciclovir for 2 weeks till symptom resolution .In case of resistance, foscarnet (nephrotoxic) or cidofovir can be used.
References:
Anat Stern and Genovefa A. Papanicolaou, CMV Prevention and Treatment in Transplantation: What’s New in 2019, Curr Infect Dis Rep. ; 21(11): 45.
Thank you, Ahmed
What is the differential diagnosis?
The indexed case of dry cough with low-grade fever and desaturation on exertion in HIV – post kidney transplantation status still the possibility of early PJP in the top of DDX despite normal CXR and few physical signs, other DDX viral pneumonia including HSV, adenovirus, RSV and atypical pneumonia-like covid 19, CMV, mycoplasma, legionella.
The epidemiology of PJP has changed over time with the improvement in the diagnosis and introduction of antiviral agents so recently
HIV-infected patients on HAART treatment like our case and C4D > 200 still they can have PJP and usually can develop a subacute course of the disease, unlike the non-HIV-infected immunocompromised patients they usually have a progressive and rapid disease with a higher risk of respiratory failure and higher mortality (1).. and main symptoms in HIV immunocompromised patient includes exertional dyspnea with low-grade fever and nonproductive cough with few physical sings including normal CXR so should keep a high index of clinical suspicion of early pjp infection
How do you manage this case?
ABG
FBC, LDH ( will be high level ), CMV PCR, COVID 19 screen, HSV , adenoviral screen
HRCT with the typical finding of diffuse bilateral ground glass appearance with or without cystic lesions on the background of HIV changes.
Bronchoscopy with BAL fluid assay will be the best diagnostic test to confirm the diagnosis of PJP immunofluorescence is superior to conventional staining. A combination of different diagnostic tests such as microscopy, polymerase chain reaction, and β-D-glucan is recommended.
early empirical chemotherapy with IV TMP-CTM 15-20 mg/kg as tolerated for a total course of 21 days with frequent renal, liver, and electrolytes monitoring for the side effects and drug intolerance, alternative or second-line therapy including dapsone with trimethoprim, clindamycin with primaquine, atovaquone, or pentamidine.
Continue on HAART therapy, in moderate to severe infection need to add steroids therapy and need prolonged secondary prophylaxis.
References
1. Hoffmann C, Kalsdorf B, Alanio A, Lange C. Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia. Respiration. 2018;96(1):52-65.
Thank you
Differential diagnosis
Management
Treatment – Given for 21 days.
Reference
Thankyou
Pentamidine is better used as an airosol.
This patient has features of a pneumonia in the early period post kidney transplantation. She is HIV positive with a CD4 of 250. The CXR is reported as normal but has increased bronchopulmonary lung markings. Her degree of hypoxia (mainly on exertion) is disproportionate to the radiological findings
The differential diagnosis includes:
Management:
Investigations:
Treatment:
Thankyou
DDX:
-PCP
-CMV Pneumonitis
-Hospital acquired Bacterial Pneumonia
-Covid Pneumonia
Management
I would manage at general ward level
CT thorax would be imperative on this case, even with normal CXR
Lab tests including LDH, ABGs, BD Glucan, CMV PCR
Sputum induction and PCR including metagenomic NGS
This case seems mild, so I would consider not doing bronchoscopy and VATS
I would also start on therapeutic oral cotrimoxazole double strength 2tabs tid
I would increase the steroid cover and reduce MMF and Tacro to a bare minimum
Pneumocystis Jiroveci
CMV Pneumonia
Tuberculosis
COVID 19 infection
ARDS
Mycoplasma infection
Legionella infection
Maintain oxygen and hydration status
Laboratory studies: CBC ESR CRP Procalcitonin RFT LFT PCR pneumocystis CMV igG, igM, PCR CMV, TT , LDH
BDG test
bronchoalveolar lavage for culture and PCR pneumocystis
CXR HRCT Drug level DSA
steroid because HIV and if arterial oxygen pressure less than 70 mm Hg in room air
Intravenous antibiotics
Reduce calcinurine inhibitors and stop anti metabolites
Pentamidine is better as a a airosol.
Thankyou
History
====================================================================
What is the differential diagnosis?
==================================================================== How do you manage this case?
IF sulfa allergies and mild to moderate disease include:
====================================================================
Reference
Well done
Many thanks Prof.Dawlat
Thankyou
D/D:
PCP.
Covid-19.
CMV pneumonia.
Pulmonary T.B.
Fungal infection.
Bacterial pneumonia.
· How do you manage this case?
Investigation:
CBC.
Sputum smear for AFB and COVID-19 RTPCR.
CT chest.
Sputum for Gram stain, bacterial culture, AFB smear, CBNAAT, AFB culture, fungal smear,
Fungal Culture,Nocardia stain, Pneumocystis
Jirovecii stain, And Cytomegalovirus (CMV) quantitative PCR.
Plasma CMV quantitative PCR.
Treatment:
Trimethoprim-sulfamethoxazol
Thankyou
early post operative infections (0-30 days) DDX.: all infections ,mostly nosocomial infections , donor derived and recipient derived
this case scenario ….immunocompromised patient (HIV, tacrolimus ) pluc clinical findings …..highly suspicious for PCP, covid-19
required more work ups such as chest CT Scan , BAL , +/- BIOPSY , …ETC
management:
same as previous case scenarios / MDT ( nephrologist, pulmonologist, microbiologist)
HIV patient
With Lymphocyte count of 250/ml.
kidney transplant recipient on tacrolimus based immune suppression protocol.
presented with mild fever and dyspnea on exertion.
Minimal crackles bilaterally.
Chesr X-Ray is normal .
Impression:
He is already immune suppressed from HIV infection, prone to have opportunistic infection. However, Lymphocytes count is more than 200, less likely to be predisposed to opportunistic infection.Some cases of opportunistic infection reported with lymphocytes count below 500.
Plan:
HRCT has to be performed to verify the findings.
differential diagnosis:
1] PCP, as it might be showing normal chest Xray in a signifigcant number of patients.
2] CMV.
What are the conclusive tests to diagnose or rule out this fatal infection.
If you confirm it what is the therapy plan!
Diagnostic test:
1]is PCR for DNA of PJ which is either done on sputum or fluid specimen collected by Bronchoalveolar lavage BAL,
2] A blood test to detect B-D-glucan which is a part of cell wall of several fungi is diagnostic as well.
Treatment:
1]Trimethoprim-sulfamethoxazole TMS is first line treatment.
2] pentamidine
3] Dapson with pyrimethamine
4] Atovagon are second line treatment.
Immunosuppression:
significant reduction of immunosuppression is recommended by reducing or stopping anti-metabolites and reducing calcineurin inhibitors.
Long term prophylaxis:
With TMS is recommended post treatment
references:
1]Taeb AM, Sill JM, Derber CJ, et al. Nodular granulomatous Pneumocystis jiroveci pneumonia consequent to delayed immune reconstitution inflammatory syndrome. Int J STD AIDS. 2018 Dec. 29 (14):1451-3.
What is your differential diagnosis?
Symmetrical infiltration is the chest radiographic
PCP.
Covid-19.
CMV pneumonia.
Pulmonary T.B.
Fungal infection.
Bacterial pneumonia.
· How do you manage this case?
Investigation:
CBC.
RFT.
Drug level (Tac).
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:
Trimethoprim-sulfamethoxazol orally.
Reduction of IS.
What kind of reduction in IS would you implement?
optimal strategy for immunosuppression reduction is uncertain.
MMF stop for 14-21 days with adjunctive glucocorticoids.
Sever PJP patients requiring ICU care need saving their lives rather than
maintaining grafts function, discontinue temporarily both MMF and CNIs with
pulse therapy of methylprednisolone sodium succinate injection.
HIV postrenal transplant patients complain of fever dry cough ,excretion dyspnoea and desaturation on excretion and normal CXR
1-pneumocystic jirovecii pneumonia
all above mention favor PCP.
3-CMV Pneumonia with or without pcp
3-covid19 pneumonia.
4-pulmonary T.B.
Typing whole sentence in bold or capitals equals to shouting ! Capitals are more difficult to read.
👉 The index case with HIV and presented with fever, dry cough and exertional desaturation and in the context of minimal bilateral interstitial infiltration so the most probable diagnosis is PCP.
👉 Differential diagnosis includes;
_ PCP.
_COVID 19.
_CMV .
👉 Management:
⭐ investigations required
_Basic lab as CBC, LFT, KFT.
_HRCT chest is more sensitive than CXR in diagnosis.
_Blood PCR for CMV and COVID 19.
_sputum induction by hypertonic saline for PCP PCR or use BAL.
⭐ Treatment with SMX_TMP either oral or IV.
_If allergic to SMX_TMP, use pentamidine or dapson.
_Reduction of immunosupression as decrease dose of MMF to 50% or stop it.
_decrease dose of Tacrolimus to trough level around 7 .
_cover with steroids to prevent rejection.
_Folow up of SPo2 as oxygen therapy, respiratory support with CPAP or mechanical ventilation may be required.
_Lifelong secondary prophylaxis against PCP with SMX_TMP.
_ttt of CMV by ganciclovir as indicated.
What is your differential diagnosis?
How do you manage this case?
Successful treatment of opportunistic infections requires early identification and targeted treatment. To avoid broad antibiotic treatment in immunocompromised individuals with pulmonary infiltrates, aggressively pursue a precise microbiologic diagnosis using invasive diagnostic methods.
Chest radiography or CT scans determine pulmonary infiltrates. The pattern of engagement may assist determine the cause. If respiratory symptoms or history imply pulmonary involvement, a chest radiograph alone cannot rule it out. Immunocompromised patients should get chest CTs.
Differential blood count
Creatinine, electrolytes, BUN, CRP, and LDH
Blood culture (minimum of two sets, with at least one peripheral set and one set from any indwelling catheter)
Urine sediment inspection and culture
Gram stain, culture, and fungal smear sputum.
Imaging of any problematic area and the lungs (chest radiography or CT scanning, if possible) (eg, abdomen)
skin examination for metastatic infection.
CMV quantitative molecular testing and patient-specific viral PCR assays may assist (adenovirus, parvovirus B19, severe acute respiratory syndrome coronavirus 2)
BAL samples with microbiologic testing boost test sensitivity (such as cultures, polymerase chain reaction, and Aspergillus galactomannan antigen).
Quntiferon TB test.
Preferred regimen: TMP-SMX is the preferred regimen for the treatment of PCP in patients with HIV. Therapy should be administered for 21 days
Alternative regimens: Trimethoprim-dapsone: Oral trimethoprim at 5 mg/kg three times a day with 100 mg dapsone.
Clindamycin-primaquine: Oral clindamycin (450 mg every six hours or 600 mg every eight hours) with a primaquine base of 30 mg per day.
Atovaquone suspension treats mild PCP.
Clindamycin-primaquine—600 mg intravenously every six hours or 900 mg every eight hours.
REFERENCES;
Smego Jr., R. A., Nagar, S., Maloba, B., & Popara, M. (2001). A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia. Archives of internal medicine, 161(12), 1529–1533.
Helweg-Larsen, J., Benfield, T., Atzori, C., & Miller, R. F. (2009). Clinical efficacy of first-and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-center cohort study. Journal of antimicrobial chemotherapy, 64(6), 1282-1290.
Under the heading ” How do you manage this case”, please use bold or underline for sub-headings to make it easier to read.
What is the differential diagnosis?
o Symptoms of dry cough, low grade fever, and dyspnoae in kidney transplant patient inspite of normal chest x-ray is highly suggestive of pneumocystis Jirovecii Pneumonia. Normal x-ray does not exclude the diagnosis and CT scan is indicated here. CT chest is more sensitive than routine chest radiography often demonstrate abnormalities not appreciated on routine chest radiography and should be obtained in case of normal plain chest radiographs with a consistent clinical presentation
Other differential diagnoses include:
1. Pulmonary tuberculosis
2. CMV disease
3. EBV disease
4. SARS-Covid-2 infection
5. Atypical bacterial infections
How do you manage this case?
Diagnosis:
o Complete history and clinical examination
o CBC, e GFR, electrolytes, CRP, s. albumin, liver enzymes and blood culture
o O2 saturation and ABG
o Serological tests for atypical bacterial infections
o PCR test for SARS-Covid-2 from nasopharyngeal swab
o Tuberculin skin test (TST) and interferon gamma for tuberculosis
o Viral load for CMV and EBV
o High-resolution chest CT scan is more sensitive and specific for PJP and exclude other causes
Diagnosis of PJP:
1. Measurement of plasma (1→3) b-D-glucan: may suggest diagnosis. Meta-analysis suggests a sensitivity of almost 95%, but with a specificity in the mid-80%
2. LDH: elevated in almost all cases of (over 300 IU/ml)
3. Multiple induced sputum samples: stain using antibodies for PCP (immunoflourescent, immunoperoxidase) and for Pneumocystis and other organisms (Giemsa, Silver, and others). Use PCR-based diagnostics on respiratory secretions. Samples should also be assayed for routine bacterial, fungal, mycobacterial, and other organisms to rule outconcomitant infections. Evaluate for CMV or other respiratory viral coinfection
4. PCR for PJP
5. Bronchoscopy with BAL: yield generally ≥70% in non-AIDS immunocompromised hosts when coupled with antibody staining
6. Bronchoscopy for transbronchial biopsies: increases yield of routine BAL
7. Open lung biopsies when other diagnostic fails or where other concomitant diseases may be a concern. Often considered to be a gold standard, but early patchy disease may decrease yield
Treatment:
v O2 therapy (maintain 0xygen > 92%)
v Duration of antimicrobial treatment is for at least 14days (21 days in severe infection)
Trimethoprim sulfamethoxazole (TMP-SMX):
o Is the drug of choice and is considered to be the most effective systemic therapy for PCP
o Dose is 15–20 mg/kg/day of the TMP component given IV in divided doses every 6–8 hours often in combination with corticosteroids (oral in milder disease)
o Side effects include bone marrow suppression, rash including Stevens-Johnson syndrome, hepatitis, interstitial nephritis, aseptic meningitis, and pancreatitis
o Hydration should be maintained
o Patients on high-dose TMP-SMX should have regular monitoring of cell counts, creatinine and potassium
Pentamidine isesthionate:
o In severe infection (second line treatment)
o Dose is 4 mg/kg/day IV initially over 1–2 hours
o Side effects include pancreatitis, hypoglycemia, hyperglycemia, bone marrow suppression, renal failure and electrolyte disturbances
Atovaquone:
o Dose is 750 mg po bid (optimal dose uncertain; 1500 bid used anecdotally)
o Available in an oral suspension only
o Has variable oral absorption (best with fatty foods)
o Approved only for mild and moderate PCP
Primaquine and clindamycin:
o Primaquine 15–30 mg po qd in combination with clindamycin 600–900 mg IV or po q6–8 hours This combination studied in mild to moderate PCP in AIDS
o Long-term use of clindamycin can predispose to infection with Clostridium difficile
o Primaquine should be avoided in G6PD deficiency
Dapsone and trimethoprim:
o Dapsone 100 mg po qd used in combination with trimethoprim 15 mg/kg/day po divided tid
o This combination is used with sulfa allergy, though dapsone may elicit sulfa allergies as well
Trimetrexate with folinic acid:
o Trimetrexate 45 mg/m 2/day IV (or 1.5 mg/kg/day IV in patients <50 kg) with folinic acid 20 mg/m2 po or IV every 6 hours (80 mg/m2 total daily)
o Folinic acid therapy extends≥3 days beyond trimetrexate therapy
o Trimetrexate causes bone marrow suppression and must be used with folinic acid, 10 mg po qd Outcomes are inferior to TMP-SMX in AIDS
Pyrimethamine and sulfadiazine:
o Pyrimethamine load of 100–200 mg po, followed by 50–100 mg po qd in combination with sulfadiazine 4 g po qd in divided doses
o Limited data available on this regimen
o Usually with folinic acid 10mg po qd to reduce bone marrow toxicity
Adjunctive agents Corticosteroids:
o 40 mg–60 mg of prednisone (or equivalent) po bid with taper after 5–7 days over a period of 1–2 weeks
o Best administered within 72 hours in the setting of hypoxia (pAO2 < 70 mmHg)
o Commonly used but not well studied in transplantation
o May require prolonged taper to avoid immune reconstitution pneumonitis
Prophylaxis:
For any transplant patient with a history of prior PJP infection, lifelong prophylaxis is often indicated
1. First line therapy: TMP-SMX (80 mg TMP/400 mg SMX or 160 mg TMP/800 mg SMX po (single or double strength) daily or three times weekly)
2. Second line therapy: dapsone (50–100 mg po qd), atovaquone (1500 mg po as single dose), Pentamidine (300 mg administered through aerosolized nebulizer q 3–4 weeks), Clindamycin and pyrimethamine (Up to 300 mg of clindamycin po qd with 15 mg of pyrimethamine po qd)
References
1. Martin, S.I., Fishman, J.A. and (2013), Pneumocystis Pneumonia in Solid Organ Transplantation. American Journal of Transplantation, 13: 272-279.
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.
I like you clinical approach and I quote you, hereby:
‘Normal x-ray does not exclude the diagnosis and CT scan is indicated here’.
Thank you prof Sharma
HIV related nephropathy on HAART therapy underwent a kidney transplantation from a deceased donor, CD4 count 250/ml. cough and SOB , with exercise desatutration.
What is the differential diagnosis?
The opportunistic infections in HIV patients underwent a kidney transplant are:
Bacterial pneumonia., and Tuberculosis
Viral infections, CMV, corona viruses.
Fungal infections, PJP, aspergillus
Non fungal infections, coccidioidomycosis, histoplasmosis, Cryptococcus
Non- infectious pulmonary diseases, PE, Kaposi sarcoma, non-Hodgkin’s lymphoma, and AIDS associated lymphoma.
However; the subacute symptoms, exertional desaturation, normal chest x ray and scattered wheezes, make the diagnosis of PJP.
How do you manage this case?
Detailed history, any travel history with and endemic infections, if there is animals around, history of exposure to TB.
Clinical examination: thorough examination including skin, lymphnodes, fundus examination.
CD4 count and infection in HIV patients:
Upper respiratory and sinusitis can occur at any CD4 count, pneumonia and malignancies can occur at any CD4 level as well.
PJP usually occur at CD4 <200/ml, Toxoplasma occurs at CD4 <150/ml.
Chest radiography: about 10% of HIV patients+PJP has normal CXR, pneumothorax, pneumtacele, and cavitation
CT chest: sensitive with certain findings suggest the diagnosis.
Nuclear scanning: Thalium 201 is diagnostic for Kaposi sarcoma.
Diffusing capacity for carbon monoxide: decreases in patients with PJP, even before CXR findings.
Antibody, antigen, and beta-D-glucan testing: a component of cell wall protein in fugus.
Polymerase chain reaction (PCR) testing.
Smear and culture of peripheral blood.
Flexible bronchoscopy and transbronchial biosy is the modality of choice, BAL culture, PCR, and cytology.
CT guided biopsy, and open lung biopsy can be used for diagnosis, indications for open lung biopsy in patients with HIV:
Treatment:
Trimethoprim-sulphamethexazole is the drug of choice, if allergic to sulfa drugs then: Atovaquone, pentamidine, dapson, or a combination of clindamycin+pyrimethamine, and pentamidine can be used.
Lower MMF or stopping it in hemodynamically unstable patients, but continue on CNI.
References:
(1) Catherinot E, Lanternier F, Bougnoux ME, et al. Pneumocystis jirovecii Pneumonia. Infect Dis Clin North Am 2010; 24:107.
(2) UpToDate- evaluation of pulmonary symptoms in HIV patients.
(3) Cillóniz C, Dominedò C, Álvarez-Martínez MJ, Moreno A, García F, Torres A, Miro JM. Pneumocystis pneumonia in the twenty-first century: HIV-infected versus HIV-uninfected patients. Expert Rev Anti Infect Ther. 2019 Oct;17(10):787-801. doi: 10.1080/14787210.2019.1671823. Epub 2019 Oct 4. PMID: 31550942.
Early BAL is the key to prompt diagnosis and timely treatment. Why to do lung biopsy when BAL is a better option? We never needed to do lung biopsy, I know it is mentioned as one of the options.
Thank you Prof. Ajay; i totally agree but it is mentioned in the literature
What is your differential diagnosis?
How do you manage this case?
Diagnosis
Treatment- According to the cause
Hi Dr Yusuf,
Very humbly, please allow me not to agree with your comment, “Pneumocystitis carenii pneumonia (PCP) is possible but remote possibility due to absence of hypoxemia. Please analyse this clinical information:
“Sat 100% on air and desaturates to 95% on exertion.” This is a presentation typical of an early PCP (or PJP). I would keep in mind concurrent CMV in such a patient.
Yes … noted prof
Case scenario of 2 weeks of non-productive cough with low grade fever and dyspnea on exertion with chest x-ray showing interstitial infiltrates
Most probable diagnosis are
Pneumocystis jirovecii Pneumonia PJP
Aspergillosis
CMV
Varicella pneumonia
Covid 19
Influenza
How to manage
Monitoring and Support hemodynamics as appropriate (help of ICU team) ABG 12 hourly
CBC, chemistry (LFT, KFT and electrolytes) LDH, PT, INR, APTT
Sputum CS (BAL or tracheal tube aspiration for better yield)
Blood CS
B D- glucan
Metagenomic next-generation sequencing (mNGS):
Start empirical antimicrobial including TMP/SUL every 6 hours: Co-trimoxazole 120mg/kg (sulphamethoxazole 100mg + trimethoprim 20mg)/day (usually four divided doses) for 14 days.
Sensitivity to co-trimoxazole
Sensitivity to co-trimoxazole (sulphamethoxazole > trimethoprim) is common. Alternative treatments include: dapsone + trimethoprim, atovaquone, clindamycin + primaquine, and nebulized pentamidine
Change according to the results of culture and sensitivity
Immunosuppressive and HAART interaction
· there are clinically important interactions between the calcineurin inhibitors (CNIs) and protease inhibitors (PIs) and the non-nucleoside reverse tranctriptase (NNRTI),
· Mycophenalate (MMF) may increase intracellular levels of abacavir, didanosine and tenofovir and could result in enhanced toxicity.
· In the presence of PIs a major dose-reduction of CNIs may be required
· Regular follow up for IS drug level
If CMV : IV ganciclovir or oral valganciclovir
Prophylaxis for 6-12 months according to risk assessment
Ref:
https://bts.org.uk/wp-content/uploads/2016/09/KidneyHIV.pdf
OSH Renal Transplantation: P347-349
Stopping antimetabolites until this patient is in ITU and reducing CNI to bare minimum with steroid cover.
-What is the differential diagnosis?
*History of non productive cough , low grade fever, and desaturation in context of HIV and immune suppression is highly suggestive for PJP and should be excluded.
*Normal CXR, does not ruled out PJP and it may be just a sign of an early disease process.
*The differential diagnosis of respiratory infection from 1 to 6 months after transplantation:
-How do you manage this case?
Management is MDT as usual & PJP on the top of the differential diagnosis although it is commonly present one to six month after transplantation.
Source:
Nephrology secrets ,chapter 60, posttransplant infections by Beje Thomas and Metthew R. Weir, oxford hand book of nephrology 2th edition
It is good to keep in mind aspiration pneumonia, as you mention, but this is not a clinical or radiological picture of that diagnosis. I would compare this chest X ray with pre-op chest X ray. This is a presentation typical of an early
PCP (or PJP). I would keep in mind concurrent CMV in such a patient.
Absolutely prof
The findings of exertional dyspnoea
Two weeks of non productive cough
low grade fever
with almost normal CRX
in a patient of cadaveric Tx (primary disease HIV Nephropathy on HAART)
Raises strong possibility of PJP pneumonia as 13 to 39% of these patients will have normal CXR
A HRCT chest will show more definitive findings and further testing like BAL and PJP PCR can confirm the diagnosis.
one can think of other viral pneumonia s
Atypical Pneumonia
TB in context of HIV as well
Managment
Once confirmed PJP pneumonia one can start standard therapy which includes TMP and sulfamethoxazole.
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.
The drug interactions of HAART should be kept in mind as well.
Please use bold or underline for headings or sub-headings to make it easier to read.
Sure sir . I will in future
Differential Diagnosis;
Based on clinical scenario and early normal radiological findings the differential would be,
· Pneumocystis Jirovecii the most likely diagnosis
· Bacterial Pneumonia like mycoplasma
· CMV pneumonitis
· TB
Management
Investigation like
· CBC, LDH, CRP, ABGS, RFTS. S Electrolytes
· Sputum staining,
· B D- glucan and
· PCP PCR.
· HRCT
· BAL
· CMV PCR.
· CD4/8
Treatment
· Oxygen inhalation.
· Maintain steroids,IS and HAART .
· TMP-SMX 20mg/kg IV in divided doses 3-4(dosing is based on TMP component) OR can give oral for 21 days. Patients who are failed to show improvement on 7th day should be re- evaluate FOR co-infection.
· Allergic patients can be desensitized (but not for sever allergy like Stevens-johnson) are other agents can be used.
Alternative agents
· Atovaquone; 750mg bid with food.
· Clindamycin plus primaquine; those who are not responding to TMP-SMX in a week after switching to IV if receiving oral.
· TMP plus dapsone; dapsone 100mg daily and TMP 5mg/kg orally TDS.
· TMP plus dapsone
· Clindamycin plus primaquine.
· Pentamidine inhalational as last choice
ART should be continued as evidence are suggestive of benefits of early vs deferred ART.
If the patient is not on gaincyclovir it should be started on gaincyclovir/valgaincyclovi for CMV .
Referernces; Topic 3709 Version 47.0 UpToDate 2023.
Typing whole sentence in bold or capitals equals to shouting !
I would compare this chest X ray with pre-op chest X ray.
This is a presentation typical of an early PCP (or PJP
Differential diagnosis
– Pneumocystosis
– Bacterial pneumonia
– Mycobacteria (especially Tuberculosis)
– Histoplasmosis
– invasive aspergillosis (less common)
– COVID 19 + CAPA
Management
1. Diagnosis
Non-contrast-enhanced computed tomography (in the case of Pneumocystosis, heterogeneous bilateral interstitial lesion with clinical-radiological dissociation).
Sputum test
Bronchoalveolar lavage with an investigation for BAAR, Gene Xpert for Tuberculosis, RT PCR for Pneumocystosis, Culture for aerobes, fungi, Ziehl Neelsen, Galactomannan, RT PCR COVID-19.
Specimen biopsy with specific staining (Hematoxylin-Eosin, Gomori Crockott – Silver, PAS)
Arterial blood gases – Low levels of PaO2 (PaO2 < 70mmHg) and high difference between alveolar and arterial PaO2 (D(A-a)O2 > 35) suggest pneumocystosis and concomitant need for corticosteroids
New CD4 values must be measured. Absolute values lower than 200 cells or low CD4/CD8 index suggest reactivation of latent Pneumocystosis.
Urinary and serum antigen for Histoplasmosis (higher sensitivity and specificity in SOT)
2. Clinical management
Define the need for corticosteroids and their progressive withdrawal during treatment.
Low-dose corticosteroids (Dexamethasone 6mg/day) associated with Remdesivir in case of COVID-19
Measures to increase O2 supply with non-invasive pressure-assisted pressure (BIPAP) in case of low PaO2 values
Beginning of treatment with Sulfamethoxazole + Trimethoprim at a therapeutic dose (monitor with blood count, liver transaminases, and nitrogenous slags)
Measure immunosuppressant, mainly tacrolimus, due to the high interaction with Sulfas (Evaluate its exchange for another immunosuppressant)
Investigate and treat CMV reactivation
If the patient is allergic to Sulfa, there are alternative treatments with inhaled Pentamidine, oral Atovaquone, and intravenous combinations of Clindamycin + Pyrimethamine/Primaquine or Sulfadiazine + Pyrimethamine (the same treatment is available orally).
3. Post-treatment care
HAART must be individualized in this case. Tenofovir and protease inhibitors carry a high risk of kidney damage and should be avoided. Formulations with Alaphenyl of Tenofovir are safer or its replacement for Abacavir, since Zidovudine is closely related to megaloblastic anemia.
In this case, the appropriate regimen would be Tenofovir Alaphenyl (or Abacavir), emtricitabine, and dolutegravir.
We should avoid protease inhibitors for drug interactions with CNI
Secondary prophylaxis with Sulfas for at least six to twelve months Monitor serum CNI (high risk of interaction, increasing risk of rejection due to insufficient doses of immunosuppression) AND CD4 levels higher than 200 cells.
I appreciate that you consider CPAP or BiPAP availability at a very short notice.
Thank you, Professor
Thankyou this is an exellent answer as you aknowleged that she is an HIV patient with the potential interactions of HAART and IS DRUGS.
Thank you, Professor
The PA and lateral CXR above show bilateral hilar opacity with interstitial opacity.
Differential diagnosis
Investigations
Treatment
Note: Steroid treatment is only indicated if arterial oxygen pressure is less than 70 mmHg or an alveolar-arterial gradient greater than 35 mmHg
If the patient is allergic to sulfur-containing medications, alternatives are
Secondary prophylaxis with single doses ( 480mg) of TMP-SMX will be considered for the patient for 6 -12 months
References
I would compare this chest X ray with pre-op chest X ray.
This is a presentation typical of an early PCP (or PJP).
I would keep in mind concurrent CMV in such a patient.
A 39-year-old CKD 5 secondary to HIV associated nephropathy had a deceased donor kidney transplantation. CD4 count is 250/ml and receiving HAART. Currently she is on Tacrolimus-based triple immunosuppression. Her kidney function has improved and started to pass more urine. She presented with 2 weeks history of non-productive cough, low grade temperature (37.5 °C). She has dyspnoea on excretion (respiratory rate at rest is 20/min) but chest X-Ray reported normal. Clinically there were few physical findings only few scattered wheezes. Sat 100% on air and desaturates to 95% on exertion.
What is your differential diagnosis?
The Chest X-ray picture showing bilateral diffuse hazy pulmonary rnterstitial infiltrates with hilar opacity
DD:
1- Pneumocystis jirovecii (PJP), Fungal pneumonia(need high clinical suspicion)
2- Other Viral (Influenza, COVID-19)infections
3- Bacterial Infection
4- PTB
5- CMV Pneumonitis
6- Aspergillosis
How do you manage this case?
Diagnosis is challenging due to:
1- Nonspecific presenting signs and symptoms , need high clinical suspicion
2- Inadequate conventional diagnostic methods
Diagnostic tests:
1- Sputum (BAL)Gomori methenamine silver (GMS) staining on samples (sputum or bronchoalveolar lavage fluid, and tissue( Staining for Trophozoite or cysts)
2- Serum β-D-glucan (BDG) test: Widely used method, PPV 96 % NPV 60%
3- ABGs, LDH
3- PCR testing:
•Fast & more sensitive than GMS staining.
•Not widely used in clinical practice
•Variable cut values in different studies.
4.Metagenomic next-generation sequencing (mNGS):
•Is a new diagnostic method.
•Both sputum and serum can be used.
•Can help detect a large amount of complex and rare pathogens quickly & accurately.
5. CT scan will show ground glass appearance, honeycombing, and cystic lesions.
Treatment of PJP:
All Post Solid organ Transplant with signs and symptoms of infections, feeling unwell==> should be admitted for viral, septic, radiology screening , beside the routine blood work (LDH) and stabilization his general conditions (IV Fluids, Empirical Ab, decrease IS accord. to severity and you assessment ).
American Society of Transplantation guidelines suggest that 40–60 mg of
prednisone is administered per oral twice daily and tapered after 5–7 days over a
period of 1–2 weeks
1.Atovaquone 1500 mg po daily
2.Dapsone. 50-100 mg po daily
3.Inhaled pentamidine. 300 mg nebulizer monthly
4.Primaquine combined with clindamycin.
5.Combined dapsone and trimethoprim
6.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.
10-CMV prophylaxis by valganciclovir should be given and needs renal dose adjustment.
11-if proved CMV pneumonia will treat by iv ganciclovir
Factors Associated with poor outcomes:
Complications:
References :
Thank you for your reply
·What is the differential diagnosis?
==========================
·How do you manage this case?
Treatment of PJP:
Treatment of CMV:
References
Thank you for your excellent reply
DD:
1- viral pneumonia like CMV, COVID infection
2- bacterial pneumonia
3-fungal pneumonia like PCP, aspergillus infection
management:
1- hospitalization
2-lab investigations CBC, LDH (non-specific)
3-PCR for CMV
4-PCR for PCP
5-BAL which is a sample of choice or induced sputum as it is simple and cost effective , for microbiological diagnosis
6- CT chest will show ground glass appearance in PCP
7- detection of the β-d-glucan antigen in blood samples facilitates detection of PCP.
8-presence of dry cough and hypoxia with this picture of CXR may suggest a diagnosis of PCP which can be treated as follow:
1- Trimethoprim-Sulfamethoxazole (TMP-SMX) which is the first-line agent for the treatment of mild to severe PCP in both HIV and non-HIV-infected patients and in SOT, The recommended daily dose is TMP 15–20 mg/kg plus SMX 75–100 mg/kg, preferably by IV administration for severe PCP for 14-21 days.
2-Intravenous pentamidine remains probably the best second-line agent after TMP-SMX for SOT recipients.
3-Atovaquone, clindamycin-primaquine, or dapsone-TMP.
4-clindamycin-primaquine combination seems to be the most effective regimen, particularly in cases where TMP-SMX has failed.
5-In HIV-negative patients with moderate-to-severe PCP, the use of adjunctive glucocorticoids remains questionable and is highly controversial.
6-KDIGO and the American Society of Transplantation guidelines recommend treatment with adjunctive corticosteroids for SOT recipients with moderate to severe PCP (as defined by PaO2 <70 mmHg in room air)
7-Corticosteroids should be administered with antimicrobial therapies, ideally within 72 h of initiating the antimicrobial therapy to obtain the maximum benefits
8-American Society of Transplantation guidelines suggest that 40–60 mg of prednisone is administered per oral twice daily and tapered after 5–7 days over a period of 1–2 weeks
9-Reduction in Immunosuppressive Medications
10-CMV prophylaxis by valganciclovir should be given and needs renal dose adjustment.
11-if proved CMV pneumonia will treat by iv ganciclovir
references:
1-Xavier Iriart, Marine Le Bouar, Nassim Kamar, Antoine Berry.Pneumocystis Pneumonia in Solid-Organ Transplant Recipients. J Fungi (Basel). 2015 Dec; 1(3): 293–331.2-Dominykas Varnas, 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.
Thank you for your reply
What is the differential diagnosis?
PCP pneumoniae
Viral(CMV) or bacterial pneumonia
Tuberculosis
Legionella pneumonia
Mycoplasma infections
COVID-19 pneumonia
How do you manage this case?
considering PCP as the diagnosis ,TMP 15 to 20 mg/kg/day and SMX 75 to 100 mg/kg/day, given orally in 3 or 4 divided doses or TMP-SMX DS, two tablets three times per day for 21 days.
For moderate to severe cases (e.g., PaO ≤ 60 mmHg, respiratory rate > 25), TMP 15 to 20 mg/kg/day and SMX 75-100 mg/kg/day are given intravenously (IV) every 6 to 8 hours with a switch to oral when the patient shows clinical improvement.
Decrease MMF dose by half.
Will you explain the clinical picture of mTORi-induced interstitial pneumonitis and how it differs from PCP?
present with cough or dyspnea, especially on exertion, or hypoxemia
Patients may also exhibit occasional systemic symptoms, such as fever and fatigue, making the distinction from infectious causes more difficult. mTOR inhibitor‐associated pneumonitis may also remain asymptomatic in some patients.
Pulmonary function tests have revealed that mTOR inhibitor‐associated pneumonitis may be associated with a restrictive pattern or an isolated reduction in diffusing capacity.
On CT
ground‐glass and reticular opacities that predominantly involve the lower lobes of the lungs.
On occasion, patchy areas of focal parenchymal consolidations and pleural effusions are seen.
mTOR inhibitor‐associated pneumonitis most commonly presents as either cryptogenic organizing pneumonia (COP) or nonspecific interstitial pneumonia (NSIP).
In PCP
The symptoms include dyspnea, nonproductive cough, and fever.
Chest radiography demonstrates bilateral infiltrates which are peri hilar, sparing the peripheries.
Emerging Perspectives on mTOR Inhibitor‐Associated Pneumonitis in Breast Cancer
Ricardo H. Alvarez
Clinical picture of Pneumocystis jiroveci pneumonia in cancer patients
Guillaume Bollée et al
What is the clinical picture of aspergillosis?
Invasive aspergillosis principally involves the sinopulmonary tract, a reflection of inhalation being the most common route of entry of Aspergillus spores .
Fever, cough, and dyspnea are frequent, although non-specific, findings of pulmonary aspergillosis, the most common site of invasive aspergillosis.
Vascular invasion may manifest as pleuritic chest pain due to pulmonary infarction or hemoptysis.
Central nervous system involvement is a devastating consequence of disseminated aspergillosis, and may manifest with seizures or focal neurological signs from mass effect or stroke.
Pulmonary Aspergillosis: clinical presentation, diagnostic tests, management and complications
Rami Sherif et al