CONTENTS
- Rapid Reference 🚀
- Background: HIV(-)PJP vs. HIV(+)PJP
- Epidemiology
- Clinical presentation
- Radiology
- Blood tests
- Microbiology tests
- Approach to diagnosis
- Treatment
- Prognosis
- Podcast
- Questions & discussion
- Pitfalls
noninvasive PJP pathway:
PJP (previously known as Pneumocystis Carinii Pneumonia) presents differently, depending on whether the patient is HIV-negative or HIV-positive [HIV(-)PJP versus HIV(+)PJP]. HIV causes PJP pneumonia to present in a more indolent manner, with a higher burden of organisms. This makes HIV(+)PJP somewhat easier to diagnose and to treat. Alternatively, HIV(-)PJP tends to present in a more fulminant fashion with a lower burden of organisms – presenting a greater diagnostic and therapeutic challenge.
HIV
- Previously, PJP was extremely common and a leading cause of death in HIV. However, with increased use of antiretroviral therapy, the frequency of PJP has decreased substantially. Patients who are unaware of their HIV status (and thus untreated) continue to present with PJP.
- 90% of patients have a CD4 count <200/uL. (22623570)
- PJP can occur as a component of immune reconstitution inflammatory syndrome (IRIS), following initiation of antiretroviral therapy for HIV.
other forms of immunosuppression
- Steroid accounts for >90% of non-HIV pneumocystis pneumonia.
- Risk increases after a minimum exposure of roughly >15 mg/day prednisone for >2 months.
- Patients are at especially high risk if:
- They are being treated for glioblastoma.
- They are being treated for rheumatologic diseases (e.g., lupus, granulomatosis with polyangiitis).
- Steroid is combined with other immunosuppressives (e.g., cyclophosphamide).
- PJP may manifest when patients are tapering off steroids (when immune system is reconstituting).
- Malignancy
- Hematologic malignancy (especially acute leukemia, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia)
- Chemotherapy (especially fludarabine, cladribine, cytarabine, and temozolomide)
- Organ transplantation
- Stem cell transplantation: PJP is rare (0.6% of alloSCT; 0.3% of autoSCT).(26726945)
- Solid organ transplantation: PJP typically occurs 4-6 months post-transplantation. Treatment of rejection with steroid or lymphocyte depletion also increases risk.(Fishman 2023) The rate may be high (~5-15%), but this is dramatically reduced by PJP prophylaxis.(Murray 2022) PJP must be differentiated from sirolimus-induced pneumonitis, which may appear radiographically similar.📖
- Immunosuppressive medications, for example: (32185915)
- Alkylating agents (cyclophosphamide, temozolomide)
- Anti-metabolites (methotrexate, cytarabine, fluorouracil)
- Purine analogs (azathioprine, cladribine, fludarabine, mycophenolate mofetil)
- Calcineurin inhibitors (cyclosporine, tacrolimus)
- mTOR inhibitors (everolimus, sirolimus, temsirolimus)
- TNF-alpha inhibitors (e.g., adalimumab, certolizumab, etanercept, infliximab, golimumab)
- IL-6 inhibitors (sarilumab, tocilizumab)
HIV(+)PJP
- This typically evolves gradually, over weeks or months (e.g., may cause insidious weight loss).
- Classical symptom triad:
- Fever (~90%): fevers, night sweats, and fatigue can be a predominant feature.
- Cough (95%) – generally nonproductive.
- Progressive dyspnea (95%).
- Oral thrush coinfection is common (thrush may be a sign of underlying HIV).
- Symptoms that may argue against a diagnosis of HIV(+)PJP: (Murray 2022)
- High fevers, rigors.
- Purulent sputum (although this can occur if there is a bacterial co-infection in addition to PJP).
- Pleuritic chest pain.
HIV(-)PJP
- This presents more acutely (typically about one week from symptom onset to respiratory failure).(32185915)
- Common features include fever, dry cough, and hypoxemic respiratory failure.
- This often progresses to requiring mechanical ventilation.
- Chest X-ray may be normal, or it may demonstrate reticular or hazy opacities.
- Parenchymal abnormalities may be diffuse, or most pronounced in the perihilar region.
- Occasionally, pneumothorax may be seen.
- Patients may be disproportionately hypoxemic and symptomatic, seemingly out of proportion to their radiographic findings. (Walker 2019)
ground glass opacities (most common finding)
- Distribution:
- Often predominates in the perihilar and upper lung zones. Upper lobe infiltrates may also occur in patients who received inhaled pentamidine for PJP prophylaxis, since the upper lobes are less well ventilated and thus receive lower doses of pentamidine.
- Ground glass may be either uniformly distributed, or in a patchy/mosaic pattern.(15671387)
- Peripheral sparing occurs in ~40% of patients.
- Smooth septal thickening commonly occurs. The combination of ground glass opacification plus septal thickening may generate a crazy-paving pattern that mimics heart failure.
pneumatoceles (thin-walled cysts)
- Pneumatoceles occur in about a third of patients. They are seen in about half of HIV(+)PJP, but infrequently in HIV(-)PJP. Occasionally, cysts may be the predominant radiographic finding.
- Cysts are most often located in the upper lobe, in a subpleural location.
- Cysts may be single or multiple.
- Size may vary in size from millimeters to several centimeters. (Fishman 2023)
- Cysts predispose to the development of pneumothorax.
- Following successful therapy, cysts usually resolve (similar to other pneumatoceles). (Fishman 2023)
less common findings:
- Consolidation:
- Severe cases may progress to patchy, bilateral consolidation.
- Consolidation is more common in HIV(-)PJP.(22623570)
- Nodular patterns: (“granulomatous PJP”)
- Rarely, solitary or multiple nodules may occur. These are usually upper-lobe predominant, and may cavitate.
- A nodular pattern may occur in the context of limited immunodeficiency (e.g., early in the course of HIV infection, or in the context of hematologic malignancies).(22623570)
findings that are generally inconsistent with PJP
- If seen, these findings suggest either another superimposed process, or an alternative diagnosis entirely:
- Lymphadenopathy.
- Pleural effusion.
- PJP pneumonia can be the presenting finding of AIDS.
- For patients with unknown HIV status, there should be a low threshold for evaluating for HIV (e.g., if CT scanning suggests possible PJP).
- The Centers for Disease Control recommends fairly broad screening for HIV, so this is reasonable whenever there is a question of possible HIV.
- The presence of absolute lymphopenia (e.g., absolute lymphocyte count below ~1,500 cells/uL) might suggest the possibility of HIV. However, lymphopenia isn't very good test for HIV, so this cannot be relied upon.
basic properties of assay
- Beta-D glucan is a cell wall component present in most fungi (except cryptococcus or zygomycetes).
- This is not specific for PJP, but rather can be seen with a variety of fungal infections (e.g., aspergillus, histoplasma, cryptococcus, or candida).
- Even colonization with candida may generate a positive assay.(30561560)
- Causes of a false-positive assay include:
- Treatment with intravenous immunoglobulin (IVIG).
- Exposure to cellulose membranes (used in hemodialysis, or processing of albumin/blood products).
- Exposure to gauze packing.
- Some bacterial infections (e.g., Pseudomonas).
- (Note: assay is not affected by piperacillin-tazobactam).
performance in HIV(-)PJP
- The largest and most recent study evaluated 438 cancer patients at Memorial Sloan Kettering.(30561560)
- Exact numbers are a little fuzzy because of the existence of some patients with “possible” PJP.
- Using a cutoff of >80 pg/ml had a sensitivity of 88% and specificity of 85%. Within this patient population, a value <80 pg/ml had a negative predictive value of 95% (however, negative predictive value depends on the pre-test probability of disease, so it will vary among patients and populations).
- Using a cutoff of >200 pg/ml had a sensitivity of 70% and specificity of 100%. In the presence of a positive PCR, this strongly argues for invasive disease (rather than colonization).
- Receiver – operator curve is shown above.
performance in HIV(+)PJP
- The largest study involves analysis of 252 patients with AIDS and opportunistic infections:(21690628)
- Among all patients: 173/252 patients were diagnosed with PJP
- Patients with PJP had beta-D-glucan levels with median of 408 pg/ml (IQR 209-500 pg/ml).
- Patients without PJP had beta-D-glucan levels with median of 37 pg/ml (IQR 31-235 pg/ml).
- A cutoff value of 80 pg/mL yielded a sensitivity of 92% and specificity of 65%.
- Receiver – operator curve is shown above.
- Among patients presenting with respiratory symptoms: 139/159 patients were diagnosed with PJP.(23698062)
- A cutoff value of 80 pg/ml yielded sensitivity of 93% and specificity of 75%.
- Among all patients: 173/252 patients were diagnosed with PJP
lactate dehydrogenase
- Lactate dehydrogenase (LDH) historically was used as a test to evaluate for HIV(+) PJP. However, more recent studies have found that it has poor performance for this.(21690628)
- Elevated lactate dehydrogenase is extremely nonspecific (especially in the context of critical illness or malignancy).
- LDH probably adds nothing meaningful to the diagnostic evaluation.
inflammatory markers
- Not generally part of the evaluation of PJP (performance is unclear).
- One study showing typical results is shown below.
- If procalcitonin is obtained for another reason, a value >>10 ug/L suggests an alternative or superimposed diagnosis (not solely PJP).
conventional stain (i.e., silver stain)
- Sensitivity ~97% for HIV(+)PJP, but considerably lower in HIV(-)PJP (perhaps on the order of 50%).(Fishman 2023)
PCR for PJP
- PCR has increased sensitivity compared to conventional stain (sensitivity approaches 100%, specificity varies depending on population).
- Specificity is limited by colonization.
PCR for other pathogens
- Consider testing PCR for CMV in patients with HIV, as this may occur with PJP (or it may develop clinically as patients are recovering from PJP pneumonia).
induced sputum
- Specimen quality may vary across different hospitals.
- If PCR is utilized, a sensitivity of ~90% may be achieved.(Fishman 2023)
- (Expectorated sputum is generally considered inadequate for testing).(Fishman 2023)
endotracheal aspirate
- There is not much data regarding this.
- In HIV(+)PJP, one study found 12/13 (93%) sensitivity using endotracheal aspirate with immunostaining techniques.(9201045) Note that these authors instilled saline into the endotracheal tube, so this was a bit of a tracheal wash.
early-invasive approach
- Traditionally, diagnosis has centered around bronchoscopy with bronchoalveolar lavage. The main drawback of this strategy is that bronchoscopy may be a risky procedure in patients with severe hypoxemia.
- Bronchoscopy has the greatest utility in patients with a broader differential diagnosis, for example due to:
- i) More profound immunosuppression (which could place the patient at risk for a variety of opportunistic infections).
- ii) Nonspecific chest CT findings (e.g. patchy consolidation which could be consistent with pneumocystis, dimorphic fungi, or invasive mold).
empiric therapy +/- delayed bronchoscopy
- An alternative approach is to initiate empiric therapy for PJP (as well as other pathogens) while simultaneously awaiting the results from non-invasive studies.(23698062) Factors that could argue for this strategy could include the following:
- i) Patient is extremely hypoxemic and not expected to tolerate bronchoscopy well.
- ii) Patient is relatively less profoundly immunosuppressed (narrowing the differential diagnosis).
- iii) Chest CT scan is somewhat helpful in narrowing the possibilities (e.g., the CT scan shows diffuse ground-glass opacification).
- The drawback of this strategy is that if none of the diagnostic tests reveal a pathogen, then the patient may be left on a rather unwieldy regimen of several antibiotics and steroid. In this situation, delayed bronchoscopy (often after a few days when the patient may have started recovering) may be helpful to assist in narrowing antibiotic therapy. Notably, delaying bronchoscopy for a few days should still allow for a good yield for PJP (dead organisms or PCR positivity should still remain, even after viable organisms are gone).
1st line therapy: trimethoprim-sulfamethoxazole (TMP-SMX)
- TMP-SMX is front-line therapy (even if the patient was previously on this agent for PJP prophylaxis).
- More on trimethoprim-sulfamethoxazole is in the antibiotics chapter here.
- HIV(+)PJP patients often have difficulty tolerating trimethoprim-sulfamethoxazole due to various adverse reactions. This seems to be better tolerated by HIV(-)PJP patients.
- Patients with prior allergy to TMP-SMX may undergo desensitization, since this is the front-line therapy. However, severe non-allergic reactions (e.g., Stevens-Johnson syndrome) are a permanent contraindication to the use of TMP-SMX.
- Improvement should occur within ~5-7 days (otherwise consider transition to 2nd line therapy). This often occurs sooner in HIV-negative patients (~5 days) than HIV-positive patients (~7-10 days).(Fishman 2023)
- A 21-day course is standard.
2nd line therapy is generally clindamycin-primaquine
- Usual combination:
- Primaquine 30 mg PO daily.
- Clindamycin 900 mg q8hr IV (initially).
- Clindamycin-primaquine seems to have equivalent efficacy compared to trimethoprim-sulfamethoxazole as initial therapy.(8610948) Clindamycin-primaquine has also been found to have a high efficacy as salvage therapy for patients failing to respond to trimethoprim-sulfamethoxazole.(11427101)
- A primary limitation to this combination is lack of an IV form of primaquine, so this relies on some form of enteral access.
- Toxicities related to clindamycin-primaquine include neutropenia, anemia, thrombocytopenia, C. difficile, and methemoglobinemia.(Fishman 2023)
- Primaquine is contraindicated in G6PD deficiency. However, therapy may be started before G6PD results return, if the patient is in a low-risk ethnic group.
- Among patients failing to respond to trimethoprim-sulfamethoxazole, another option might be the addition of an echinocandin.(31886310, 35740126)
- Consider consulting an infectious disease specialist for patients not responding to trimethoprim-sulfamethoxazole.
antiretroviral therapy (ART) for HIV(+)PJP
- There is benefit to starting reasonably soon (e.g., within ~2 weeks).
- Infectious disease consultants may help clarify the optimal timing and regimen.
indication
- HIV(+)PJP
- The classical indication is: PaO2 <70 mm or A-a gradient > 35 mm.
- Patients requiring supplemental oxygen to maintain adequate saturation will meet these criteria, so you don't need to bother getting an ABG on them. Likewise, critically ill patients with severe pneumonia will invariably meet these criteria.
- HIV(-)PJP
- The role of steroid is less clear. However, steroid is generally still used in a similar fashion to that in HIV(+)PJP.
regimen
- Traditional regimen is as follows:
- Prednisone 40 mg BID days # 1-5.
- Prednisone 40 mg daily days #6-11.
- Prednisone 20 mg daily days #12-21.
- An equivalent dose of other steroid may be used as needed (e.g., methylprednisolone in a patient unable to take oral medications).
- Prognosis of PJP in general:
- HIV(+)PJP carries a ~15% mortality.
- HIV(-)PJP carries a ~40% mortality.
- Prognosis is worse for patients in the ICU and who require mechanical ventilation (especially patients with advanced malignancy).
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- Failure to consider the diagnosis of PJP (e.g., in a patient without known HIV, or a patient on relatively modest doses of chronic steroid therapy).
- Delaying initiation of treatment until the diagnosis has been definitively reached (in many situations, it will be appropriate to empirically initiate therapy prior to confirmation of the diagnosis).
- A rigid diagnostic approach to PJP which insists on early bronchoscopy for all patients.
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References
- 09201045 Alvarez F, Bandi V, Stager C, Guntupalli KK. Detection of Pneumocystis carinii in tracheal aspirates of intubated patients using calcofluor-white (Fungi-Fluor) and immunofluorescence antibody (Genetic Systems) stains. Crit Care Med. 1997 Jun;25(6):948-52. doi: 10.1097/00003246-199706000-00009 [PubMed]
- 18024536 Davis JL, Welsh DA, Beard CB, Jones JL, Lawrence GG, Fox MR, Crothers K, Morris A, Charbonnet D, Swartzman A, Huang L. Pneumocystis colonisation is common among hospitalised HIV infected patients with non-Pneumocystis pneumonia. Thorax. 2008 Apr;63(4):329-34. doi: 10.1136/thx.2007.088104 [PubMed]
- 21690628 Sax PE, Komarow L, Finkelman MA, Grant PM, Andersen J, Scully E, Powderly WG, Zolopa AR; AIDS Clinical Trials Group Study A5164 Team. Blood (1->3)-beta-D-glucan as a diagnostic test for HIV-related Pneumocystis jirovecii pneumonia. Clin Infect Dis. 2011 Jul 15;53(2):197-202. doi: 10.1093/cid/cir335 [PubMed]
- 22623570 Kanne JP, Yandow DR, Meyer CA. Pneumocystis jiroveci pneumonia: high-resolution CT findings in patients with and without HIV infection. AJR Am J Roentgenol. 2012 Jun;198(6):W555-61. doi: 10.2214/AJR.11.7329 [PubMed]
- 23698062 Wood BR, Komarow L, Zolopa AR, Finkelman MA, Powderly WG, Sax PE. Test performance of blood beta-glucan for Pneumocystis jirovecii pneumonia in patients with AIDS and respiratory symptoms. AIDS. 2013 Mar 27;27(6):967-972. doi: 10.1097/QAD.0b013e32835cb646 [PubMed]
- 30561560 Morjaria S, Frame J, Franco-Garcia A, Geyer A, Kamboj M, Babady NE. Clinical Performance of (1,3) Beta-D Glucan for the Diagnosis of Pneumocystis Pneumonia (PCP) in Cancer Patients Tested With PCP Polymerase Chain Reaction. Clin Infect Dis. 2019 Sep 27;69(8):1303-1309. doi: 10.1093/cid/ciy1072 [PubMed]
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- 32185915 Tasaka S. Recent Advances in the Diagnosis and Management of Pneumocystis Pneumonia. Tuberc Respir Dis (Seoul). 2020 Apr;83(2):132-140. doi: 10.4046/trd.2020.0015 [PubMed]
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.