CONTENTS

• Background: HIV(-)PJP vs. HIV(+)PJP
• Epidemiology
• Clinical presentation
• Radiology
  • Chest radiograph
  • Chest CT scan
• Blood tests
  • Serum beta-D-glucan ➡️
  • Other labs (LDH, CRP, PCT)
• Microbiology tests
  • Bronchoscopy
  • Non-bronchoscopic sampling
• Approach to diagnosis
  • Early invasive approach
  • Early noninvasive approach
• Treatment
  • Antibiotics
  • Steroid
• Prognosis
• Podcast
• Questions & discussion
• Pitfalls

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HIV-negative vs HIV-positive PJP

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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 more indolently, with a higher burden of organisms. This makes HIV(+)PJP somewhat easier to diagnose and 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.

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epidemiology

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Subacute/chronically reduced lymphocyte count before admission is a crude guide to immunity against PJP. An absolute lymphocyte count <800 had 80% sensitivity for PJP in one study of patients with rheumatologic diseases. (28223177) Clinical pneumocystis pneumonia often coincides with a reduction of immunosuppression and rising lymphocyte counts (immune reconstitution). (15141339)

[1] steroid (most common cause)

• For patients who are otherwise immunocompetent, the risk of PJP increases after a minimum exposure of roughly ≧20 mg/day prednisone for ≧1 month. (38948111) However, lower doses of steroids may be associated with PJP in the context of additional risk factors that lead to more net immunosuppression.   
• Patients are at higher risk if:
  • They are being treated for glioblastoma.
  • They are being treated for rheumatologic diseases that may independently affect the immune system (e.g., lupus, granulomatosis with polyangiitis).
  • The steroid is combined with other immunosuppressives (see the section below 👇).
• PJP typically manifests when patients are tapering off steroids (due to immune reconstitution).

[2] non-steroid immunosuppressives, including:

• 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). (32185915)
• Anti-CD20 monoclonal antibodies (rituximab, obinutuzumab, ofatumumab) (38948111)
• Combined T and B-cell depleting anti-CD52 alemtuzumab.
• Kinase inhibitors:
  • Bruton's tyrosine kinase inhibitors (including ibrutinib and acalabrutinib).
  • Phosphoinositide 3-kinase inhibitors (including idealisib, duvelisib, copanlisib). (38948111)

[3] malignancy

• Hematologic malignancy (especially acute leukemia, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia)
• Chemotherapy (especially fludarabine, cladribine, cytarabine, gemcitabine, and temozolomide).
• Immune checkpoint inhibitors: These don't directly cause PJP, but they often cause inflammation, which requires prolonged therapy with steroids.

[4] organ transplantation

• Stem cell transplantation:
  • PJP is rare (0.6% of alloSCT; 0.3% of autoSCT). (26726945)
  • There is a higher risk in the late recovery phase (>100 days after engraftment). (37086781)
• Solid organ transplantation:
  • PJP typically occurs 4-6 months post-transplantation and during periods of augmented immunosuppression for management of graft rejection. (36354934)
  • PJP is mostly seen in lung and kidney recipients. (37086781)
  • Treatment of rejection with steroid or lymphocyte depletion also increases risk. (Fishman 2023)
  • PJP risk is 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. 📖

[5] HIV

• 🔑 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.
• 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.
  • PJP pneumonia can be the presenting finding of AIDS.
• 90% of patients have a CD4 count <200/uL. (22623570) 
• PJP can occur as a component of immune reconstitution inflammatory syndrome (IRIS) following the initiation of antiretroviral therapy for HIV.

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clinical presentation

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HIV(+)PJP

• This typically evolves gradually over weeks or months (e.g., it 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 usually presents more acutely (typically about one week from symptom onset to respiratory failure). (32185915)
• Common features include fever, nonproductive cough, and hypoxemic respiratory failure.
• This often progresses to requiring mechanical ventilation.

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chest radiograph

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• Chest radiograph 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)

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chest CT scan

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ground glass opacities (rarely progressing to consolidation)

• Distribution:
  • It 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 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.
• Progression of GOO to consolidation:
  • Severe cases may progress to patchy, bilateral consolidation.
  • Consolidation is more common in HIV(-)PJP. (22623570)

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 often located in the upper lobe, in a subpleural location.
• Cysts may be single or multiple.
• Size may vary 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: 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 the context of hematologic malignancies). (22623570)

findings that suggest an alternative/superimposed diagnosis:

• Lymphadenopathy.
• Pleural effusion.
• Cavitation. (37086781)

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serum beta-D glucan

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• See the chapter on approaches to pulmonary infection here: 📖

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other labs

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inflammatory markers

• One study showing typical results is shown below. If procalcitonin is obtained for another reason, a procalcitonin >10 ug/L suggests an alternative or superimposed diagnosis (not solely PJP).

lactate dehydrogenase is unhelpful

• Lactate dehydrogenase (LDH) historically was used as a test to evaluate for HIV(+) PJP. However, more recent studies have found that it performs poorly for this. (21690628)
• Elevated lactate dehydrogenase is extremely nonspecific (especially in critical illness or malignancy).

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bronchoscopy

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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)

direct fluorescence antibody staining

• Performance is superior to conventional stains.
• These don't seem to be widely available.

PCR for PJP

• PCR has increased sensitivity compared to conventional stain (sensitivity approaches 100%, specificity varies depending on population).
• Specificity is limited by colonization.
  • Up to 20% of healthy adults may be colonized with Pneumocystis jirovecii. Colonization may be even more common among patients with HIV. (18024536)
  • A beta-D-glucan assay may help determine whether a positive PCR reflects colonization or invasive infection. (30561560)
• Quantitative PCR with a lower cycle count (Ct <32) supports true infection. (38948111, 27008872)

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).

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non-bronchoscopic sampling

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induced sputum

• Induced sputum PCR:
  • A meta-analysis found that induced sputum PCR has 99% sensitivity and 82% specificity (compared with bronchoalveolar lavage, which has 99% sensitivity and 89% specificity). (38860786)
  • Performance could be lower outside clinical trials, but this sensitivity appears adequate to exclude PJP.
  • The specificity of induced sputum is lower than bronchoalveolar lavage since it is more likely to be contaminated by upper airway colonization. Roughly 20% of normal people may have transient colonization by pneumocystis at any given time. (37086781)
• Induced sputum cytology has a lower sensitivity (~50%) but a higher specificity (~100%). (34464734) Most studies on cytology involved HIV(+)PJP, so performance is likely worse in HIV(-)PJP.  
• Expectorated sputum is generally considered inadequate for testing. (Fishman 2023) The high concentration of mucins in non-induced sputum may reduce PCR efficiency. (38948111)

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, which was a bit of a tracheal wash.

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approach to diagnosis

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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).

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early-noninvasive approach

[1] appropriate candidate for noninvasive strategy:

• The differential is reasonably narrow so that empiric coverage is possible without a highly toxic antibiotic regimen.
  • This judgment involves a careful review of the CT scan. A noninvasive strategy may be most appropriate when the CT scan shows diffuse ground-glass opacification since this has a limited differential diagnosis. 📖
• Performing bronchoscopy would involve a high risk of deterioration (e.g., intubation).
• The patient prefers a less invasive diagnostic/therapeutic approach (consider shared decision-making if possible). (23698062)

[2] initial approach

• Noninvasive diagnostic evaluation:
  • Induced sputum for PJP PCR.
  • Nasopharyngeal PCR for COVID-19, influenza, and expanded respiratory virus panel.
  • Blood studies:
    • Blood cultures.
    • CRP (C-reactive protein).
    • Procalcitonin.
    • 1-3 beta-D glucan.
  • Urine pneumococcus and legionella antigens.
  • Other relevant noninvasive diagnostic studies: 📖
• Empiric coverage of likely pathogens:
  • If PJP is likely, treat empirically with prednisone 60 mg daily plus an intermediate dose of trimethoprim-sulfamethoxazole (10 mg/kg in divided doses 💉). Note that trimethoprim-sulfamethoxazole provides coverage for a range of typical bacterial pathogens, so it may also cover typical bacterial pneumonia. A useful empiric regimen is often prednisone, trimethoprim-sulfamethoxazole, and doxycycline (the doxycycline provides atypical coverage).
  • If PJP is unlikely, withhold therapy for PJP. Consider treating for other potential pathogens as clinically appropriate.

[3] re-evaluate therapy as data emerges

• As data emerges, treatment should be adjusted accordingly.
• If there is persistent confusion about whether the patient has PJP, bronchoscopy may be performed later (e.g., after a few days). However, in practice, the above data will generally be sufficient to reach a diagnosis.
• Notably, delaying bronchoscopy for a few days should still allow for a good yield for PJP (dead organisms or PCR positivity should remain, even after viable organisms are gone). In some cases, delaying bronchoscopy for a few days allows the patient to improve and thus undergo the procedure with improved safety.

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antibiotics

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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 TMP-SMX allergies 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 ~7 days (otherwise, consider the transition to 2nd-line therapy). Improvement often occurs sooner in HIV-negative patients (~5 days) than in HIV-positive patients (~7-10 days). (Fishman 2023)
• A 21-day course is standard.
• The addition of an echinocandin could be considered in patients who are deteriorating or not responding to therapy. (33277811, 29399131, 31886310, 35740126)  This might make more sense than switching to clindamycin-primaquine because it retains front-line therapy with trimethoprim-sulfamethoxazole.  

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 the 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.
• Consider consulting an infectious disease specialist for patients not responding to trimethoprim-sulfamethoxazole.

antiretroviral therapy (ART) for HIV(+)PJP

• There is a benefit to starting reasonably soon (e.g., within ~2 weeks).
• Infectious disease consultants may help clarify the optimal timing and regimen.

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steroid

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indication

• HIV(+)PJP
  • The classical indication is room air PaO2 <70 mm or A-a gradient >35 mm.
    • (MDCalc calculator for A-a gradient: 🧮)
  • 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 steroids is less clear.  However, a steroid is generally still used similarly to that in HIV(+)PJP.

regimen

• The 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 another steroid may be used as needed (e.g., methylprednisolone in a patient unable to take oral medications).

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prognosis

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• Prognosis of PJP in general:
  • HIV(+)PJP carries a ~15% mortality.
  • HIV(-)PJP carries a ~40% mortality.
• The prognosis is worse for patients in the ICU and who require mechanical ventilation (especially patients with advanced malignancy).

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• 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 before confirmation of the diagnosis).
• A rigid diagnostic approach to PJP insists on early bronchoscopy for all patients.

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