Pneumocystis Pneumonia

Background

Pneumocystis jiroveci pneumonia (previously called Pneumocystis carinii pneumonia, and still abbreviated PCP), is caused by an unusual fungus, P. jiroveci. Many humans appear to be infected in childhood, but clinical illness occurs only in people with advanced immunosuppression, either through new infection or reactivation of latent infection. More than 90% of PCP cases occur in patients with CD4 counts of <200 cells/µL. Cases of PCP in otherwise healthy young homosexual men were among the first recognized manifestations of AIDS, in 1981. The organism can affect many organ sites, but pneumonia is by far the most common form of disease. In the United States, the incidence of PCP has declined sharply since the use of prophylaxis and effective antiretroviral therapy (ART) became widespread, but PCP is still many patients' initial presenting opportunistic infection, and it is a significant cause of morbidity and mortality among HIV-infected patients.

S: Subjective

The patient reports fever, shortness of breath, particularly with exertion, nonproductive cough, night sweats, weight loss, or fatigue. Typically, the symptoms worsen over the course of days to weeks. Pleuritic pain and retrosternal pain or burning also may be present. There may be minimal symptoms early in the disease course of PCP.

Ask the patient about fever, fatigue, and weight loss, which may be present for weeks, with gradual worsening of shortness of breath. PCP may present less commonly with acute onset symptoms of fevers, chills, sweats, dyspnea, and cough.

Note: Given the possibility of HIV-associated tuberculosis (TB), patients with cough should be kept in respiratory isolation until TB is ruled out.

O: Objective

Perform a full physical examination, with particular attention to the following:

• Vital signs, including temperature, heart rate, blood pressure, respiratory rate, oxygen saturation at rest and after exertion (there is often a sharp drop in oxygen saturation with exertion)
• Appearance
• Lung examination

Patients may appear relatively well, or acutely ill. Tachypnea may be pronounced, and patients may exhibit such a high respiratory rate (e.g., >30 breaths per minute) that they are unable to speak without stopping frequently to breathe. Chest examination may be normal, or reveal only minimal rales, although coughing is common on deep inspiration. Cyanosis may be present around the mouth, in the nail beds, and on mucous membranes. Cough is either unproductive, or productive of a thin layer of clear or whitish mucus.

A: Assessment

A partial differential diagnosis includes the following:

• Pneumococcal pneumonia
• Other bacterial pneumonias
• TB
• Influenza
• Mycobacterium avium complex
• Lymphocytic interstitial pneumonitis
• Bronchitis
• Cytomegalovirus (CMV) pneumonitis
• Histoplasmosis
• Other fungal pneumonia, especially cryptococcosis
• Pulmonary Kaposi sarcoma
• Asthma, chronic obstructive pulmonary disease
• Congestive heart failure
• Pulmonary hypertension

P: Plan

Diagnostic Evaluation

• CD4 cell count: Check records for a recent CD4 count (CD4 is <200 cells/µL in >90% of PCP cases). Note that a CD4 count obtained in the setting of acute illness (e.g., when the patient presents with pneumonia) may be substantially lower than the usual baseline, and may be difficult to interpret.
• Pulse oximetry at rest and after exercise: Oxygen desaturation with exercise suggests an abnormal alveolar-arterial O₂ gradient (A-a gradient).
• Arterial blood gas (ABG): Hypoxemia is common, as is elevation in A-a gradient. Generally, PO₂ levels and A-a gradient are associated with disease severity. Poorer outcomes are seen with PO₂ <70 mm Hg and A-a gradient >35 mm Hg.
• Lactate dehydrogenase (LDH): Elevated serum LDH (>300-500 IU/L) is common.
• Chest X ray: Typically shows bilateral interstitial infiltrates, but atypical patterns with cavitation, lobar infiltrates, nodules, or pneumothorax may occur, and chest X-ray findings may be normal in some cases. Upper-lobe predominance is common if the patient is receiving aerosolized pentamidine for PCP prophylaxis.
• Thin-section chest computed tomography (CT) scan: May show ground-glass opacities; in a patient with clinical signs or symptoms of PCP, these are suggestive but not diagnostic of PCP.
• Sputum induction: The patient inhales saline mist to mobilize sputum from the lungs. The respiratory therapist collects expectorated sputum, which is stained with Giemsa and examined for P. jiroveci organisms. This technique is useful because of its noninvasive approach, but it requires an experienced technician, and therefore may not be available at all centers. Sensitivity varies widely (10-95%), depending on the expertise level of the staff at a particular center. (If there is any chance that the patient has TB, sputum induction should be performed in a confined space in a negative pressure area or near an exhaust fan vented safely outside, and samples should be sent for acid-fast bacilli [AFB] smear and culture.)
• Bronchoscopy with bronchoalveolar lavage (BAL): If induced sputum tests negative for PCP organisms, definitive diagnosis is made through detection of organisms in BAL fluid obtained during bronchoscopy. Sensitivity is >95% at centers with an experienced staff. BAL fluid can be evaluated for bacteria, mycobacteria, and fungi, as well as for P. jiroveci.
• Transbronchial biopsy may be performed if lung disease is progressive despite treatment, to look for diagnoses other than PCP. Open lung biopsy rarely is performed.

Treatment

Presumptive treatment often is initiated on the basis of clinical presentation, chest X-ray findings, and ABG results, while definitive diagnostic tests are pending. The standard and alternative treatment regimens are shown in Table 1.

Standard Therapy

Trimethoprim-sulfamethoxazole

Trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra, cotrimoxazole) is the drug of choice: 15-20 mg/kg of the TMP component plus 75-100 mg/kg of the SMX component, divided into three or four doses daily and administered IV or PO for 21 days (a typical PO dose is two double-strength tablets TID). Adverse effects of TMP-SMX (e.g., rash, fever, leukopenia, anemia, gastrointestinal intolerance, hepatotoxicity, hyperkalemia) are common, mostly mild, and usually "treated through" successfully. Patients who have had previous reactions to sulfa drugs also may be desensitized successfully (see chapter Sulfa Desensitization). TMP-SMX requires dosage adjustment for patients with renal insufficiency.

Adjunctive corticosteroids

Adjunctive corticosteroids should be given if the patient's PO₂ is <70 mm Hg (breathing room air) or the A-a gradient is >35 mm Hg. Corticosteroids should be given as early as possible (preferably before or with the first dose of antibiotic therapy) and within 36-72 hours of the start of anti-PCP therapy:

• Prednisone 40 mg BID days 1-5; 40 mg once daily on days 6-10; 20 mg once daily on days 11-21. IV methylprednisolone can be given, at 75% of the prednisone dosage.

Other therapy notes

• Patients started on IV therapy can be switched to an oral treatment regimen to complete the 3-week course when they are afebrile, have improved oxygenation, and are able to take oral medications.
• Paradoxical worsening of PCP resulting from presumed immune reconstitution inflammatory syndrome (see chapter Immune Reconstitution Inflammatory Syndrome) has been reported in some patients who initiated ART close to the time of diagnosis and treatment for PCP. However, recent data suggest that unless other compelling contraindications are present, early initiation of ART (near the time of initiating OI treatment) should be considered for most patients with most acute OIs, including PCP.
• Consultation with HIV experts is advisable when considering initiation of ART in the setting of PCP.

Treatment failures

The average time to clinical improvement for hospitalized patients is 4-8 days, so premature change in therapy should be avoided. For patients who fail to improve on appropriate therapy, it is important to exclude other diagnoses, rule out fluid overload, and consult an infectious disease specialist. Some patients do not respond to any therapy, and the mortality rate of hospitalized patients is about 15%.

Secondary Prophylaxis

Anti-PCP prophylaxis (chronic maintenance therapy) should be given to all patients who have had an episode of PCP. Prophylaxis should be continued for life, unless immune reconstitution occurs as a result of ART and the CD4 count has been >200 cells/µL for more than 3 months.

In patients with stable CD4 count of >200 cells/µL on effective ART, it is recommended that PCP prophylaxis be discontinued because it offers little clinical benefit but may cause drug toxicity, drug interactions, and selection of drug-resistant pathogens, plus it adds to the cost of care and to the patient's pill burden.

If PCP occurred at a CD4 count of >200 cells/µL, it is recommended to continue prophylaxis for life despite immune reconstitution; however, data to support this approach are limited.

Prophylactic therapy

Preferred:

• TMP-SMX, one double-strength tablet PO once daily, or one single-strength tablet PO once daily

Alternative:

• TMP-SMX: one double-strength tablet PO TIW (e.g., Monday, Wednesday, Friday)
• Dapsone* 100 mg PO once daily, or 50 mg PO BID
• Dapsone* 50 mg PO once daily + pyrimethamine 50 mg PO once weekly + leucovorin 25 mg PO once weekly
• Dapsone* 200 mg PO + pyrimethamine 75 mg + leucovorin 25 mg, all once weekly
• Aerosolized pentamidine 300 mg once monthly, via Respirgard II nebulizer (note: does not prevent toxoplasmosis). Warning: May increase the risk of extrapulmonary pneumocystosis, pneumothorax, and bronchospasm.
• Atovaquone suspension 1,500 mg PO once daily (with or without pyrimethamine 25 mg PO once daily + leucovorin 10 mg PO once daily)

* Use with caution in G6PD deficiency.

Primary Prophylaxis

Primary prophylaxis against PCP should be given to all HIV-infected patients with CD4 counts of <200 cells/µL or CD4 percentages of <14%, or a history of oral candidiasis; see chapter Opportunistic Infection Prophylaxis.

Patient Education

• Patients should be instructed to take all medications exactly as prescribed.
• Patients should call their health care providers if symptoms worsen.
• Patients being treated with TMP-SMX or dapsone who develop rash, fever, or other new symptoms should call their providers to be evaluated for a drug reaction.
• Patients should understand that taking anti-PCP prophylaxis is extremely important for preventing repeat episodes of illness. Patients should not stop taking these medicines without talking with their health care providers, and should not let their supply of medications run out.

References

• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Leoung GS. Pneumocystosis and HIV. In: Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF Center for HIV Information; April 2005.
• Masur H. Pneumocystosis. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy, 2nd Edition. Philadelphia: Churchill Livingstone; 2003:403-418.
• Stringer J, Beard CB, Miller RF, et al. A new name (Pneumocystis jiroveci) for Pneumocystis from humans. Emerg Infect Dis. 2002 Sep;8(9):891-6.
• Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575.