Walter T. Hughes
Pneumocystis pneumonia (PCP) occurs almost exclusively in the severely immunocompromised host, especially patients with congenital immunodeficiency diseases, AIDS, and cancer, and those who have had organ transplantation. The causative agent is a protozoan-like fungus known for the past century as Pneumocystis carinii. Recently, the term Pneumocystis jirovecii has been proposed for the organism found in humans,1 but acceptance has not been universal.2
EPIDEMIOLOGY
Pneumocystis organisms have been found in the lungs of most mammals in most parts of the world. Transmission of the organism seems to be host-specific. The natural habitat and mode of transmission in man are unknown, but animal studies suggest animal-to-animal transmission occurs by the airborne route.3-5 Animal-to-human transmission has not been reported, and available evidence suggests that human-to-human transmission is possible.11
Considerable data show that at least 75% of normal children reaching 4 years of age have acquired antibody to Pneumocystis and that more than 90% of normal adults have detectable antibody.16-18,19 The incidence of PCP in cancer patients is influenced more by the extent of immunocompromise from treatment than the primary disease. In a controlled study of 160 children with acute lymphocytic leukemia without PCP prophylaxis and on intensive antileukemia therapy, 20% were found to have developed PCP.28 Other at risk populations include those immunosuppressed for solid organ transplantation30, rheumatoid arthritis, lupus erythematosus, and other connective tissue diseases in adults with CD4+ T lymphocyte counts less than 250/mm3.31
Early in the AIDS epidemic, when no antiviral therapy was available and chemoprophylaxis for PCP was not applied, some 75% of adults and 39% of infants with AIDS acquired PCP.32,33,34 In infants and children with HIV infection, PCP occurs most often in infants between 3 and 6 months of age.33-35 The use of PCP prophylaxis and highly active antiretroviral therapy (HAART) has profoundly reduced PCP in patients with AIDS. The Perinatal AIDS Collaborative Transmission Study showed a 95% decrease in PCP (cases per 100 patient-years), from 5.8 in the pre-HAART era to 0.3 in the HAART era.37,38
As with other immunosuppressed states, highly significant risk factor for PCP in HIV-infected patients is a marked reduction in the CD4+ T lymphocyte count.
PATHOPHYSIOLOGY
The portal of entry for Pneumocystis is believed to be the respiratory tract via the airborne route. In the infected lung, the organism is found in both cystic and extracystic forms. The cyst is a round, oval, or cup-shaped structure approximately 4 to 6 microns in diameter (Fig. 353-1). Within the mature cyst are as many as eight daughter cells, referred to as sporozoites, that are pleomorphic and often crescent shaped. These cells eventually excyst through breaks in the cyst wall. Outside the cyst, the daughter cell, now termed a trophozoite, varies from 2 to 5 microns in diameter. These thin-walled trophozoites tend to cluster in masses.
In the normal, healthy individual, Pneumocystis may lie dormant in the alveoli, eliciting no tissue response and leaving the host asymptomatic.42 In the severely immunocompromised host, organisms replicate to large numbers and an extensive diffuse alveolar disease and interstitial infiltration may progress to death.
Pneumocystis attaches to the alveolar epithelial cells, and alveolar macrophages ingest and degrade the organisms; this provokes neutrophil, lymphocyte, and monocyte infiltration and cytokine release. Alveolar disruption impedes gas exchange and leads to respiratory failure.43,44 The CD4+ T lymphocyte serves to recruit and activate other immune effector cells.45,46 There is an increase in CD8+ lymphocytes in the lungs.47 Surfactant phospholipids are reduced in PCP, further impairing pulmonary function.48-51
FIGURE 353-1. Cyst forms of Pneumocystis as seen in bronchoalveolar lavage specimen stained with Gomori methenamine silver nitrate method.
CLINICAL FEATURES
The clinical manifestations of PCP may present abruptly as an acute febrile episode with respiratory symptoms or a more subtle subacute illness with little or no fever. In all cases, tachypnea, cough, dyspnea, and oxygen desaturation occur. Typically, the chest radiograph shows bilateral, diffuse alveolar disease with symmetric reticular (interstitial) or granular opacites (eFig. 353.1 ). However, by the time pneumonitis is discernible by radiograph, tachypnea, flaring of nasal alae, intercostal retractions, and even cyanosis may be evident on examination. Even with diffuse pneumonitis, rales may not be heard. Once pneumonitis is evident, the infection progresses to a fatal outcome in nearly 100% of cases if untreated.
A recent study of HIV-infected children with pneumonia showed four clinical factors were independently associated with PCP: respiratory rate greater than 59 respirations per minute, arterial hemoglobin saturation (SaO2) less than or equal to 92%, less than 6 months of age, and the absence of vomiting.54
In a study of 56 cancer patients with PCP, the clinical manifestations included fever in 86%, dyspnea in 79%, and cough in 57% of the cases. The pneumonitis presented with severe hypoxemia (PaO2 = 50–70 mm Hg) and bilateral interstitial infiltrates (80%) and bilateral ground-glass appearance (89%) by computed tomography.55
DIAGNOSIS
A definitive diagnosis requires the demonstration of Pneumocystis in infected lung tissue or in material from the lung that is obtained by bronchoalveolar lavage (BAL); induced sputum; or open lung, transbronchial, percutaneous, or endobronchial brush biopsies. The specimen is stained with Gomori, toluidine blue O, calcofluor white, or Giemsa stains (see Fig. 353-1 and eFigs. 353.2, 353.3, and 353.4 ). A fluorescence-conjugated monoclonal antibody (Meri-flour, Meridian Bioscience, Cincinnati) is highly sensitive and specific (eFig. 353.5 ).
Table 353-1. Drugs for the Treatment of Pneumocystis Pneumonia.
Table 353-2 Pneumocystis Pneumonia Prophylaxis Regimens.
Pneumocystis DNA/RNA has been detected in lung tissue, in sputum, and in oral and nasal secretions by polymerase chain reaction (PCR), but this approach has not been adequately standardized and studied to adopt for diagnosis. While lung biopsy is the most sensitive and specific procedure and provides histopathology on the extent of disease process (eFigs. 353.4 and 353.5 ), BAL is usually the procedure initially used because of the possible complications from general anesthesia, pneumothorax, hemorrhage, and pneumomediastinum with biopsy. The reported diagnostic sensitivity of BAL ranges from 89% to greater than 98%.56,57
TREATMENT
Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred drug for treating Pneumocystis pneumonia (Table 353-1). TMP-SMX is usually administered intravenously at first. When there is evidence of clinical improvement and the patient can take and tolerate oral therapy, the drug combination can be given orally, using either tablets or suspension. The dosage is based on 20 mg of TMP and 100 mg SMX per kg per day orally, or three fourths of this dose given IV in 3 or 4 doses. A 2-week course is usually adequate for patients without AIDS, but at least 3 weeks of treatment is needed for patients with AIDS.
Because patients who have one episode of PCP and recover are at high risk for a recurrent episode, all individuals treated for PCP should be maintained on TMP-SMX at prophylactic doses indefinitely or until the immunocompromised state is resolved.63 TMP-SMX is generally well tolerated, but HIV-infected patients have an exceptionally high rate of adverse reactions.64 These include rash, fever, anorexia, nausea, vomiting, diarrhea, leukopenia, thrombocytopenia, anemia, renal toxicity, and exfoliative skin disorders (Stevens-Johnson syndrome). Unless the reaction is mild and insignificant, TMP-SMX should be discontinued and therapy continued with another drug, usually pentamidine. About 15% of HIV-infected children have substantial adverse reactions to TMP-SMX.65
Pentamidine is recommended for patients who cannot tolerate or who do not respond to TMP-SMX. The drug must be administered parenterally and is frequently associated with nephrotoxicity, hypoglycemia, and other adverse effects. Pentamidine is given as a single IV dose at 4 mg/kg. Adverse reactions occur in up to 80% of patients receiving pentamidine, and the drug must be discontinued in half the cases.66-70
Other drugs with demonstrated efficacy for treating PCP are atovaquone, dapsone plus trimethoprim, fansidar, and clindamycin plus primaquine. Atovaquone offers a safe alternative to TMP-SMX and is available only as an oral suspension (750 mg per 5 ml).
The combination of dapsone and trimetho-prim has proven effective in treating PCP in adults with AIDS.
Lack of data on the use of clindamycin plus primaquine to treat PCP in children relegates this regimen to cases where the aforementioned regimens cannot be used.
Supportive measures are important in managing PCP. Administering oxygen and using assisted mechanical ventilation are indicated with severe hypoxia. Evidence suggests that using a corticosteroid may enhance survival in patients with moderate and severe PCP.77-79 With PaO2 values less than 70 mm Hg or an alveolar-arterial gradient of greater than 35 mm Hg, the administration of a corticosteroid such as prednisone is recommended (see Table 353-1for doses).
Once pneumonitis is evident on chest radiograph, PCP is fatal in approximately 100% of cases if untreated. When defervescence reveals signs of clinical improvement from treatment, a decrease in respiratory rate and an increase in PaO2 may be seen at a mean of 4.5 ±2.5 days and improvement in chest radiograph may be seen at 7.7 ±4.5 days after treatment begins.80
PREVENTION
Pneumocystis pneumonitis can be prevented by the prophylactic use of TMP-SMX in a dosage of 5 mg of TMP and 25 mg of SMX per kg per day orally (daily or 3 days a week) in equally divided doses. For patients who cannot tolerate TMP-SMX, atovaquone, dapsone, and aerosolized pentamidine are effective alternatives (Table 353-2).76,81-83,84 The host is protected for only as long as the drug is administered. Updated CDC and NIH guidelines established for prophylaxis in infants and children with HIV infection recommend the following individuals receive PCP prophylaxis: all HIV-infected and indeterminate infants ages 1 to 12 months; children ages 1 through 5 years with CD4+ T lymphocyte counts of less than 500/mm3 (or < 15%); and children age 6 years and older with CD4+ T lymphocyte counts of less than 200/mm3 (or < 15%).38 Other patients at high risk for PCP and who warrant prophylaxis are those who have received organ transplants, those who have certain malignancies and congenital immunodeficiency syndromes, and those who require prolonged immunosuppressive therapy.
When non-life-threatening adverse effects occur, TMP-SMX can be discontinued; when the reaction has resolved, the drug combination can be restarted with a desensitizing scheme.86 If the initial adverse reaction is life-threatening, stop TMP-SMX and use an alternative drug. Usually atovaquone or dapsone is the drug of second choice.
Daily atovaquone prophylaxis has been shown to be as effective as dapsone82 and aerosolized pentamidine.88 Dapsone is as effective as atovaquone or aerosolized pentamidine for prophylaxis but is possibly less effective than TMP-SMX.76,82