Pneumocystis pneumonia

Pneumocystis jirovecii pneumonia (PCP), previously known as Pneumocystis carinii pneumonia, is an opportunistic fungal lung infection occurring almost exclusively in immunocompromised individuals. It is an HIV-associated condition but may be caused by other immunodeficiencies, including primary immunodeficiency disorders, immunodeficiency resulting from malignancy, following a solid organ or stem cell transplant, or secondary to the long-term use of immunosuppressants such as high-dose steroids. PCP should be suspected in immunocompromised patients with a history of progressive dyspnea, dry cough, or hypoxia. Other findings that further support the diagnosis include an increase in β-D-Glucan and LDH levels, and diffuse bilateral infiltrates on chest imaging. PCP is confirmed if P. jirovecii is detected on an induced sputum sample, bronchoalveolar lavage, or lung tissue biopsy. Management of PCP includes high-dose trimethoprim/sulfamethoxazole (TMP/SMX), treatment of the underlying immunodeficiency disorder, and, in some cases, adjunctive glucocorticoids. Prophylaxis regimens for PCP should be considered for patients with significant immunosuppression and commonly include the use of long-term, low-dose TMP/SMX.

• Interstitial pneumonia caused by the yeast-like fungal organism Pneumocystis jirovecii ^[1]

• Pathogen: P. jirovecii (former P. carinii): ubiquitous, yeast-like fungus previously classified as a protozoan
• Route of transmission: airborne ^[2]
• Risk factors
  • HIV infection ; ^[3]
    • CD4 count: usually < 200/μL
    • Poor compliance with PCP prophylaxis or cART
    • History of PCP infection
  • Primary immunodeficiency disorders ^[4]
    • Severe combined immunodeficiency disorder
    • Hyper IgM syndrome
  • Immunosuppressive treatment (e.g., chronic glucocorticoid therapy)
  • Malignancy (e.g., leukemia, non-Hodgkin lymphoma)
  • Malnutrition

Symptoms of PCP ^[5][6]

• May be asymptomatic initially
• Symptoms can have a gradual onset (days to weeks) and include:
  • Low-grade fever and malaise
  • Dyspnea, tachypnea, and nonproductive cough
  • Fatigue, weight loss, chills
• May progress to fulminant respiratory failure

The clinical course of PCP is usually more acute and severe in HIV-negative patients compared to HIV-positive patients. HIV-positive patients often initially have an indolent course with mild exertional symptoms and no fever or cough. ^[5][6][7]

Clinical examination ^[5][6]

• Chest auscultation
  • Bilateral crackles and rhonchi
  • Unremarkable auscultatory findings are possible in the early stages of disease.
• Pulse oximetry: ↓ oxygen saturation (e.g., < 90% at rest and worsens with exertion)

PCP is often misdiagnosed as atypical pneumonia or bronchitis because of the persistent cough and similar auscultatory findings.

Consider PCP in patients with respiratory symptoms or unexplained hypoxia and a history of HIV or other causes of impaired humoral immunity (e.g., organ transplantation, immunosuppressive medications, malignancy). See also “Diagnosis of pneumonia.”

Approach ^[6][8]

• Order an initial pneumonia workup, including:
  • Routine laboratory studies: CBC, BMP, LFTs
  • Imaging studies: chest x-ray; if findings are inconclusive, consider CT chest.
  • ABG: used to determine the severity of disease and to guide therapy
• Confirm the presence of PCP.
  • Consider initial testing for nonspecific PCP markers to further support the diagnosis, i.e., β‑D‑Glucan, LDH.
  • Obtain a sample (e.g., induced sputum) to test for P. jirovecii.
• Identify the underlying cause of immunosuppression (if unknown). ^[8]
  • Perform HIV testing and order a CD4 count if HIV positive.
  • Review the patient's medications for immunosuppressants (e.g., corticosteroids, cyclophosphamide, TNF-α inhibitors).
  • Consider specialist consultation (e.g., allergy and immunology) if no other cause of immunosuppression can be determined.

Clinical presentation, laboratory studies, and imaging studies are not pathognomonic for PCP. Maintain a broad differential diagnosis and seek a definitive diagnosis of PCP when possible.

Because P. jirovecii cannot be routinely cultured, it requires confirmation via histopathological, cytopathological, or molecular identification of P. jirovecii from respiratory secretions or lung tissue.

Initial studies

Laboratory studies ^[6]

• Nonspecific markers for PCP
  • ↑ β-D-Glucan ^[9]
  • ↑ LDH ^[10]
• Arterial blood gas: ↓ PaO₂ and ↑ A-a gradient
• ↓ CD4 count (in HIV-positive patients): typically < 200 cells/mm³

Imaging studies ^[6]

• X-ray chest
  • Order initially for all patients.
  • Findings
    • Diffuse, bilateral, symmetrical, interstitial infiltrates extending from the perihilar region (butterfly pattern)
    • May be normal in the early stages of PCP
• CT chest without contrast (HRCT may increase diagnostic accuracy)
  • Indicated if PCP is still suspected in a patient with a normal chest x-ray
  • Findings
    • Ground-glass attenuation: symmetrical, diffuse, interstitial infiltrates
    • Pneumatoceles: cystic air-filled spaces within the lung tissue
  • A normal CT effectively rules out the diagnosis.

Patients with PCP rarely present with lung cavitations or pleural effusions on chest x-ray. If these findings are present, consider alternative diagnoses or additional pathology. ^[6]

Diagnostic confirmation ^[6]

• Histopathology (preferred confirmatory test): identification of P. jirovecii
  • Specimen
    • First-line: induced sputum
    • Second-line: bronchoalveolar lavage or lung tissue biopsy
  • Method: Staining enables visualization of disc-shaped P. jirovecii cysts with central spores.
    • Giemsa, Wright, and Diff-Quik stain the cystic and trophic forms but not the cyst wall.
    • Methenamine silver, cresyl violet, and toluidine blue stain the cyst wall.
    • Immunofluorescence
• Molecular testing: alternative to histopathology or cytopathology for PCP diagnosis
  • Specimen: sputum, blood, or nasopharyngeal aspirates
  • Types
    • Polymerase chain reaction (PCR)
    • Quantitative PCR

Spontaneously expectorated sputum should not be used for diagnostic studies because it has poor sensitivity for PCP. Use induced sputum instead. ^[6]

PCP treatment ^{[5][6][7][11]}

• General considerations
  • If clinical suspicion is high, treatment can be initiated before a definitive diagnosis is established.
  • Treatment recommendations vary depending on the patient's HIV status and PCP disease severity.
• Disease severity
  • Mild to moderate PCP: PaO2 ≥ 70 mm Hg and A-a gradient < 35 mm Hg on room air
  • Moderate to severe PCP: PaO₂ < 70 mm Hg or A-a gradient ≥ 35 mm Hg on room air
• Antibiotic therapy
  • High-dose TMP/SMX is the treatment of choice.
  • A 21-day antibiotic course is recommended for most patients, regardless of the antibiotic regimen. ^[7]
  • For patients with treatment failure :
    • Consider changing to an alternative antibiotic regimen under the guidance of an infectious disease specialist.
    • Exclude concomitant infections.

• Adjunctive therapy
  • HIV-positive patients
    • Moderate to severe PCP: Start glucocorticoids (e.g., prednisone; ) as soon as possible and within 72 hours of starting antibiotics. ^[6]
    • Initiate cART in consultation with an infectious diseases specialist within 2 weeks of PCP diagnosis. ^[6]
  • HIV-negative patients: decision on a case-by-case basis in consultation with a specialist ^[12]
• Supportive care (see also “Supportive therapy” in “Pneumonia”)
  • Start oxygen therapy for hypoxemia.
  • Consider indications for invasive mechanical ventilation.
  • Start immediate hemodynamic support for patients with hypotension and/or shock.

TMP/SMX can still be an effective treatment for patients who develop PCP despite TMP/SMX prophylaxis.

The benefit of adjunctive glucocorticoid therapy for PCP in HIV-negative patients is unclear. ^[12]

PCP prophylaxis ^{[5][6][13][14]}

• Goal: to reduce the probability of opportunistic infections from PCP in at-risk populations (specialist consultation is advised)
• Primary prophylaxis; indicated for patients with no history of PCP with either:
  • HIV infection with a CD4 cell count < 200 cells/mm³
  • Immunosuppression from other causes, e.g:
    • High-dose glucocorticoid treatment (e.g., ≥ 20–30 mg/day of prednisone) lasting for ≥ 4 weeks
    • Cytotoxic and/or biologic therapies
    • Primary immunodeficiencies or hematological malignancies (e.g., acute lymphocytic leukemia)
    • Following solid organ , or stem cell transplant
• Secondary prophylaxis: indicated for patients with a history of PCP with immunosuppression in order to prevent recurrence
• Prophylactic regimens: See also “Prevention of opportunistic infections in HIV” for dosages. ^[6]
  • Low‑dose TMP/SMX
  • Alternative (e.g., if allergic to TMP/SMX) ^[15][16];
    • Dapsone
    • OR atovaquone

• ARDS
• Bullous formation with risk of rupture → secondary pneumothorax
• Pleural effusion

We list the most important complications. The selection is not exhaustive.

• PCP was formerly the most common cause of death in HIV‑positive patients during the early years of the HIV epidemic. ^[2]
  • The introduction of HAART (highly active antiretroviral therapy) and TMP/SMX prophylaxis in patients with a CD4 count < 200/μL has significantly improved the long-term outcome of the disease.
  • Despite adequate prophylaxis, PCP infection may lead to death in patients presenting with severe symptoms (e.g., respiratory failure).