James J. Chamberlain MD
Kristen Ries MD
Essentials of Diagnosis
Of AIDS patients who do not receive prophylaxis against P carinii, ≤80% will develop at least one episode of PCP and ~ 25% of AIDS patients not receiving prophylaxis will die from PCP. Of patients who have experienced PCP as their AIDS-defining illness, ≤70% will develop recurrent disease in the ensuing 2 years without the use of prophylactic medication, and 50% of these cases will occur in the 9 months after the initial episode.
CD4 lymphocyte levels in immunocompromised patients have become the most useful factor in predicting risk for developing P carinii infections. Retrospective data have demonstrated that PCP rarely occurs in patients with CD4+ counts of > 200 cells/mm3 and that > 90% of AIDS patients will have a CD4 count of < 200 cells/mm3 in the 2 months before becoming infected with P carinii. The percentage of lymphocytes that are CD4 also seems an important prognostic factor because > 95% of patients had a CD4+ percentage of < 20% in the 2 months before infection.
Although P carinii infection in children is clinically similar to that seen in adults, the numbers of CD4 lymphocytes in pediatric patients differ from those of adults and vary by the age of the patient. The relationship of the CD4 count and the age of a child must be understood to ascertain the degree of immunosuppression. Severe immunosuppression in children < 12 months old is seen with a total CD4 count of < 750 cells/mm3 or a CD4 percentage of < 15%. For HIV-infected children between 1 and 5 years old, a CD4 T-lymphocyte count of < 500 cells/mm3 or a CD4 percentage of < 15% is indicative of immunosuppression and increased risk for PCP.
New information suggests that PCP occurs as a result of transmission from human hosts and not from reactivation of latent infection as once thought. The organism is probably not maintained in the lungs of immunocompetent humans for any significant period, and it has been difficult to detect in normal individuals at autopsy. Further support for the theory of person-to-person spread is that PCP infections seem to peak ~ 4 months after winter viruses. The organism may be spread via aerosolized secretions by persons in the community with viral infections. Clustered outbreaks of PCP also suggest person-to-person spread.
Mortality in cases of mild to moderate PCP (partial arterial oxygen pressure [PaO2] ≥70 mm Hg and alveolar-arterial oxygen gradient [A-a] ≤35 mm Hg) has substantially decreased as physicians treating the disease have gained experience. The early to mid 1980s saw mortality rates of ≤25% in mild to moderate disease. More recent large, multicenter trials have demonstrated mortality rates of < 1%. However, patients with PCP who develop respiratory failure still suffer profound mortality rates (≤45–72%).
The molecular biology of P carinii is interesting, and new discoveries have led to significant modification in the understanding and classification of this organism. P carinii has long been considered a member of the protozoan kingdom. However, in 1988, P carinii ribosomal RNA sequences were found to more closely parallel certain fungal ribosomal RNA sequences. More recent inspection of P carinii gene sequences and fungal sequences from each of the seven fungal phyla seems to suggest that P carinii is a fungal organism. In particular, there appears a noticeable morphologic similarity between P cariniiand the ustomycetous red yeast fungi, which is evidenced by a striking resemblance in mitochondrial RNA segments by PCR analysis.
It is interesting that the strain of P carinii that infects organisms may not be clonal. Within humans, the organism appears to be genetically diverse; isolates from four distinctly different geographic regions of the world show DNA diversity. Different mammalian hosts appear to harbor genetically diverse strains of P carinii as well. P carinii has been proven unable to grow when organisms from one species are deposited in the lungs of a differing species.
Impaired gas exchange at the alveolar level, a hallmark of PCP infection, appears to be caused by both the extensive proliferation of P carinii organisms and the subsequent host response. The presence of a foamy alveolar exudate, alveolar macrophages, interstitial edema, and type I alveolar cell destruction has been demonstrated by electron and light microscopy during the course of infection. The efficacy of corticosteroids in moderate to severe PCP infection is presumably caused by blunting of the host immune response. The importance of the correlation between the degree of immune response and the severity of disease is supported by the association between the number of neutrophils seen on BAL specimens and increased mortality.
P CARINII PNEUMONIA
The physical exam is relatively nonspecific in diagnosing PCP because ≤50% of patients may have normal pulmonary examinations. Fine rales may be auscultated in ≤40% of patients, most with severe PCP. Patients may have restriction of their inspiratory ability, which is usually not mentioned unless the patient is questioned specifically.
EXTRAPULMONARY P CARINII INFECTIONS
Extrapulmonary P carinii infections occur in < 3% of patients and must be diagnosed with histopathologic samples. Primary prophylaxis for PCP with pentamidine may confer a higher risk for extrapulmonary infection. Symptoms of extrapulmonary involvement are nonspecific, usually consisting of fevers, chills, and sweats. Although any area of the body may be involved, splenomegaly with cysts and thyroiditis are most common.
BOX 79-1 Signs and Symptoms of Pneumocystis carinii Pneumonia
The practice of diagnosing PCP morphologically by traditional staining methods (silver methenamine and toluidine blue) of induced sputum samples in HIV-infected individuals has fallen out of favor. Although relatively simple and inexpensive, staining of sputum samples induced by hypertonic saline inhalation is clearly dependent on operator and laboratory experience, and sensitivity varies tremendously between centers. These classic staining techniques yield a diagnosis in only 30–90% of patients suspected of being infected with PCP. Subsequently, a large number of patients may continue to be treated with potentially toxic drug regimens without a definitive diagnosis. The practice of indirect immunofluorescent stain with monoclonal antibodies has increased the sensitivity of induced sputum samples to ~ 70% or to > 90% in some reports.
Bronchoscopy with BAL with or without transbronchial biopsy has become the gold standard in the diagnosis of PCP. Several studies have demonstrated a sensitivity of > 90% for both BAL and transbronchial biopsy. The combination of BAL and transbronchial biopsy leads to a sensitivity of ~ 100%. The complications of transbronchial biopsy, including bleeding and pneumothorax, have led most clinicians to use BAL as the initial diagnostic method during bronchoscopy if diagnosis is not obtained by induced sputum.
PCR technology on induced sputum samples has improved sensitivity to ~ 100% but appears to result in diminished specificity. PCR may become a reasonable diagnostic tool as PCR technique improves, resulting in less contamination and fewer false-positive results.
Chemoprophylaxis for PCP with aerosolized pentamidine has led to a considerable reduction in the rate of recovery of PCP in sputum and bronchoscopy samples. Performing BAL bilaterally or on multiple lobes seems to maintain sensitivity at > 90%.
The primary treatment of moderate to severe pulmonary or extrapulmonary infection caused by P carinii remains the combination of trimethoprim (TMP) and sulfamethoxazole (SMX), either orally or intravenously (IV).
Several medications (atovaquone, trimetrexate, and pentamidine) and combination regimens (dapsone + TMP and clindamycin + primaquine) probably afford nearly equal efficacy to TMP-SMX in mild to moderate PCP and may be better tolerated in specific populations of patients (Boxes 79-2 and 79-3).
In moderate to severe pulmonary infection with P carinii, TMP-SMX has been shown to significantly improve survival when compared with IV pentamidine (86% vs 61%) in randomized trials. Several drug regimens subsequently discussed appear to have similar efficacy compared with TMP-SMX in mild to moderate PCP and may be better tolerated. However, the fact that TMP-SMX also has excellent antimicrobial activity against organisms causing community-acquired bacterial pneumonia and Toxoplasma infections should be considered when choosing an agent for treating P carinii infections.
Treatment with TMP-SMX is often limited by adverse effects, which occur in the majority of patients to some degree (65–100%). A morbilliform rash is the most commonly observed adverse reaction among patients treated with TMP-SMX; the rash occurs ~ 20–45% of the time and limits treatment in ≤20% of patients. Antihistamines may be used to reduce the severity of the rash. Additional side effects of TMP-SMX include fever, nausea and vomiting, neutropenia, anemia, thrombocytopenia, and elevated serum aminotransferase levels.
Aerosolized pentamidine isethionate has been used in the treatment of mild to moderate PCP. Unfortunately, although it results in fewer systemic adverse effects, the aerosolized form of pentamidine isethionate has resulted in lower response rates and a higher frequency of relapse. The use of aerosolized pentamidine isethionate is expensive and requires compressed air to be delivered effectively.
The most common adverse effects associated with the use of pentamidine isethionate include nephrotoxicity, hyperkalemia, hypocalcemia, hypomagnesemia, hypoglycemia, and hypotension. The hypotension seems to be related to the rate at which the drug is administered and usually responds to IV fluids. Hyperglycemia and insulin dependence can also occur. Acute pancreatitis has also been reported.
Trimetrexate has been compared with TMP-SMX in a randomized, double-blind, multicenter trial in a group of patients with moderate to severe PCP. Trimetrexate was relatively well tolerated; only 8% of patients terminated treatment before 21 days because of adverse effects. By comparison, 28% of patients who received TMP-SMX had discontinued therapy by 21 days (P < 0.001). However, by 21 days after initiation of treatment, a significantly larger number of patients receiving trimetrexate had been considered treatment failures as measured either by lack of efficacy or death (38%) vs those receiving TMP-SMX (20%). Thus, trimetrexate should be considered a relatively safe treatment option in patients with moderate to severe PCP who do not respond to or are intolerant of TMP-SMX or in patients in whom TMP-SMX is contraindicated.
Trimetrexate, as mentioned, has been well tolerated, with ≤10% of patients discontinuing therapy at 21 days. The principal dose-limiting side effect has been myelosuppression, especially neutropenia and thrombocytopenia, occurring in 10–15% of patients. Elevated serum aminotransferase, alkaline phosphatase, and creatinine levels have been reported as well. Rash and anemia may also occur in patients receiving trimetrexate.
The adverse effects of atovaquone that lead to termination of treatment seem to occur in < 10% of patients over a typical 21-day course of treatment. Gastrointestinal complications arise most frequently and include nausea, vomiting, diarrhea, hepatitis, and constipation. In addition, an erythematous rash has occurred in ≤25% of patients who take atovaquone. Fever and cough are also common side effects.
Several prospective trials have proven that clindamycin and primaquine are ≥90% effective in treating mild to moderate PCP. No significant difference has been demonstrated between clindamycin and primaquine when compared with either TMP-SMX or dapsone-TMP, in mild to moderate disease.
Adverse effects have occurred in up to one-third of patients receiving clindamycin and primaquine, and they may be related to the dose of primaquine used. When primaquine has been dosed at 30 mg/d instead of the more frequently used dose of 15 mg/d, the incidence of dose-limiting side effects has nearly doubled. The most significant dose-limiting adverse effect observed in patients taking clindamycin and primaquine is a vesicular, desquamating, or ulcerating rash. Anemia is a frequent problem as well, which is likely related to the strong oxidative effects of primaquine that lead to its contraindication in patients with glucose-6-phosphate dehydrogenase deficiency. The primaquine component of this treatment combination may lead to methemoglobinemia as well. Less common side effects include nausea and vomiting, neutropenia, and gastrointestinal complaints.
Adverse reactions to this combination regimen seem to occur at a much lower rate than to either pentamidine or TMP-SMX. Side effects requiring termination of treatment have occurred in < 10% of patients receiving dapsone and TMP. In clinical trials, the major side effects most commonly include rash (occasionally requiring discontinuation of therapy), elevated hepatic transaminases, neutropenia and thrombocytopenia, hemolytic anemia, and methemoglobinemia with serum levels that can exceed 20%. Of note, dapsone is a potent oxidant, an effect that can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, and it should be used with caution in this population of patients.
BOX 79-2 Treatment of Pneumocystis carinii Pneumonia in Adults
BOX 79-3 Treatment of Pneumocystis carinii Pneumonia in Children
Many clinical markers or scoring systems have been suggested to diagnose and predict outcome in PCP. Most if not all of these factors have been shown to have little value in the management of disease. The degree of hypoxia is an important prognostic factor that affects recommended treatment. The adjuvant use of corticosteroids and choice of treatment regimen should be based on whether the disease is classified as mild to moderate (PaO2 > 70 mm Hg and P[A-a]O ≤35 mm Hg) or moderate to severe (PaO2 < 70 mm Hg or P[A-a]O ≥35 mm Hg). However, it is probably better to err on the side of using corticosteroids.
Prevention & Control
Prophylaxis for PCP has clearly been shown to be effective in reducing the incidence of disease and improving survival in patients at risk for developing the disease (Box 79-4). No chemoprophylactic treatment regimen has been shown to be more effective than TMP-SMX. In addition, TMP-SMX provides protection against the bacteria that cause community-acquired pneumonia, as well as against toxoplasmosis. Aerosolized pentamidine isethionate and dapsone with or without pyrimethamine or TMP should continue to be regarded as second-line agents in the prevention of PCP.
Of patients receiving prophylaxis against PCP with TMP-SMX, ≤75% may not tolerate the drug. Because TMP-SMX is cheaper and more effective than other treatment options, desensitization protocols have been used to allow some patients who were previously intolerant to TMP-SMX to continue taking the drug. Several published reports indicate that the majority of patients with previous mild to moderate adverse reactions and some with severe anaphylactic responses to TMP-SMX may be safely and successfully desensitized with oral protocols. Thus, most patients who were previously thought to be unable to tolerate TMP-SMX for prophylaxis against PCP may be safely and effectively desensitized with oral desensitization protocols and continue to take TMP-SMX. Some physicians have recommended that all patients who started treatment with SMX should use a desensitization protocol, thus preventing many allergic reactions.
Twice weekly dapsone and pyrimethamine appears to be an effective and perhaps better tolerated alternative to daily dosing regimens. Toxicities associated with prophylactic dapsone are the same as those listed in the treatment section.
When adverse effects are encountered with inhaled pentamidine isethionate, they are mainly limited to a dry cough and bad taste in the mouth. Spontaneous pneumothorax is a potentially dangerous effect of aerosolized pentamidine isethionate. The small amount of systemic absorption may occasionally result in rash, renal impairment, and pancreatitis. Use of an albuterol inhaler before the nebulized pentamidine isethionate is recommended as routine by some to prevent bronchospasm and to promote better penetration of the drug.
BOX 79-4 Prophylaxis for Pneumocystis carinii Pneumonia
American Academy of Pediatrics, Committee on Infectious Diseases: Pneumocystis. In Peter G: 1997 Red Book: Report of the Committee on Infectious Diseases, 24th ed. American Academy of Pediatrics, 1997.
Bozzette SA, et al: A randomized trial of three antipneumocystis agents in patients with advance human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995;332:693.
Chien SM, et al: Changes in hospital admissions patterns in patients with human immunodeficiency virus infection in the era of Pneumocystis carinii prophylaxis. Chest 1992;102:1035.
Dohn MN, et al: Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1994;121:174.
Fulton B, Wagstaff AJ, McTavish D: Trimetrexate: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia. Drugs 1995;49(4):563.
Girard P-M, et al: Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med 1993;328:1514.
Hughes W, et al: Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). N Engl J Med 1993;328:1521.
Kennedy CA, Goetz MB: Atypical roentgenographic manifestations of Pneumocystis carinii pneumonia. Arch Intern Med 1992;152:1390.
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.
Lipschik GY, et al: Improved diagnosis of Pneumocystis carinii infection by polymerase chain reaction on induced sputum and blood. Lancet 1992;340:203.
Mason GR, et al: Prognostic implications of bronchoalveolar lavage neutrophilia in patients with Pneumocystis carinii pneumonia and AIDS. Am Rev Respir Dis 1989;139:1336.
Masur H, et al: Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1500.
Miller RF, et al: Pneumocystis carinii infection: current treatment and prevention. J Antimicrob Chemother 1996;37(Suppl B):33.
Nelson JD: Pocket Book of Pediatric Antimicrobial Therapy. Williams & Wilkins, 1998.
Safrin S: New developments in the management of Pneumocystis carinii disease. AIDS Clin Rev 1993/1994:95.
Safrin S, et al: Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1996;124:792.
Sattler FR, et al: Trimethoprim-sulfamethoxazole with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 1988;109:280.
Sattler FR, et al: Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis 1994;170:165.
Sistek CJ, Wordell CJ, Hauptman SP: Adjuvant corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS patients. Ann Pharmacother 1992;26:1127.
Stringer JR, Walzer PD: Molecular biology and epidemiology of Pneumocystis carinii infection in AIDS [editorial]. AIDS 1996;10:561.
Toma E, et al: Clindamycin/primaquine versus trimethoprim-sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind trial. Clin Infect Dis 1993;17:178.
Wakefield AE, et al: Pneumocystis carinii shows DNA homology with the ustomycetous red yeast fungi. Mol Microbiol 1992;6:1903.
Yung RC, et al: Upper and middle lobe bronchoalveolar lavage to diagnose Pneumocystis carinii pneumonia. Am Rev Respir Dis 1993;148:1563.