TREATMENT OF PNEUMOCYSTIS CARINII PNEUMONIA IN AIDS
The CD4 lymphocyte plays a central role in protection against respiratory tract infections. Alveolar macrophages, natural killer cells, and B lymphocytes depend on adequate numbers and function of CD4 cells. As the CD4-cell count inevitably falls in patients with HIV infection, the ability of the lung defense mechanisms to protect against infection decreases. Pathogens such as Pneumocystis carinii and Mycobacterium tuberculosis, often residing in the host for years, overwhelm defense mechanisms as the CD4 count falls below a critical level. Although the pathogens against which an intact system of cell-mediated immunity is required are most problematic, humoral defenses are also impaired, and bacterial infections such as bacterial pneumonia are also more common and serious in AIDS patients.
Of all the respiratory infections seen in patients with AIDS, none is more common than Pneumocystis carinii pneumonia (PCP). Despite the decrease in frequency of this disease secondary to antibiotic prophylaxis, PCP remains an important cause of death in the United States. Patients are at risk for this infection once the CD4-cell count falls below 200/µL. The clinical symptoms are usually more insidious than would be seen with bacterial pneumonia. Low-grade fever with shortness of breath or exercise intolerance is frequent. Cough is present but usually nonproductive. The process is frequently associated with weight loss, fatigue, and a general decline in well-being during several weeks. Diffuse crackles may be heard on chest auscultation, but often the physical examination is not helpful. The disease is usually confined to the lungs, but in some cases, after pentamidine aerosol prophylaxis, disseminated infection can occur.
Chest roentgenography reveals a diffuse interstitial process, often affecting all portions of the lung field equally. However, variations in the characteristic picture are becoming more frequently reported. Chest roentgenographic patterns of consolidation, nodular lesions, pneumatoceles, and spontaneous pneumothoraces are all well described. Hilar adenopathy and pleural effusions are uncommon and should suggest another or a concomitant process. Initially, the chest roentgenographic findings may be normal with diffusely abnormal findings on gallium scan. Measurement of arterial blood gases is necessary to assess the need for supplementary oxygen but is not helpful in determining the specific cause of a pulmonary infection.
Survival of an acute episode is correlated with the extent of abnormalities on chest x-ray films and the alveolar-arterial oxygen gradient. Long-term survival is correlated with the degree of interstitial edema noted on transbronchial biopsy and a low alveolar-arterial oxygen gradient at the time of diagnosis. Persistence of cysts after 3 weeks of therapy also is a poor prognostic sign.
The recommended approach to the diagnosis of PCP is as follows: When clinical data and chest x-ray findings suggest PCP, induce sputum for examination of cysts and trophozoites. The patient’s mouth is cleaned to avoid extraneous debris. Sputum is induced by inhalation of 3% saline solution through an ultrasonic nebulizer. The specimen is processed by trained personnel. The specimen is digested, centrifuged, and stained with Giemsa stain, silver methenamine, or toluidine blue. Direct immunofluorescent assays are being used at some institutions. The sensitivity of sputum examination is somewhere between 50% and 90%. Sensitivity is lower in patients who have been receiving aerosolized pentamidine.
Because a negative test result does not rule out PCP, bronchoscopy is the next procedure of choice, both to increase sensitivity and to search for other potential respiratory pathogens. Both bronchoalveolar lavage (BAL) and transbronchial biopsy are sensitive to detect Pneumocystis carinii and most other respiratory pathogens in AIDS. Broaddus et al. found that both procedures had similar sensitivities of 86% to 87%. Transbronchial biopsy was somewhat more sensitive than BAL for the diagnosis of PCP (97% vs. 86%). Most centers are now using BAL alone and consider biopsy with repeated bronchoscopy when the diagnosis remains elusive after the first procedure. Open lung biopsy is now considered an infrequent last resort and must be approached in the light of overall benefits versus risk and impact on prognosis.
Many clinicians are treating PCP empirically, especially when mild, although generally this is not formally recommended. In one study, 43 of 45 patients would have been given a correct diagnosis of PCP by clinical criteria alone. However, three patients would have been given an incorrect diagnosis and treated inappropriately. Not all studies report the same success with empiric treatment. In another study, only 57% of AIDS patients treated for PCP actually had the infection.
Table 84-1 lists the potential regimens for the treatment of PCP. Treatment depends on the degree of illness, which is often categorized as mild, moderate, or severe (PaO2 µg/mL has been recommended to reduce toxicity, especially in the setting of renal insufficiency. Some toxicity can be expected with TMP-SMX regimens in more than half of all patients, although most adverse reactions are not life-threatening. Adverse reactions such as fever, rash, neutropenia, and thrombocytopenia usually develop after about 1 week. They are much more likely to occur in AIDS patients than in other immunosuppressed patients. Folic or folinic acid plays no role in preventing hematologic toxicity and is not recommended.
Table 84-1. Treatment regimens for Pneumocystis carinii pneumonia
Dapsone plus TMP may be as effective as TMP-SMX and at least as well tolerated. A randomized San Francisco General Hospital study found that either regimen was more than 90% effective for mild-to-moderate disease. Side effects include rash, neutropenia, nausea and vomiting, and hemolytic anemia, often in association with glucose-6-phosphate dehydrogenase deficiency.
Clindamycin plus primaquine has been used for mild-to-moderate disease, with 600 mg of clindamycin taken orally three times daily and 30 mg of primaquine taken orally each day. For severe disease, 900 mg of clindamycin is given intravenously every 8 hours, with the oral dose of primaquine remaining the same. In one randomized study from Canada, TMP-SMX was compared with clindamycin-primaquine. No differences in outcome, rate of relapse, survival, or adverse effects were noted. Hemolytic anemia in association with glucose-6-phosphate dehydrogenase deficiency is also a concern with primaquine.
Atovaquone is a hydroxynaphthoquinone that inhibits protozoal mitochondrial electron transport and pyrimidine biosynthesis. It is approved only for treatment of mild-to-moderate disease (PaO2 >60 mm Hg). The drug is generally well tolerated but is only half as effective (20% to 31% failure rate) as TMP-SMX. Adverse reactions include rash, fever, nausea and vomiting, and abnormal levels of liver enzymes. The drug is variably absorbed and should be avoided if a patient has diarrhea and other gastrointestinal problems. Serum levels of 15 µ/mL or greater correlate with a favorable response.
As noted, when a patient is acutely ill or hypoxic with PCP, TMP-SMX administered intravenously (TMP, 20 mg/kg per day; SMX, 100 mg/kg per day) is still the regimen of choice. If toxicity develops, IV pentamidine isethionate can be used (4 mg/kg per day over 1 to 2 hours) for 21 days. Dosage adjustment is required when the glomerular filtration rate is below 50 mL/min. IV pentamidine is about as effective as IV TMP-SMX for severe disease. Pancreatitis, azotemia, leukopenia, hyperglycemia, or hypoglycemia can all develop and make drug cessation necessary. Pentamidine-induced cardiac toxicity has been reported, including torsades de pointes and other forms of ventricular tachycardia. Delivery of the drug to the lung via aerosolization has been used in the treatment of mild disease but has been associated with a high rate of relapse and treatment failure.
Trimetrexate is a quinazoline analog of methotrexate that has been approved for moderate-to-severe disease in patients who have not responded to TMP-SMX. Leucovorin is given concomitantly to avoid the complications of myelosuppression. In a randomized study of patients with moderate-to-severe disease, TMP-SMX was more effective than trimetrexate-leucovorin. Mortality rates were twice as high with trimetrexate and relapses were more common. The drug is probably best reserved for those in whom both TMP-SMX and pentamidine are contraindicated or who have failed to respond to these preferred drugs.
A number of clinical trials have supported the use of corticosteroids in moderate-to-severe disease. Corticosteroids moderate the intense inflammatory reaction that can occur in response to protozoal killing early in the course of treatment. Based on the results of five randomized trials, a panel of experts from the National Institutes of Health recommended the adjunctive use of corticosteroids within 24 to 72 hours for patients above the age of 13 who had severe disease (defined as PaO2 35 mm Hg). Table 84-2 summarizes the recommendations for steroid use. In those with the most severe disease, corticosteroids will decrease mortality from about 40% to 20%. The potential to exacerbate certain concomitant disease, such as tuberculosis, must be recognized. However, in one study the incidence of tuberculosis was not found to be increased by the use of corticosteroids as empiric therapy of PCP. Disseminated, deep-seated fungal infection has been reported in some patients treated empirically with corticosteroids. All patients with severe disease should be hospitalized and treated with supplemental oxygen. Noninvasive ventilatory support by means of continuous positive airway pressure has been useful in buying time and avoiding mechanical ventilation. When intubation and mechanical ventilation are being considered, the prognosis, overall HIV history, and patient preferences must all be taken into account. Patients who require mechanical ventilation for respiratory failure secondary to PCP generally have a poor prognosis. (S.L.B.)
Table 84-2. Corticosteroid use in Pneumocystis carinii pneumonia
Bozzette SA, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1451.
Early corticosteroid treatment reduced risks for respiratory failure and death in PCP. There were few adverse effects.
Brenner M, et al. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Am Rev Respir Dis 1987;136:1199.
Patients in whom PCP was diagnosed before 1985 had more advanced disease at the time of diagnosis and a worse prognosis. The extent of disease on chest x-ray films and the alveolar-arterial gradient could be correlated with prognosis.
Broaddus C, et al. Bronchoalveolar lavage and transbronchial biopsy for the diagnosis of pulmonary infections in the acquired immunodeficiency syndrome. Ann Intern Med 1985;102:747.
This study compared BAL with transbronchial biopsy for the diagnosis of pulmonary infection in AIDS. Both were sensitive for Pneumocystis carinii infection. The sensitivity for Pneumocystis carinii infection when they were used together was 100%.
Brooks KR, et al. Acute respiratory failure due to Pneumocystis carinii pneumonia. Crit Care Clin 1993;9:31.
Management of PCP in AIDS is discussed with respect to ventilatory support and critical care.
Fallon J, Masur H. Infectious complications of HIV: Pneumocystis carinii and other protozoa. In: Fallon J, Masur H, eds. AIDS: etiology, diagnosis, treatment and prevention. Philadelphia: JB Lippincott Co, 1992.
Good, succinct review of PCP.
Gagnon S, et al. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1444.
Also shows that early adjunctive corticosteroid therapy improves survival and prevents respiratory failure in PCP.
Golden JA, et al. Bronchoalveolar lavage as the exclusive diagnostic modality for Pneumocystis carinii pneumonia: a prospective study among patients with acquired immunodeficiency syndrome. Chest 1986;90:18.
BAL detected PCP in 36 of 37 patients, making lung biopsy of little value in this disease.
Hughes WT, et al. Comparison of atovaquone (566C80) with trimethoprimsulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993;328:1521.
Atovaquone had a lower rate of efficacy but also a lower rate of treatment-limiting adverse effects, making it an option in mild disease when patients cannot be treated with TMP-SMX.
Jones BE, et al. Tuberculosis in patients with HIV infection who receive corticosteroids for presumed Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 1994; 149:1686.
The incidence of active tuberculosis was not increased in patients with HIV infection who were treated with corticosteroids for PCP.
Kovacs JA, et al. Diagnosis of Pneumocystis carinii pneumonia: improved detection in sputum with use of monoclonal antibodies. N Engl J Med 1988;318:589.
Examination of induced sputum was a sensitive test in the diagnosis of PCP. Immunofluorescent stain had a 92% sensitivity; Giemsa DifQuik was 76% sensitive.
Levine SJ. Pneumocystis carinii. Clin Chest Med 1997;17:665.
This article reviews in great detail the clinical manifestations, prognostic markers, and treatment options for PCP.
Miller RF, Mitchell DM. AIDS and the lung: update 1995. Thorax 1995;50:191.
Concise review article on PCP that includes molecular biology and details of treatment options.
Miller RF, et al. Empirical treatment without bronchoscopy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Thorax 1989;44:559.
Describes the experience with an empiric approach to treatment in comparison with the use of bronchoscopy for diagnosis.
Montaner JSG, et al. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990;113:14.
Oral corticosteroids prevented early deterioration in AIDS patients who were moderately ill in this prospective, randomized, double-blind, placebo-controlled study.
Murray JF, et al. NHLBI Workshop summary. Pulmonary complications of the acquired immunodeficiency syndrome: an update. Am Rev Respir Dis 1987;135:504.
An overall approach to the evaluation of AIDS patients with pulmonary infection is presented in this report from the National Heart, Lung, and Blood Institute Workshop.
National Institutes of Health. Special report: consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1500.
Excellent review of steroid trials in PCP. Includes a National Institutes of Health consensus statement recommending an oral tapering regimen of corticosteroids for patients with documented, moderate-to-severe PCP.
Phair J, et al. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. N Engl J Med 1990;322:161.
PCP is unlikely to occur in a patient who has a CD4 count above 200/mm3. Prophylaxis should be reserved for patients with a CD4-cell count below this level.
Pitchenik AE, et al. Sputum examination for the diagnosis of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Am Rev Respir Dis 1986; 133:226.
Results of sputum examination were positive in 55% of patients. Examination of induced sputum is recommended as a first step in the diagnosis of PCP.
Safrin S, et al. A double-blind, randomized comparison of oral trimethoprimsulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine for treatment of mild-to-moderate Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1996;124:792.
One third of patients were unable to tolerate an oral TMP-SMX regimen. Describes the alternative oral regimens for mild-to-moderate disease.
Sattler FR, et al. Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS. J Infect Dis 1994;170:165.
Failure rare, relapses and mortality rates higher in the trimetrexate group. Trimetrexate-leucovorin can be used to treat PCP in patients who have failed TMP-SMX and pentamidine or who have contraindications to these regimens.
Smith D, Gazzard B. Treatment and prophylaxis of Pneumocystis carinii pneumonia in AIDS patients. Drugs 1991;42:628.
Good description of treatment options in PCP, particularly with regard to toxicity profile.
Toma E, et al. Clindamycin-primaquine versus trimethoprim-sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind pilot trial. Clin Infect Dis 1993;17:178.
There were no differences in outcome, survival, or relapse between these regimens. Therapy-limiting adverse reactions occurred in 18% of patients receiving clindamycin-primaquine. Patients should be screened for deficiency of glucose-6-phosphate dehydrogenase before receiving this regimen.
Wachter RM, Luce JM, Hopewell PC. Critical care of patients with AIDS. JAMA 1992; 267:541.
Discusses medical and ethical issues involved in the management of respiratory failure in AIDS patients.