Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 6: Disease-Specific Treatment

Pneumocystis Pneumonia

Background

Pneumocystis jiroveci pneumonia (previously called Pneumocystis carinii pneumonia, and still abbreviated PCP), is caused by an unusual fungus, Pneumocystis 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. 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 far and away 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), but PCP is still many patients' initial presenting opportunistic infection and a significant cause of morbidity and mortality in HIV-infected patients.

S: Subjective

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

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

Ask 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.

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 (>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 clear or whitish mucus.

A: Assessment

A partial differential diagnosis includes the following:

• Pneumococcal pneumonia
• Other bacterial pneumonias
• Tuberculosis
• Mycobacterium avium complex
• Lymphocytic interstitial pneumonitis
• Bronchitis
• CMV pneumonitis
• Histoplasmosis
• Other fungal pneumonia, especially cryptococcus
• Pulmonary Kaposi sarcoma
• Asthma, chronic obstructive pulmonary disease
• Congestive heart failure
• Pulmonary hypertension

P: Plan

Diagnostic Evaluation

• CD4 count is usually <200 cells/µL (>90% of PCP cases occur in patients with CD4 counts <200 cells/µL).
• Arterial blood gas (ABG): hypoxemia is common, as is elevation in alveolar-arterial O₂ gradient (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.
• Elevated serum lactate dehydrogenase (LDH) (>300-500 IU is common. )
• 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.
• Chest x-ray typically shows bilateral interstitial infiltrates, but atypical patterns with cavitation, lobar infiltrates, nodules, or pneumothorax may occur, and chest x-ray may be normal in some cases. Upper lobe predominance is common if the patient is receiving aerosolized pentamidine for PCP prophylaxis.
• 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 requires an experienced technician, and may not be available at all centers. Sensitivity varies widely (10-95%) depending on the expertise of the center. If there is any chance that the patient has TB, sputum induction should be done in a confined space in a negative pressure area or near an exhaust fan vented safely outside.
• Bronchoscopy with bronchoalveolar lavage (BAL): If induced sputum is negative for PCP organisms, definitive diagnosis is made through detection of organisms in BAL fluid obtained during bronchoscopy. Sensitivity is >95% in experienced centers. BAL fluid can be evaluated for bacteria, mycobacteria, and fungi, as well as for P jiroveci.
• Transbronchial biopsy may be done if lung disease is progressive despite treatment, to look for diagnoses other than PCP. Open lung biopsy is rarely done.

Treatment

Presumptive treatment is often initiated based on clinical presentation, chest x-ray findings, and ABG results, while definitive diagnostic tests are pending. Table 1 shows the standard and alternative treatment regimens.

Standard Therapy

Trimethoprim-sulfamethoxazole

Trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra, cotrimoxazole) is the drug of choice: 15-20 mg/kg of theTMP component and 75-100 mg/kg of the SMX component, divided into 3 or 4 doses daily intravenously or orally for 21 days (a typical oral dose is 2 double-strength tablets 3 times daily). Adverse effects of TMP-SMX are common (eg, rash, fever, leukopenia, anemia, gastrointestinal intolerance), mostly mild, and can usually be "treated through." Patients who have had previous reactions to sulfa drugs also may be successfully desensitized (see chapter Sulfa Desensitization). TMP-SMX requires dose adjustment in cases of renal insufficiency.

Adjunctive corticosteroids

Adjunctive corticosteroids should be given if the room air PO₂ is <70 mm Hg 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 antipneumocystis therapy:

• Prednisone 40 mg twice daily days 1-5; 40 mg once daily on days 6-10; 20 mg once daily on days 11-21. Intravenous methylprednisolone can be given, as 75% of the prednisone dose.

Table 1. Standard and Alternative PCP Therapy

Drugs Dosages Notes Standard Therapy Trimethoprim + sulfamethoxazole (TMP-SMX) TMP: 15-20 mg/kg plus SMX: 75-100 mg/kg divided into 3 or 4 doses daily intravenously (IV) or orally for 21 days Patients who have had previous reactions to sulfa drugs may be successfully desensitized. Adjust dose in renal insufficiency. Alternative Therapies Pentamidine 4 mg/kg IV daily for 21 days Similar efficacy to TMP-SMX but greater toxicity (nephrotoxicity, pancreatitis, glucose dysregulation, cardiac arrhythmias). Usually reserved for patients with severe disease who require intravenous therapy. Dapsone + trimethoprim Dapsone* 100 mg orally daily plus trimethoprim 15 mg/kg orally daily for 21 days Appropriate for mild-to-moderate disease Clindamycin + primaquine Clindamycin 600-900 mg IV every 6-8 hours (or 300-450 mg orally every 6-8 hours) plus Primaquine* base 15-30 mg orally once daily for 21 days Appropriate for mild-to-moderate disease. Atovaquone 750 mg orally twice daily for 21 days For mild-to-moderate PCP only; not as potent as TMP-SMX Trimetrexate (+ leucovorin) Trimetrexate 45 mg/m2 (or 1.2 mg/kg) IV daily plus Leucovorin 25 mg orally every 6 hours for 21 days Not as potent as TMP-SMX. Leucovorin must be continued for 3 days beyond completion of trimetrexate

* Screen for G6PD deficiency (most common in patients of African or Mediterranean descent).

Other therapy notes

• Patients started on intravenous 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 due to presumed immune reconstitution inflammatory syndrome (see chapter) has been reported in patients who initiated ART close to the time of diagnosis and treatment for PCP. At present, there is no consensus on whether initiation of ART during an acute episode of PCP is preferable to delaying ART, and clinical trials are under way to explore this question.
• Many providers prefer to wait until completion of PCP therapy and clinical stabilization of the patient before initiating ART. Consultation with HIV experts is advisable when considering starting ART in the setting of PCP.

Treatment failures

The average time to clinical improvement in hospitalized patients is 4-8 days, so avoid premature change in therapy. In 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 at least 3 months.

Standard prophylactic therapy

TMP-SMX, 1 double-strength tablet orally daily, or 1 single-strength tablet orally daily

Alternative prophylactic therapy

• Dapsone* 100 mg orally once daily, or 50 mg orally twice daily
• Dapsone* 50 mg orally once daily + pyrimethamine 50 mg orally once per week + leucovorin 25 mg orally once per week
• Dapsone* 200 mg orally + pyrimethamine 75 mg + leucovorin 25 mg, all once per week
• Aerosolized pentamidine 300 mg once per month, 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 orally once daily
• TMP-SMX: 1 double-strength tablet orally 3 times per week (eg, Monday, Wednesday, Friday)

* Warning: Screen for G6PD deficiency before starting dapsone.

Primary Prophylaxis

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

Patient Education

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

References

• Bartlett JG, Gallant JE. 2005-2006 Medical Management of HIV Infection. Baltimore: Johns Hopkins University Division of Infectious Diseases; 2005. Available online at hopkins-aids.edu/mmhiv/order.html.
• Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association/Infectious Diseases Society of America. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. MMWR Recomm Rep. 2004 Dec 17; 53(RR15);1-112.
• Leoung, GS. Pneumocystosis and HIV. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF Center for HIV Information; April 2005. Accessed February 7, 2006.
• Masur H. Pneumocystosis. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy, 2nd ed. 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.