Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Pneumocystis Jiroveci Pneumonia Epidemiology       Pneumocystis jiroveci pneumonia (PCP) is caused by Pneumocystis jiroveci, a ubiquitous organism classified as a fungus but that shares biologic characteristics with protozoa. The taxonomy of the organism has been changed; Pneumocystis carinii now refers only to the pneumocystis that infects rodents, and Pneumocystis jiroveci refers to the distinct species that infects humans. The abbreviation PCP is still used to designate Pneumocystis pneumonia. Initial infection with P. jiroveci usually occurs in early childhood; two thirds of healthy children have antibody to P. jiroveci by age 2--4 years . PCP is a result either of reactivation of latent infection or new exposure to the organism. Rodent studies and case clusters among immunosuppressed patients indicate that spread among persons can occur by the airborne route. Disease probably occurs by new acquisition and by reactivation . Before the widespread use of primary PCP prophylaxis and effective ART, PCP occurred in 70%--80% of patients with AIDS . The course of treated PCP was associated with a mortality of 20%--40% in persons with profound immunosuppression. Approximately 90% of cases occurred among patients with CD4+ T lymphocyte counts of <200/µL. Other factors associated with a higher risk of PCP included CD4+ T lymphocyte percentage <15%, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV-1 RNA . Incidence of PCP has declined substantially with widespread use of prophylaxis and effective ART; recent incidence rates among patients with AIDS in Western Europe and the U.S. are 2--3 cases per 100 person-years . The majority of cases occur among patients who are unaware of their HIV-1 infection or are not receiving ongoing HIV care  or among those with advanced immunosuppression (CD4+ T lymphocyte counts <100 cells/µL)  Clinical Manifestations The most common manifestations of PCP among HIV-1--infected persons are the subacute onset of progressive exertional dyspnea, fever, nonproductive cough, and chest discomfort that worsens over a period of days to weeks. The fulminant pneumonia observed among non-HIV-1--infected patients is less common . In mild cases, pulmonary examination is usually normal at rest. With exertion, tachypnea, tachycardia, and diffuse dry ("cellophane") rales might be observed . Oral thrush is a common co-infection. Fever is apparent in the majority of cases and might be the predominant symptom among some patients. Extrapulmonary disease is rare but can present in any organ and has been associated with use of aerosolized pentamidine prophylaxis. Hypoxemia, the most characteristic laboratory abnormality, might range from mild-to-moderate (room air arterial oxygen [pO2] of >70 mm/Hg or alveolar-arterial O2 difference, [A-a] DO2 <35 mm/Hg) to moderate-to-severe levels (pO2 <70 mm/Hg or [A-a] DO2 >35 mm/Hg). Oxygen desaturation with exercise is indicative of an abnormal A-a gradient but is nonspecific . Elevation of lactate dehydrogenase levels to >500 mg/dL is common but nonspecific . The chest radiograph typically demonstrates diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hiLa in a butterfly pattern ; however, patients with early disease might have a normal chest radiograph . In addition, atypical presentations with nodules, asymmetric disease, blebs and cysts, upper lobe localization, and pneumothorax occur. Cavitation or pleural effusion is uncommon in the absence of other pulmonary pathogens or malignancy, and the presence of a pleural effusion might indicate an alternative diagnosis. Approximately 13%--18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction (e.g., TB, Kaposi sarcoma, or bacterial pneumonia) (57,58). Pneumothorax in a patient with HIV-1 infection should raise the suspicion of PCP . Thin-section computerized tomography (CT) demonstrating patchy ground-glass attenuation or a gallium scan showing increased pulmonary uptake increases the likelihood that a diagnostic study such as bronchoscopy would demonstrate PCP in patients with mild-to-moderate symptoms and a normal chest radiograph and might be useful in adjunctive studies. However, a negative thin-section CT scan does not rule out PCP. Diagnosis Because the clinical presentation, blood tests, or chest radiographs are not pathognomonic for PCP and the organism cannot be routinely cultivated, histopathologic demonstration of organisms in tissue, bronchoalveolar lavage fluid, or induced sputum  samples is required for a definitive diagnosis. Spontaneously expectorated sputum has low sensitivity and should not be submitted to the laboratory to diagnose PCP. Cresyl violet, Giemsa, Diff-Quik, and Wright stains detect both the cyst and trophozoite forms but do not stain the cyst wall; Gomori Methenamine Silver, Gram-Weigert and toluidine blue stain the cyst wall. Certain laboratories prefer direct immunofluorescent staining. Nucleic acid tests are being developed, but their use remains experimental . Previous studies of stained respiratory tract samples obtained by various methods indicate the following relative diagnostic sensitivities: induced sputum <50 to >90% (the sensitivity and specificity depends heavily on the quality of the specimens and the experience of the microbiologist or pathologist), bronchoscopy with bronchoalveolar lavage 90%--99%, transbronchial biopsy 95%--100%, and open lung biopsy 95%--100%. Because of the potential for certain processes to have similar clinical manifestations, a specific diagnosis of PCP should be sought rather than relying on a presumptive diagnosis. Treatment can be initiated before making a definitive diagnosis because organisms persist in clinical specimens for days or weeks after effective therapy is initiated. Treatment Recommendations Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice  (AI). The dose must be adjusted for abnormal renal function. Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral pentamidine and more effective than other regimens. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because of questionable efficacy and some evidence for a higher failure rate (DII). Oral outpatient therapy of TMP-SMX is highly effective among patients with mild-to-moderate disease  (AI). Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical outcome is uncertain. Patients who have PCP despite TMP-SMX prophylaxis are usually effectively treated with standard doses of TMPSMX (BIII). Patients with documented PCP and moderate-to-severe disease, as defined by room air pO2 <70 mm/Hg or arterial-alveolar O2 gradient >35 mm/Hg, should receive corticosteroids as early as possible, and certainly within 72 hours after starting specific PCP therapy. (AI). If steroids are started at a later time, their benefits are unclear, although the majority of clinicians would use them in such circumstances for patients with severe disease (BIII). The preferred corticosteroid dose and regimen is prednisone 40 mg by mouth twice a day for days 1--5, 40 mg daily for days 6--10, and 20 mg daily for days 11--21(AI). Methylprednisolone at 75% of the respective prednisone dose can be used if parenteral administration is necessary. Alternative therapeutic regimens include 1) dapsone and TMP for mild-to-moderate disease  (BI) (this regimen may have similar efficacy and fewer side effects than TMPSMX but is less convenient because of the number of pills); 2) primaquine plus clindamycin . (BI) (this regimen is also effective in mild-to-moderate disease, and the clindamycin component can be administered intravenously for more severe cases; however, primaquine is only available orally; 3) intravenous pentamidine  (AI) (generally the drug of second choice for severe disease); 4) atovaquone suspension  (BI) (this is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects); and 5) trimetrexate with leucovorin  (BI) (this is less effective than TMP-SMX but can be used if the latter is not tolerated and an intravenous regimen is needed). Leucovorin must be continued 3 days after the last trimetrexate dose. The addition of dapsone, sulfamethoxazole, or sulfadiazine to trimetrexate might improve efficacy on the basis of the sequential enzyme blockade of folate metabolism, although no study data exist to confirm this (CIII). Aerosolized pentamidine should not be used for the treatment of PCP because of limited efficacy and more frequent relapse .(DI). The recommended duration of therapy for PCP is 21 days  (AII). The probability and rate of response to therapy depends on the agent used, number of previous episodes, severity of illness, degree of immunodeficiency, and timing of initiation of therapy. Although the overall prognosis of patients whose degree of hypoxemia requires intensive care unit (ICU) admission or mechanical ventilation remains poor, survival in up to 40% of patients requiring ventilatory support has been reported in recent years . Because long-term survival is possible for patients in whom ART is effective, certain patients with AIDS and severe PCP should be offered ICU admission or mechanical ventilation when appropriate (e.g., when they have reasonable functional status) (AII). Because of the potential for additive or synergistic toxicities associated with anti-PCP and antiretroviral therapies, certain health-care providers delay initiation of ART until after the completion of anti-PCP therapy, despite some suggestion of potential benefit for early ART  (CIII). An immune recovery inflammatory syndrome has been described for PCP  and might complicate the concurrent administration of anti-PCP treatment and ART.     Monitoring and Adverse Events Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as soon as possible. Follow-up after therapy includes assessment for early relapse, especially when therapy has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be initiated promptly and maintained until the CD4+ T lymphocyte count is >200 cells/µL. If PCP occurred at a CD4+ T lymphocyte count >200 cells/µL, maintaining PCP prophylaxis for life regardless of the CD4+ T cell response might be prudent; however, data about the most appropriate approach in this setting are limited. Adverse reaction rates among patients with AIDS are high for TMP-SMX (20%--85%) . Common adverse effects are rash (30%--55%) (including Stevens-Johnson syndrome), fever (30%--40%), leukopenia (30%--40%), thrombocytopenia (15%), azotemia (1%--5%), hepatitis (20%), and hyperkalemia. Supportive care for common adverse effects should be attempted before discontinuing TMP-SMX (AIII). Rashes can often be "treated through" with antihistamines, nausea can be controlled with antiemetics, and fever can be managed with antipyretics. The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G-6-PD deficiency), rash, and fever with dapsone; azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, fever, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine ; anemia, rash, fever, diarrhea, and methemoglobinemia with primaquine and clindamycin ; headache, nausea, diarrhea, rash, fever, and transaminase elevations with atovaquone ; and bone marrow suppression, fever, rash, and hepatitis with trimetrexate . Management of Treatment Failure Clinical failure is defined by the lack of improvement or worsening of respiratory function documented by arterial blood gases after at least 4--8 days of anti-PCP treatment. Treatment failure attributed to treatment-limiting toxicities occurs in up to one third of patients . Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease. Adding or switching to another regimen is the appropriate management for treatment-related toxicity (BII). No convincing clinical trials exist to base recommendations for the management of treatment failure attributed to lack of drug efficacy. It is important to wait at least 4--8 days before switching therapy for lack of clinical improvement (BIII). In the absence of corticosteroid therapy, early and reversible deterioration within the first 3--5 days of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis of organisms in the lung. Other concomitant infections must be excluded as a cause for such deterioration . Bronchoscopy with bronchoalveolar lavage should be strongly considered even if it was conducted before initiating therapy. If TMP-SMX has failed or must be avoided for toxicity in moderate-to-severe disease, the common practice is to use parenteral pentamidine, primaquine combined with clindamycin, or trimetrexate (with or without oral dapsone) plus leucovorin  (BII). For mild disease, atovaquone is a reasonable alternative (BII). Although one meta-analysis concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy  no prospective clinical trials have evaluated the optimal approach to patients who fail therapy with TMP-SMX. Prevention of Recurrence Patients who have a history of PCP should be administered secondary prophylaxis (chronic maintenance therapy) for life with TMP-SMX unless immune reconstitution occurs as a result of ART  (AI). For patients who are intolerant of TMP-SMX, alternatives are dapsone, dapsone combined with pyrimethamine, atovaquone, or aerosolized pentamidine. Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ T lymphocyte cell count has increased from <200 cells/µL to >200 cells/µL for at least 3 months as a result of ART  (AI). Secondary prophylaxis should be re-introduced if the CD4+ T lymphocyte count decreases to <200 cells/µL (AIII) or if PCP recurs at a CD4+ T lymphocyte count of >200 cells/µL (CIII). Special Considerations During Pregnancy Diagnostic considerations during pregnancy are the same as for nonpregnant women. Indications for therapy are the same as for nonpregnant women. The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX  (AI). Neonatal care providers should be informed of maternal sulfa or dapsone therapy if used near delivery because of the theoretical increased risk for hyperbilirubinemia and kernicterus  Pentamidine is embryotoxic but not teratogenic among rats and rabbits.  Trimetrexate should not be used because of teratogenicity at low doses in multiple animal studies, fetopathy in humans associated with use of the biochemically similar agents methotrexate and aminopterin, and the potential negative effects on placental and fetal growth . (EIII). Adjunctive corticosteroid therapy should be used as indicated in nonpregnant adults (AIII). Maternal fasting and postprandial glucose levels should be monitored closely when corticosteroids are used in the third trimester because the risk for glucose intolerance is increased. Rates of preterm labor and preterm delivery are increased with pneumonia during pregnancy. Pregnant women with pneumonia after 20 weeks of gestation should be monitored for evidence of contractions (BII).