Pneumocystis jirovecii pneumonia (PJP)

A 33-year-old man with a known history of HIV infection presents to the emergency department with a 7-day history of progressive shortness of breath, dry cough, and fever. His CD4 count is 90 cells/µL despite antiretroviral therapy. On examination, blood pressure is 110/70 mm Hg, pulse rate is 108 beats/min, respiratory rate is 22 breaths/min, oxygen saturation is 88% on room air, and temperature is 100.9 °F. Lung auscultation reveals bilateral crackles, although the pulmonary examination may be relatively unremarkable in some patients. There is no peripheral edema or lymphadenopathy. Laboratory evaluation shows a normal total leukocyte count with lymphopenia. Chest radiography demonstrates diffuse bilateral perihilar interstitial infiltrates, and CT of the chest shows bilateral ground-glass opacities. Arterial blood gas analysis demonstrates respiratory alkalosis with significant hypoxemia, with a PaO₂ of 50 mm Hg and an increased alveolar-arterial oxygen gradient. Bronchoalveolar lavage with Grocott-Gomori methenamine silver staining demonstrates characteristic Pneumocystis cyst forms. Diagnosis?

Diagnosis is Pneumocystis jirovecii pneumonia in a patient with advanced HIV-associated immunosuppression.

1. Definition

Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening opportunistic fungal pneumonia caused by Pneumocystis jirovecii.

It occurs predominantly in individuals with impaired cell-mediated immunity and is particularly associated with advanced HIV infection and low CD4 T-lymphocyte counts.

In people with HIV, the great majority of cases occur when the CD4 count is below 200 cells/µL, with particularly high risk at counts below 100 cells/µL.

The term PCP is also widely used for Pneumocystis pneumonia and remains the abbreviation preferred by some major HIV guidelines.

2. Etiology and Risk Factors

2.1 HIV-Associated Risk

The major risk factor in people with HIV is advanced cellular immunodeficiency.

Important risk factors include:

1.      CD4 count below 200 cells/µL

2.      Particularly high risk when the CD4 count is below 100 cells/µL

3.      Detectable or uncontrolled HIV viral replication

4.      Lack of effective antiretroviral therapy

5.      Failure to receive indicated Pneumocystis prophylaxis

6.      Previous episode of PJP

This patient has a CD4 count of 90 cells/µL, placing him at substantial risk despite being prescribed antiretroviral therapy.

A persistently low CD4 count despite ART should prompt assessment of ART adherence, HIV viral load, drug interactions, treatment history, and possible virologic failure or resistance.

2.2 Non-HIV Risk Factors

PJP also occurs in other immunocompromised populations, including patients with:

1.      Prolonged systemic glucocorticoid exposure

2.      Hematologic malignancies

3.      Solid-organ transplantation

4.      Hematopoietic stem-cell transplantation

5.      Immunosuppressive or cytotoxic therapy

6.      Certain biologic and targeted immunomodulatory therapies

7.      Primary or acquired disorders of cellular immunity

3. Pathophysiology

1.      Pneumocystis jirovecii is a fungus with a particular tropism for the alveolar spaces.

2.      The organism interacts closely with the alveolar epithelium.

3.      In susceptible hosts, proliferation of the organism produces a characteristic proteinaceous and foamy intra-alveolar exudate.

4.      Host inflammatory responses contribute to injury of the alveolar-capillary interface.

5.      The resulting impairment in oxygen diffusion and ventilation-perfusion matching causes hypoxemia.

6.      The alveolar-arterial oxygen gradient becomes elevated as gas exchange deteriorates.

7.      Tachypnea and hypoxemia commonly produce respiratory alkalosis early in the disease.

8.      Severe disease may progress to diffuse alveolar injury, acute respiratory failure, and the need for mechanical ventilation.

4. Clinical Features

4.1 Typical Presentation in HIV

PJP in people with HIV typically has a subacute presentation developing over several days to weeks.

The characteristic clinical features include:

1.      Progressive dyspnea

2.      Nonproductive or dry cough

3.      Fever

4.      Chest discomfort in some patients

5.      Tachypnea

6.      Tachycardia

7.      Exertional or resting hypoxemia

The onset in people with HIV is often more indolent than PJP occurring in non-HIV immunocompromised patients.

4.2 Pulmonary Examination

Pulmonary examination may demonstrate:

1.      Bilateral inspiratory crackles

2.      Tachypnea

3.      Increased respiratory effort in advanced disease

However, particularly in mild or early disease, the lung examination may be relatively normal despite significant pulmonary pathology.

4.3 Gas Exchange Abnormalities

Hypoxemia is one of the most important physiological abnormalities in PJP.

Patients may demonstrate:

1.      Reduced PaO₂

2.      Increased alveolar-arterial oxygen gradient

3.      Exercise-induced oxygen desaturation

4.      Respiratory alkalosis due to tachypnea

In this patient, a PaO₂ of 50 mm Hg on room air indicates clinically significant disease and meets the criterion for adjunctive corticosteroid therapy.

5. Diagnostic Evaluation

5.1 Clinical Diagnosis

PJP should be strongly considered in a patient with advanced HIV infection who develops:

1.      Subacute progressive dyspnea

2.      Dry cough

3.      Fever

4.      Hypoxemia

5.      Bilateral ground-glass or interstitial pulmonary abnormalities

However, clinical and radiographic findings are not sufficiently specific to establish a definitive microbiological diagnosis.

5.2 Chest Radiography

The classic chest radiographic finding is:

Diffuse bilateral, symmetric interstitial or ground-glass infiltrates, frequently with a perihilar distribution

Important considerations include:

1.      Chest radiography may be normal in early or mild disease.

2.      Atypical findings such as cysts, nodules, asymmetric infiltrates, or upper-lobe-predominant disease may occur.

3.      Pleural effusion and prominent lymphadenopathy are unusual and should raise consideration of another or additional diagnosis.

5.3 Chest CT

Thin-section CT commonly demonstrates:

1.      Bilateral ground-glass opacities

2.      Patchy or diffuse pulmonary involvement

3.      Occasionally cystic or other atypical abnormalities

CT is highly useful when the chest radiograph is normal or equivocal.

A normal high-quality chest CT makes active PJP substantially less likely, although CT findings are not independently diagnostic.

5.4 Laboratory Findings

Laboratory abnormalities may include:

1.      Hypoxemia

2.      Increased alveolar-arterial oxygen gradient

3.      Elevated serum lactate dehydrogenase (LDH)

4.      Elevated serum 1,3-beta-D-glucan

Important limitations include:

1.      LDH elevation is nonspecific and cannot establish the diagnosis.

2.      Beta-D-glucan is often elevated and has useful sensitivity, but its specificity for PJP is limited because other fungal infections and some noninfectious conditions may also increase the level.

3.      A low beta-D-glucan concentration can make PJP less likely in the appropriate clinical setting.

5.5 Microbiological Diagnosis

Because P. jirovecii cannot be routinely cultured in standard clinical microbiology laboratories, diagnosis relies on demonstration or molecular detection of the organism in respiratory specimens.

Appropriate specimens include:

1.      Induced sputum

2.      Bronchoalveolar lavage fluid

3.      Lung tissue in selected difficult cases

Spontaneously expectorated sputum has poor diagnostic sensitivity and should not be relied upon.

5.6 Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) has a high diagnostic yield and is particularly useful when induced sputum is negative, unavailable, or inappropriate.

Diagnostic methods include:

1.      Grocott-Gomori methenamine silver staining

2.      Direct or indirect immunofluorescence

3.      Polymerase chain reaction

4.      Other specialized cytological stains

In this patient, demonstration of characteristic cyst forms on BAL confirms the diagnosis in the appropriate clinical setting.

5.7 Silver Staining

Grocott-Gomori methenamine silver staining highlights the cyst walls of P. jirovecii.

The cystic forms may appear:

1.      Round or ovoid

2.      Cup-shaped

3.      Crescentic

4.      Collapsed or irregular, sometimes described as resembling crushed ping-pong balls

Silver stains predominantly visualize the cystic forms rather than trophic forms.

5.8 PCR

PCR assays are highly sensitive for detecting P. jirovecii DNA and are increasingly used in clinical practice.

Important considerations include:

1.      PCR has excellent analytical sensitivity.

2.      A positive result does not always distinguish active pneumonia from respiratory colonization.

3.      Quantitative PCR may improve interpretation because higher organism burdens are more consistent with active disease.

4.      PCR results should therefore be interpreted together with the clinical presentation, imaging, oxygenation, and other laboratory findings.

6. Disease Severity

Severity in HIV-associated PJP is commonly assessed using room-air oxygenation.

6.1 Mild Disease

Generally associated with:

PaO₂ of 70 mm Hg or greater and an A-a gradient below 35 mm Hg

6.2 Moderate-to-Severe Disease

Adjunctive corticosteroid therapy is indicated when either of the following is present on room air:

1.      PaO₂ below 70 mm Hg

2.      A-a oxygen gradient of 35 mm Hg or greater

This patient has a PaO₂ of 50 mm Hg, clearly meeting criteria for moderate-to-severe PJP and adjunctive corticosteroid treatment.

7. Management

7.1 First-Line Antimicrobial Therapy

Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred treatment.

For moderate-to-severe PJP, the recommended regimen is:

TMP 15 to 20 mg/kg/day plus SMX 75 to 100 mg/kg/day intravenously, divided every 6 to 8 hours

Once the patient demonstrates adequate clinical improvement, therapy may be changed from intravenous to oral treatment when appropriate.

The recommended total duration of treatment in people with HIV is:

21 days

7.2 Mild-to-Moderate Disease

For mild-to-moderate PJP, oral TMP-SMX is appropriate when gastrointestinal absorption is reliable.

Recommended options include:

1.      TMP 15 to 20 mg/kg/day plus SMX 75 to 100 mg/kg/day divided into three oral doses

2.      Two double-strength TMP-SMX tablets three times daily

7.3 Adjunctive Corticosteroids

Adjunctive corticosteroids are indicated for HIV-associated PJP when:

1.      PaO₂ is below 70 mm Hg on room air, or

2.      A-a gradient is 35 mm Hg or greater

Corticosteroids should be initiated as soon as possible and ideally within 72 hours of starting PJP therapy.

A standard prednisone regimen is:

1.      Days 1 to 5: 40 mg orally twice daily

2.      Days 6 to 10: 40 mg orally once daily

3.      Days 11 to 21: 20 mg orally once daily

If oral administration is not possible, intravenous methylprednisolone may be administered at approximately 80% of the equivalent prednisone dose.

This patient meets the criteria for adjunctive corticosteroids because his room-air PaO₂ is 50 mm Hg.

7.4 Alternative Antimicrobial Therapy

When TMP-SMX cannot be used because of significant intolerance, toxicity, or contraindication, alternatives depend on disease severity.

For moderate-to-severe disease, options include:

1.      Clindamycin plus primaquine

2.      Intravenous pentamidine

For mild-to-moderate disease, alternatives include:

1.      Atovaquone

2.      Dapsone plus trimethoprim

3.      Clindamycin plus primaquine

G6PD activity should be assessed before treatment with primaquine or dapsone because of the risk of hemolysis and methemoglobinemia in patients with G6PD deficiency.

8. Antiretroviral Therapy

8.1 Patients Not Yet Receiving ART

In patients with HIV who are not receiving ART, antiretroviral therapy should generally be initiated within 2 weeks of the diagnosis of PJP, when clinically feasible.

Early ART reduces the risk of further HIV progression and additional opportunistic infections.

8.2 Patients Already Receiving ART

This patient is already receiving ART.

Management should include:

1.      Continue effective ART when clinically feasible

2.      Measure HIV viral load

3.      Assess medication adherence

4.      Review potential drug interactions

5.      Evaluate tolerability

6.      Investigate possible virologic failure or antiretroviral resistance when indicated

A CD4 count of 90 cells/µL despite ART requires assessment of whether viral suppression has been achieved and whether the current ART regimen is effective.

PJP-associated immune reconstitution inflammatory syndrome may occur after ART initiation but is uncommon and is generally not a reason to delay indicated ART.

9. Prophylaxis

9.1 Primary Prophylaxis

TMP-SMX is the preferred agent for primary PJP prophylaxis.

For people with HIV who are not receiving ART or are beginning ART, primary prophylaxis is recommended when:

CD4 count is below 200 cells/µL

For people already receiving ART, current recommendations support prophylaxis when:

1.      CD4 count is below 100 cells/µL regardless of HIV viral load, or

2.      CD4 count is 100 to 200 cells/µL with sustained detectable HIV RNA

This patient, with a CD4 count of 90 cells/µL, meets criteria for prophylaxis regardless of viral load.

Preferred prophylactic regimens include:

1.      TMP-SMX one double-strength tablet orally daily, or

2.      TMP-SMX one single-strength tablet orally daily

TMP-SMX additionally provides protection against Toxoplasma gondii and some bacterial respiratory infections.

9.2 Secondary Prophylaxis

After successful treatment of PJP, secondary prophylaxis should begin immediately to prevent recurrence.

TMP-SMX remains the preferred agent.

Secondary prophylaxis can generally be discontinued after immune reconstitution when:

CD4 count has increased from below 200 cells/µL to at least 200 cells/µL for at least 3 months in response to ART

In selected patients with sustained virologic suppression and a CD4 count between 100 and 200 cells/µL, discontinuation may be considered after individualized assessment.

10. Complications

10.1 Respiratory Failure

Progressive alveolar injury may cause severe hypoxemic respiratory failure, potentially requiring invasive mechanical ventilation.

10.2 Pneumothorax

Pulmonary cyst formation may predispose to spontaneous pneumothorax.

Pneumothorax in an immunocompromised patient with compatible respiratory symptoms should increase suspicion for PJP.

10.3 Acute Deterioration After Treatment

Respiratory status may transiently worsen during the first several days of treatment because killing of organisms may intensify pulmonary inflammation.

This possibility should not automatically be interpreted as antimicrobial treatment failure.

10.4 Treatment Toxicity

High-dose TMP-SMX can cause:

1.      Rash

2.      Fever

3.      Leukopenia

4.      Thrombocytopenia

5.      Hyperkalemia

6.      Renal dysfunction

7.      Hepatic toxicity

Laboratory monitoring is therefore important during treatment.

10.5 Extrapulmonary Pneumocystosis

Extrapulmonary involvement is rare, particularly in the modern ART era.

11. Differential Diagnosis

Important alternative or concurrent diagnoses in a patient with advanced HIV and diffuse pulmonary infiltrates include:

1.      Bacterial pneumonia

2.      Pulmonary tuberculosis

3.      Viral pneumonia

4.      Cytomegalovirus pulmonary disease

5.      Histoplasmosis or other endemic fungal infection

6.      Cryptococcosis

7.      Pulmonary Kaposi sarcoma

8.      Pulmonary lymphoma

9.      Noninfectious pulmonary edema or inflammatory lung disease

Coinfection is possible, so identification of PJP does not automatically exclude another pulmonary process when clinical findings are atypical.

12. Key Clinical Insight

Subacute progressive dyspnea, dry cough, fever, hypoxemia, bilateral ground-glass pulmonary opacities, and a CD4 count below 200 cells/µL are highly characteristic of Pneumocystis jirovecii pneumonia in a patient with HIV.

In this patient, demonstration of characteristic Pneumocystis cyst forms in bronchoalveolar lavage fluid provides definitive microbiological support for the diagnosis.

His room-air PaO₂ of 50 mm Hg indicates moderate-to-severe disease, so treatment should include high-dose TMP-SMX for 21 days plus adjunctive corticosteroids started as soon as possible.

Because his CD4 count remains 90 cells/µL despite ART, his HIV viral load, adherence, drug interactions, and possible virologic failure should also be evaluated.

References

1.      National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America Panel on Opportunistic Infections in Adults and Adolescents With HIV, A Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. [Updated 2026 May 27]. In: ClinicalInfo.HIV.gov [Internet]. Rockville (MD): U.S. Department of Health and Human Services; 2002-.

2.      McDonald EG, Afshar A, Assiri B, et al. Pneumocystis jirovecii pneumonia in people living with HIV: a review. Clin Microbiol Rev. 2024;37(1):e0010122. doi:10.1128/cmr.00101-22.

3.      Jaramillo Cartagena A, Asowata OE, Ng D, Babady NE. An overview of the laboratory diagnosis of Pneumocystis jirovecii pneumonia. J Clin Microbiol. 2025;63(3):e0036124. doi:10.1128/jcm.00361-24.