| Pneumocystis Pneumonia |  | | September 4, 2009 |  |
| | From Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children. National Institutes of Health, the Centers for Disease Control and Prevention, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Vol. 58, No. RR-4. September 4, 2009. | | | Epidemiology | | Pneumocystis spp. are found worldwide in the lungs of humans and lower animals. The organisms are host specific, and cross-infection between humans and other animals does not occur. Pneumocystis spp. from all sources are morphologically, tinctorially, and biologically similar, but surface antigens and gene sequencing have demonstrated host-specific differences. Since the original designation of Pneumocystis carinii a century ago, several changes in terminology have been suggested. The most recent proposal to change P. carinii to P. jirovecii for isolates from human lungs has gained some popularity but remains controversial. Pneumocystis has been designated a fungus on the basis of DNA analysis, but it has several biologic features of protozoa. It is one of the most frequent causes of infection in humans. By age 2-4 years, more than 80% of children in most countries have acquired antibodies to Pneumocystis (405Vargas SL, Hughes WT, Santolaya ME, et al. Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants. Clin Infect Dis 2001;32:855-61., 406Respaldiza N, Medrano FJ, Medrano AC, et al. High seroprevalence of Pneumocystis infection in Spanish children. Clin Microbiol Infect 2004;10:1029-31., 407Pifer LL, Hughes WT, Stagno S, et al. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics 1978;61:35-41.). Immunocompetent infants with the infection are either asymptomatic or have mild respiratory symptoms. Pneumocystis pneumonia (PCP) occurs almost exclusively in the immunocompromised host. PCP remains a common AIDS-indicator disease among HIV-infected children. The highest incidence of PCP in HIV-infected children is in the first year of life, with cases peaking at age 3-6 months (408Simonds RJ, Oxtoby MJ, Caldwell MB, et al. Pneumocystis carinii pneumonia among US children with perinatally acquired HIV infection. JAMA 1993;270:470-3., 409Gibb DM, Davison CF, Holland FJ, et al. Pneumocystis carinii pneumonia in vertically acquired HIV infection in the British Isles. Arch Dis Child 1994;70:241-4., 410Williams AJ, Duong T, McNally LM, et al. Pneumocystis carinii pneumonia and cytomegalovirus infection in children with vertically acquired HIV infection. AIDS 2001;15:335-9.). Data from the CDC Pediatric Spectrum of Disease Project (1994-2001) indicate a decline in PCP infection rates (cases per 1000 HIV-infected children) from 25 in 1994 to 18 in 1996 to six in 2001 (1Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001;20:40-8., 411Morris A, Lundgren JD, Masur H, et al. Current epidemiology of Pneumocystis pneumonia. Emerg Infect Dis 2004;10:1713-20.). Similarly, analyses of data from the Perinatal AIDS Collaborative Transmission Study revealed a 95% decline in PCP (cases per 100 child-years) from 5.8 (pre-HAART era) to 0.3 (HAART era) (4Nesheim SR, Kapogiannis BG, Soe MM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics 2007;120:00 100–9.). Finally, the incidence rate of PCP (cases per 100 child-years) was 1.3 during the pre-HAART era (1981-1988) and <0.5 during the HAART era (2001-2004) (3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.). This decline probably resulted from implementation of interventions to prevent mother-to-child transmission of HIV, introduction of HAART in HIV-infected children in 1995, and chemoprophylaxis for PCP. PCP is a major cause of death among HIV-infected infants and children in Africa. Autopsies revealed PCP in 16% of children dying with HIV/AIDS during 1992 and 1993 (412Ikeogu MO, Wolf B, Mathe S. Pulmonary manifestations in HIV seropositivity and malnutrition in Zimbabwe. Arch Dis Child 1997;76:124-8.), in 29% of those dying during 1997 and 2000 (413Chintu C, Mudenda V, Lucas S, et al. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet 2002;360:985-90.), and in 44% of those dying during 2000 and 2001 (414Madhi SA, Cutland C, Ismail K, et al. Ineffectiveness of trimethoprim- sulfamethoxazole prophylaxis and the importance of bacterial and viral coinfections in African children with Pneumocystis carinii pneumonia. Clin Infect Dis 2002;35:1120-6.). The mode of transmission of Pneumocystis among HIV-infected infants, children, and adults is not firmly established, but airborne human-to-human transmission is likely. Animal studies show Pneumocystis is transmitted by air from infected to susceptible rats (415Hendley JO, Weller TH. Activation and transmission in rats of infection with Pneumocystis. Proc Soc Exp Biol Med 1971;137:1401-4., 416Hughes WT. Natural mode of acquisition for de novo infection with Pneumocystis carinii. J Infect Dis 1982;145:842-8.). Human-to-human transmission has been suggested by molecular epidemiology and global clustering of PCP cases in recent studies (417de Boer MG, Bruijnesteijn van Coppenraet LE, Gaasbeek A, et al. An outbreak of Pneumocystis jiroveci pneumonia with 1 predominant genotype among renal transplant recipients: interhuman transmission or a common environmental source? Clin Infect Dis 2007;44:1143-9., 418Hocker B, Wendt C, Nahimana A, et al. Molecular evidence of Pneumocystis transmission in pediatric transplant unit. Emerg Infect Dis 2005;11:330-2., 419Rabodonirina M, Vanhems P, Couray-Targe S, et al. Molecular evidence of interhuman transmission of Pneumocystis pneumonia among renal transplant recipients hospitalized with HIV-infected patients. Emerg Infect Dis 2004;10:1766-73.). Intrauterine transmission is considered rare. However, in one report, one of eight infants born to women who had AIDS and PCP during pregnancy had evidence of Pneumocystis infection (420Mortier E, Pouchot J, Bossi P, et al. Maternal-fetal transmission of Pneumocystis carinii in human immunodeficiency virus infection. N Engl J Med 1995;332:825.). The single most important factor in susceptibility of HIV-infected patients of all ages to PCP is the status of cellmediated immunity of the host. Severe compromise, reflected by a marked decrease in CD4 count and percentage, is the hallmark of high risk for PCP and is discussed further in the prevention section. |
| | Clinical Manifestations | | Prominent clinical features of PCP among HIV-infected children are fever, tachypnea, dyspnea, and cough. The severity of these signs and symptoms varies from child to child. Onset can be abrupt or insidious with nonspecific symptoms (e.g., mild cough, dyspnea, poor feeding, diarrhea, and weight loss). Some patients may not be febrile, but almost all will have tachypnea by the time pneumonitis is evident on chest radiograph. Physical examination sometimes shows bilateral basilar rales with evidence of respiratory distress and hypoxia. In HIV-infected children with pneumonia, four clinical variables are independently associated with PCP: age <6 months, respiratory rate >59 breaths per minute, arterial percentage hemoglobin saturation ≤92%, and the absence of vomiting (421Fatti GL, Zar HJ, Swingier GH. Clinical indicators of Pneumocystis jiroveci pneumonia (PCP) in South African children infected with the human immunodeficiency virus. Int J Infect Dis 2006;10:282-5.). A high plasma HIV RNA concentration strongly predicts PCP and other OIs (422Podlekareva D, Mocroft A, Dragsted UB, et al. Factors associated with the development of opportunistic infections in HIV-1-infected adults with high CD4+ cell counts: a EuroSIDA study. J Infect Dis 2006;194:633-41.). Extrapulmonary Pneumocystis organisms are found in <2.5% of HIV-infected adults and children (423Ng VI, Yajko DM, Hadley WK. Extrapulmonary pneumocystosis. Clin Microbiol Rev 1997;10:401-18., 424Chen A, Zaidi AK, Mueller BU, et al. Pneumocystis carinii presenting as a mediastinal mass in a child with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1999;18:827-31.). This can occur without concurrent PCP and can be located at multiple noncontiguous sites. Involved sites have included ear, eye, thyroid, spleen, GI tract, peritoneum, stomach, duodenum, small intestine, transverse colon, liver, and pancreas. Less frequently involved sites include adrenal glands, muscle, bone marrow, heart, kidney, ureter, lymph nodes, meninges, and cerebral cortex. |
| | Diagnosis | | Most children with PCP have substantial hypoxia with low arterial oxygen pressure and a PaO2 >30 mm Hg. The CD4 count is often <200 cells/mm3 and the CD4 percentage <15% in children aged >5 years. Lactic dehydrogenase is often increased, but this is not specific for PCP. Serum albumin may be depressed. Chest radiographs most commonly indicate bilateral diffuse parenchymal infiltrates with "ground-glass" or reticulogranular appearance, but they also can be normal or have only mild parenchymal infiltrates. The earliest infiltrates are perihilar, progressing peripherally before reaching the apical portions of the lung. Rarely, lobar, cavitary, nodular, or miliary lesions; pneumothorax; or pneumomediastinum are observed. A definitive diagnosis of PCP requires demonstration of the organism in pulmonary tissues or fluids in the presence of pneumonitis. Diagnostic procedures are the same as for adults suspected to have PCP (see Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults) (16CDC. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.), but some procedures may be more difficult to perform in children. Several procedures for collecting and staining specimens are available. Induced sputum analysis, during which the patient produces sputum after inhalation of nebulized 3% hypertonic saline, may be difficult among children aged <2 years because of small airways and poor ability to produce sputum. Complications from the procedure include nausea, vomiting, and bronchospasm. Sensitivity of sputum analysis in adults ranges from 25% to 90%. After a negative induced sputum sample, a bronchoalveolar lavage for definitive diagnosis may be necessary. Nasogastric aspirates, if positive, are of diagnostic value. Pneumocystis organisms were found in 48.6% of HIV-infected children with respiratory illnesses in whom gastric aspirates were obtained on three consecutive mornings (425Surve TY, Rathod AD. Role of nasogastric aspirate in HIV-positve children presenting with respiratory symptoms. J Trop Pediatr 2006;52:451-3.). Other studies have shown the organism is not found in gastric contents without PCP (426Chan H, Pifer L, Hughes WT, et al. Comparison of gastric contents to pulmonary aspirates for the cytologic diagnosis of Pneuomcystis carinii pneumonia. J Pediatr 1977;90:243-4.). Bronchoscopy with bronchoalveolar lavage is the diagnostic procedure of choice for most infants and children. Sensitivity ranges from 55% to 97% and may be positive for ≥72 hours after initiation of PCP treatment; treatment should not be delayed while awaiting results. Complications include hemoptysis, pneumothorax, transient increase in hypoxemia, a transient increase in pulmonary infiltrates at the lavage site, and postbronchoscopy fever. Fiberoptic bronchoscopy with transbronchial biopsy is recommended only when bronchoalveolar lavage is negative or nondiagnostic despite a clinical picture consistent with PCP. Sensitivity is 87%-95%, and cysts can be identified up to 10 days after initiation of treatment (up to 4-6 weeks in certain patients). Complications include pneumothorax and hemorrhage; this procedure is contraindicated in children with thrombocytopenia. Open-lung biopsy is the most sensitive and specific diagnostic technique, but because it requires thoracotomy and often chest tube drainage, is not recommended routinely. It has the advantage of revealing the type and extent of disease as well as the organism. Histopathology shows alveoli filled with eosinophilic, acellular, proteinaceous material that contains cysts and trophozoites but few inflammatory cells. Complications include pneumothorax, pneumomediastinum, and hemorrhage. Three types of stains can be used to identify Pneumocystis organisms in specimens. Gomori methenamine-silver method stains the cyst wall brown or black. Toluidine blue stains the cyst wall blue or lavender. Both methods stain fungal elements. Giemsa, Diff-Quick®, and Wright stains depict the trophozoites and intracystic sporozoites pale blue with a punctate red nucleus, but unlike other stains, these do not stain the cyst wall. Monoclonal immunofluorescent antibodies (Merifluor®, Meridian Bioscience, Inc., Cincinnati, OH) that stain the cyst wall also can be used for diagnosis and have enhanced specificity compared with the other methods. A cyst wall, trophozoite, and immunofluorescent antibody stain is recommended for each specimen studied. PCR assays to amplify the human Pneumocystis MSG gene, mitochondrial large subunit (mtlsu) rRNA, the dihydropteroate synthase gene, and the internal transcribed spacer region genes have been developed for diagnostic evaluation. These tests are usually more sensitive but less specific than microscopic methods and are not standardized or available in most centers (427Huang L, Morris A, Limper AH, et al. An Official ATS Workshop Summary: Recent advances and future directions in Pneumocystis pneumonia (PCP). Proc Am Thorac Soc 2006;3:655-64., 428Lebovitz E, Pollack H, Rigaud M, et al. Polymerase chain reaction is more sensitive than standard cytologic stains in detecting Pneumocystis carinii in bronchoalveolar lavages from human immunodeficiency virus type 1-infected infants and children with pneumonia. Pediatr Infect Dis J 1995;14:714-6.). Pneumocystis-specific DNA is found in 18% of bronchoalveolar lavage samples from patients without clinical PCP, HIV, and other infections (429Maskell NA, Waine DJ, Lindley A, et al. Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study. Thorax 2003;58:594-7.). Coinfection with other organisms (e.g., CMV or pneumococcus) has been reported in HIV-infected children (410Williams AJ, Duong T, McNally LM, et al. Pneumocystis carinii pneumonia and cytomegalovirus infection in children with vertically acquired HIV infection. AIDS 2001;15:335-9., 430Glatman-Freedman A, Ewig JM, Dobroszycki J, et al. Simultaneous Pneumocystis carinii and pneumococcal pneumonia in human immunodeficiency virus-infected children. J Pediatr 1998;132: 169-71., 431Jeena PM, Coovadia HM, Chrystal V. Pneumocystis carinii and cytomegalovirus infections in severely ill, HIV-infected African infants. Ann Trop Paediatr 1996;16:361-8.). Children with dual infections may have more severe disease. Although CMV in lung secretions of children with PCP indicates colonization, it usually does not require therapy. The presence of Pneumocystis is always an indication for treatment. |
| | Prevention Recommendations | | | | Preventing Exposure | | The need for isolation of hospitalized persons who have PCP has been neither demonstrated nor discounted. PCP patients
clearly do not need to be isolated from persons with normal immune responses and from immunocompromised high-risk
patients who are receiving PCP prophylaxis. Under unusual circumstances where prophylaxis cannot be administered,
avoid placement in the same room with an immucompromised patient (CIII). |
| | Preventing First Episode of Disease | | Chemoprophylaxis is highly effective in preventing PCP. Criteria for its use are based on the patient's age and CD4 count or percentage (AII). Prophylaxis is recommended for all HIV-infected children aged ≥6 years who have CD4 counts <200 cells/mm3 or CD4 <15%, for children aged 1-5 years with CD4 counts of <500 cells/mm3 or CD4 <15%, and for all HIV-infected infants aged <12 months regardless of CD4 count or percentage (432CDC. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus.). Infants born to HIV-infected mothers should be considered for prophylaxis beginning at 4-6 weeks of age. HIV-infected infants should be administered prophylaxis until 1 year of age, at which time they should be reassessed on the basis of the age-specific CD4 count or percentage thresholds mentioned above (AII). Infants with indeterminate HIV infection status should receive prophylaxis until they are determined to be HIV-uninfected or presumptively uninfected with HIV (AIII). Prophylaxis is not recommended for infants who meet criteria for definitively or presumptively HIV-uninfected. In nonbreast-feeding infants with no positive HIV virologic test results, presumptive exclusion of HIV infection can be based on two negative virologic test results: one obtained at ≥2 weeks and one obtained at ≥4 weeks of age, one negative virologic test result obtained at ≥8 weeks of age, or one negative HIVantibody test result obtained at ≥6 months of age. Definitive exclusion of HIV infection is based on two negative virologic test results: one obtained at ≥1 month of age and one obtained at ≥4 months of age, or on two negative HIV-antibody test results from separate specimens obtained at ≥6 months of age. For both presumptive and definitive exclusion of infection, the child should have no other laboratory (e.g., no positive virologic test results) or clinical (e.g., no AIDS-defining conditions) evidence of HIV infection. Four drug regimens have been found effective and relatively safe for preventing PCP in high-risk HIV-infected children
and adults. Trimethoprim-sulfamethoxazole (TMP-SMX) (Cotrimoxazole) is the drug of choice for prophylaxis because of its high
efficacy, relative safety, low cost, and broad antimicrobial spectrum (AI). TMP alone has little, if any, anti-Pneumocystis activity, but it enhances the activity of the sulfonamide. The prophylactic dosage is 150 mg/m2 body surface area/day TMP and 750 mg/m2 body surface area/day SMX (approximately 5.0 mg/kg/day TMP and 25 mg/kg/day SMX) administered orally in equally divided doses twice a day on 3 consecutive days per week (433Hughes WT, Rivera GK, Schell MJ, et al. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1987;316:1627-32.). The total daily dose should not exceed 320 mg TMP and 1600 mg SMX. For patients with impaired renal function, a reduced dose may be necessary. Alternatively, TMP-SMX can be administered daily 7 days a week (AI) (434Hughes WT, Kuhn S, Chaudhary S, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1977;297:1419-26.). TMP-SMX also is effective in preventing toxoplasmosis (435Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim- sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992;117:106-11.) and some bacterial infections (e.g., Salmonella, Haemophilus, Staphylococcus) (434Hughes WT, Kuhn S, Chaudhary S, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1977;297:1419-26., 436Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995;332:693-9., 437Hardy WD, Feinberg J, Finkelstein DM, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. N Engl J Med 1992;327:1842-8., 438Dworkin MS, Williamson J, Jones JL, et al. Prophylaxis with trimethoprim-sulfamethoxazole for human immunodeficiency virusinfected patients: impact on risk for infectious diseases. Clin Infect Dis 2001;33:393-8.). Dihydropteroate synthase gene mutations in Pneumocystis from humans have been observed with TMP-SMX and dapsone
prophylaxis, suggestive of possible drug resistance, but studies for clinical correlates have not provided conclusive
results (427Huang L, Morris A, Limper AH, et al. An Official ATS Workshop Summary: Recent advances and future directions in Pneumocystis pneumonia (PCP). Proc Am Thorac Soc 2006;3:655-64.). More apparent is the association of prolonged TMP-SMX prophylaxis for PCP with the emergence of selective
pressure resistance of clinically important bacterial species to TMP-SMX, a point to be considered in managing bacterial
infections in patients receiving prophylaxis (439Martin JN, Rose DA, Hadley WK, et al. Emergence of trimethoprim- sulfamethoxazole resistance in the AIDS era. J Infect Dis 1999;180: 1809-18., 440Huovinen P. Resistance to trimethoprim-sulfamethoxazole. Clin Infect Dis 2001;32:1608-14.). Other effective and safe prophylaxis regimens are available for patients unable to take TMP-SMX. A second choice would
be either atovaquone or dapsone (BI) (441El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. N Engl J Med 1998;339:1889-95.). Atovaquone
is effective and safe but expensive. Dapsone is effective and inexpensive but associated with more serious adverse effects
than atovaquone. Atovaquone is administered with a meal as an oral yellow suspension in single dosage of 30 mg/kg/day for patients 1-3
months and >24 months of age, and 45 mg/kg/day for infants aged 4-24 months (442Hughes WT. Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review. Clin Infect Dis 1998;27: 191-204.). Unlike TMP-SMX, atovaquone has no antibacterial activity but is effective against Toxoplasma gondii. Azithromycin, in a single dosage of 5.0 mg/kg/day
has been used to supplement atovaquone for greater broadspectrum prophylaxis. The randomized, double-blind, placebocontrolled
study PACTG 254 compared TMP-SMX and atovaquone plus azithromycin for 3 years (median) in 366 HIV-infected children qualifying for PCP prophylaxis (95Hughes WT, Dankner WM, Yogev R, et al. Comparison of atovaquone and azithromycin with trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection. Clin Infect Dis 2005;40:136-45.). Results showed atovaquone-azithromycin to be as effective as TMP-SMX for preventing serious bacterial infections, as well as PCP. Dapsone can be administered on a daily or weekly schedule as 2.0 mg/kg/day (maximum total dosage of 100 mg/day) or
4.0 mg/kg/week (maximum total dosage of 200 mg/week) orally. Approximately two thirds of patients intolerant to TMPSMX
can take dapsone successfully. Studies in adults show dapsone is as effective as atovaquone or aerosolized pentamidine
but slightly less effective than TMP-SMX (441El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. N Engl J Med 1998;339:1889-95., 442Hughes WT. Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review. Clin Infect Dis 1998;27: 191-204.). Aerosolized pentamidine is recommended for children who cannot take TMP-SMX, atovaquone, or dapsone and are old
enough to use nebulization with a Respirgard II® nebulizer (Marquest, Englewood, CO) (BI). The dosage for all ages is 300 mg once a month (437Hardy WD, Feinberg J, Finkelstein DM, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. N Engl J Med 1992;327:1842-8.). Adverse reactions among HIV-infected children include cough, sneezing, and bronchospasm
(443Principi N, Marchisio P, Onorato J, et al. Long-term administration of aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia in infants and children with symptomatic human immunodeficiency virus infection. The Italian Pediatric Collaborative Study Group on Pentamidine. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12:158-63.). Pyrimethamine-sulfadoxine (Fansidar®) also is recognized as an effective prophylaxis regimen in adults (CIII). Although this drug was effective in preventing PCP in Iranian orphanages in the 1960s, it has not been evaluated adequately among HIV-infected children. The use of IV pentamidine is not recommended for prophylaxis (EIII) (444Milstone AM, Balakrishnan SL, Foster CB, et al. Failure of intravenous pentamidine prophylaxis to prevent Pneumocystis pneumonia in a pediatric hematopoietic stem cell transplant (HSCT) patient. Pediatr Blood Cancer 2006;47:859-60.). |
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| | Discontinuing Primary Prophylaxis | | Studies of HIV-infected adults and children following immune reconstitution after receipt of HAART demonstrate acceptable low risks for PCP after discontinuation of prophylaxis (46Nachman S, Gona P, Dankner W, et al. The rate of serious bacterial infections among HIV-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis. Pediatrics 2005;115:e488-94., 445Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med 1999;340:1301-6., 446Schneider MM, Borleffs JC, Stolk RP, et al. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy. Lancet 1999;353:201-3., 447Dworkin MS, Hanson DL, Kaplan JE, et al. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis 2000;182:611-5., 448Ledergerber B, Mocroft A, Reiss P, et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. N Engl J Med 2001;344:168-74., 449Lopez Bernaldo de Quiros JC, Miro JM, Pena JM, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98. N Engl J Med 2001;344:159-67.). Data from the PACTG 1008 study evaluated 235 HIV-infected children and adolescents on antiretroviral therapy who received PCP prophylaxis ≥6 months and achieved CD4 percentages of ≥20% for patients aged >6 years and ≥25% for patients aged 2-6 years, after which the prophylaxis was stopped (46Nachman S, Gona P, Dankner W, et al. The rate of serious bacterial infections among HIV-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis. Pediatrics 2005;115:e488-94.). During the median follow-up of 2.5 years (547 person-years), no cases of PCP occurred; 9.4% of patients enrolled required reinstitution of PCP prophylaxis during observation. These data, along with data from studies in adults, support the expectation for very low risk for PCP after prophylaxis is discontinued in children who have achieved immune reconstitution. Discontinuation of PCP prophylaxis should be considered for HIV-infected children when, after receiving HAART for ≥6 months, CD4 percentage is ≥15% or CD4 count is ≥200 cells/mm3 for patients aged >6 years (BII) and CD4 percentage is ≥15% or CD4 count is ≥500 cells/mm3 for patients aged 1-5 years (BII) for >3 consecutive months. Subsequently, the CD4 percentage and count should be reevaluated at least every 3 months and prophylaxis reinstituted if the original criteria for prophylaxis are reached (BIII). PCP prophylaxis is not to be discontinued in HIV-infected infants aged <1 year. |
| | Treatment Recommendations | | | | Treatment of Disease | | TMP-SMX is the recommended treatment for PCP (AI).
The dose for HIV-infected children aged >2 months is 15-20 mg/kg/day of the TMP component and 75-100 mg/kg/day
of the SMX component administered intravenously in 3 or 4 divided doses, with the dose infused over 1 hour for 21 days
(AI). As the acute pneumonitis subsides, children with mild
to moderate disease who do not have malabsorption or diarrhea can be administered oral treatment with the same dose of TMP-SMX in 3 or 4 divided doses to complete a 21-day course (AII). Effective therapeutic serum concentrations of 5-10 µg/mL TMP can be reached with the recommended dose administered orally in HIV-infected children (450Zar JH, Langdon G, Apolles P, et al. Oral trimethoprim- sulphamethoxazole levels in stable HIV-infected children. S Afr Med J 2006;96:627-9.). IV pentamidine isethionate once daily is recommended for patients who cannot tolerate TMP-SMX or who demonstrate
clinical treatment failure after 5-7 days of TMP-SMX therapy (AI). No evidence exists for synergistic or additive effects on efficacy of these agents; therefore, because of potential increased
toxicity, their combined use is not recommended (DIII).
Among patients with clinical improvement after 7-10 days of IV therapy with pentamidine, an oral regimen (e.g., atovaquone
or TMP/dapsone) might be considered to complete a 21-day course (BIII). Atovaquone is an alternative for treatment of mild to moderately severe PCP in adults (BI) (95Hughes WT, Dankner WM, Yogev R, et al. Comparison of atovaquone and azithromycin with trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection. Clin Infect Dis 2005;40:136-45.). Therapeutic data are limited for children, but the dosage of 30-40 mg/kg/day in two divided doses administered orally is established for children <3 months and ≥24 months of age. Children aged 3-24 months require a higher dosage of 45 mg/kg/day (AII) (442Hughes WT. Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review. Clin Infect Dis 1998;27: 191-204.). The dosage for adolescents and adults is 750 mg twice daily. Food increases the bioavailability of atovaquone approximately threefold compared with that achieved with the fasting state. Atovaquone concentration increases with coadministration of fluconazole and prednisone and decreased by coadministration with acyclovir, opiates, cephalosporins, rifampin, and benzodiazepines. Dapsone/TMP is effective in treating mild to moderate PCP among adults (BI) (451Leoung GS, Mills J, Hopewell PC, et al. Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 1986;105:45-8.); data on toxicity and efficacy among children are limited. The dosage of dapsone for adolescents
and adults is 100 mg (total dose) orally once daily and TMP 15 mg/kg/day divided into three daily doses administered for
21 days. Among children aged <13 years, a dapsone dosage of 2 mg/kg/day is required to achieve therapeutic levels in children
(AII) (452Mirochnick M, Cooper E, McIntosh K, et al. Pharmacokinetics of dapsone administered daily and weekly in human immunodeficiency virusinfected children. Antimicrob Agents Chemother 1999;43:2586-91.). The pediatric dose of TMP is 15 mg/kg/day divided into three daily doses. Dapsone is less effective than the combination (453Mills J, Leoung G, Medina I, et al. Dapsone treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1988;32:1057-60.). Clindamycin/primaquine has been used to treat mild to moderate PCP among adults (BI); data for children are not available (CIII). Primaquine is contraindicated for patients with glucose-6-dehydrogenase deficiency because of the possibility of inducing hemolytic anemia. Dose information for treating PCP is available only for adults. For patients weighing >60 kg, clindamycin 600 mg intravenously every 6 hours for 10 days, then 300-450 mg orally every 6 hours to complete 21 days of treatment is recommended. Primaquine is administered as 30 mg of base orally for 21 days. Dosing for children is based on use of these drugs for treating other infections: the usual pediatric dose of clindamycin for treating bacterial infection is 10 mg/kg/dose every 6 hours, and the pediatric dose of primaquine equivalent to an adult dose of 20 mg base (when used for malaria) is 0.3 mg/kg/day of the base. On the basis of studies in adults, a short course of corticosteroids is recommended in cases of moderate or severe PCP,
starting within 72 hours of diagnosis (AI). Pediatric studies
have indicated reduced acute respiratory failure, decreased need for ventilation, and decreased mortality with early use
of corticosteroids in HIV-infected children who have PCP (454Sleasman JW, Hemenway C, Klein AS, et al. Corticosteroids improve survival of children with AIDS and Pneumocystis carinii pneumonia. Am J Dis Child 1993;147:30-4., 455Bye MR, Cairns-Bazarian AM, Ewig JM. Markedly reduced mortality associated with corticosteroid therapy of Pneumocystis carinii pneumonia in children with acquired immunodeficiency syndrome. Arch Pediatr Adolesc Med 1994;148:638-41., 456McLaughlin GE, Virdee SS, Schleien CL, et al. Effect of corticosteroids on survival of children with acquired immunodeficiency syndrome and Pneumocystis carinii-related respiratory failure. J Pediatr 1995;126 (5 Pt 1):821-4.). Indications for corticosteroid treatment include a PaO2 value of <70 mm Hg or an alveolar-arterial gradient of >35 mm Hg. Doses for children vary between studies. A commonly used scheme is prednisone on days 1-5, 1 mg/kg/dose twice daily; days 6-10, 0.5 mg/kg/dose twice daily; and days
11-21, 0.5 mg/kg once daily. Alternative regimens include 1) adult dosage prednisone on days 1-5, 40 mg twice daily; days
6-10, 40 mg once daily; days 11-21, 20 mg once daily; and 2) methylprednisolone (IV) on days 1-7, 1 mg/kg/dose every
6 hours; days 8-9, 1 mg/kg/dose twice daily; days 10 and 11, 0.5 mg/kg/dose twice daily; days 12-16, 1 mg/kg once daily. Some case reports have documented improved pulmonary function with use of surfactant in cases of severe disease (e.g.,
respiratory distress syndrome with established respiratory failure requiring ventilation) (457Creery WE, Hashmi A, Hutchison JS, et al. Surfactant therapy improves pulmonary function in infants with Pneumocystis carinii pneumonia and acquired immunodeficiency syndrome. Pediatr Pulmonol 1997;24: 370-3., 458Marriage S, Underhill H, Nadel S. Use of natural surfactant in an HIV-infected infant with Pneumocystis carinii pneumonia. Intensive Care Med 1995;22:611-2., 459Slater A, Nichani SH, Macrae D, et al. Surfactant adjunctive therapy for Pneumocystis carinii pneumonitis in an infant with acute lymphoblastic leukaemia. Intensive Care Med 1995;21:261-3.). Alterations in surfactant
function and composition have been demonstrated in HIV-infected adults with PCP (460Schmidt R, Markart P, Ruppert C, et al. Pulmonary surfactant in patients with Pneumocystis pneumonia and acquired immunodeficiency syndrome. Crit Care med 2006;34:2370-6.). Data are insufficient to
recommend surfactant administration for PCP. |
|
| | Monitoring and Adverse Events, Including IRIS | | Clinical parameters to monitor the status of disease include temperature, respiratory rate, arterial oxygen saturation, and chest radiograph (461Datta D, Ali SA, Henken EM, et al. Pneumocystis carinii pneumonia: the time course of clinical and radiographic improvement. Chest 2003;124:1820-3.). Clinical improvement can be expected at a mean of approximately 4.5 + 2.5 days and radiographic improvement at approximately 7.7 + 4.5 days (461Datta D, Ali SA, Henken EM, et al. Pneumocystis carinii pneumonia: the time course of clinical and radiographic improvement. Chest 2003;124:1820-3.). IRIS has been less frequently associated with Pneumocystis infection (2% of 44 adults with IRIS) than with several other OIs in HIV-infected adults and children (462Ratnam I, Chiu C, Kandala NB, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clin Infect Dis 2006;42:418-27.). Whether this low rate is related to PCP prophylaxis is not known. In children, adverse reactions to TMP-SMX include rash (mild maculopapular in most cases but rarely erythema multiforme and Stevens-Johnson syndrome), hematologic abnormalities (e.g., neutropenia, thrombocytopenia, megaloblastic or aplastic anemia), GI complaints (usually mild), hepatitis, and renal disorders (e.g., interstitial nephritis) (463Gutman LT. The use of trimethoprim-sulfamethoxazole in children: a review of adverse reactions and indications. Pediatr Infect Dis J 1984;3:349-57., 464Rieder MJ, King SM, Read S. Adverse reactions to trimethoprim- sulfamethoxazole among children with human immunodeficiency virus infection. Pediatr Infect Dis J 1997;16:1028-31.). Data from a PACTG study of HIV-infected children at high risk for PCP receiving TMP-SMX for a median of 3 years showed 28% had a rash, 9.3% had neutropenia, 8.8% had thrombocytopenia, and 2.2% had anemia (95Hughes WT, Dankner WM, Yogev R, et al. Comparison of atovaquone and azithromycin with trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection. Clin Infect Dis 2005;40:136-45.). None were fatal or nonreversible reactions. Some very mild reactions will resolve while the drug is continued. With any significant adverse effect, TMP-SMX should be withheld until the reaction has subsided. Unless the reaction has been life-threatening, TMP-SMX prophylaxis can be resumed, preferably by beginning with low desensitizing daily doses and gradually increasing to full doses (BII) (465Para MF, Finkelstein D, Becker S, et al. Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268. J Acquir Immune Defic Syndr 2000;24:337-43., 466Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim- sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis 2001;184:992-7.). In adults, 75% of patients affected tolerate rechallenge with TMP-SMX (466Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim- sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis 2001;184:992-7.). The overall frequency of adverse reactions appears to be lower among HIV-infected children than among adults; approximately 15% of children have substantial adverse reactions to TMP-SMX (446Schneider MM, Borleffs JC, Stolk RP, et al. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy. Lancet 1999;353:201-3.). If an urticarial rash or Stevens-Johnson syndrome occurs, TMPSMX should be discontinued and not readministered (EIII). The most common adverse drug reaction to pentamidine isethionate is renal toxicity, which usually occurs after 2 weeks of therapy and can be averted by adequate hydration and careful monitoring of renal function and electrolytes. Severe hypotension (particularly if infused rapidly), prolonged QT interval (torsades de pointes), and cardiac arrhythmias can occur. Hypoglycemia (usually after 5-7 days of therapy) or hyperglycemia, hypercalcemia, hyperkalemia, pancreatitis, and insulin-dependent diabetes mellitus also have been reported. The patient may experience a metallic or bitter taste. Serious adverse reactions to pentamidine have been reported in approximately 17% of children receiving the drug (467Goodwin SD. Pneumocystis carinii pneumonia in human immunodeficiency virus-infected infants and children. Pharmacotherapy 1993;13: 640-6.). This drug should not be administered with other nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, cisplatin, or vancomycin) and with agents associated with pancreatitis (e.g., didanosine). With dapsone and TMP, the primary adverse reaction is reversible neutropenia; other reactions include skin rashes, elevated serum transaminases, methemaglobinemia, anemia, and thrombocytopenia (451Leoung GS, Mills J, Hopewell PC, et al. Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 1986;105:45-8., 453Mills J, Leoung G, Medina I, et al. Dapsone treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1988;32:1057-60.). Dapsone is the problematic component of the combination and accounts for most of the adverse reactions (442Hughes WT. Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review. Clin Infect Dis 1998;27: 191-204.). Skin rashes (10%-15%), nausea, and diarrhea can occur with atovaquone administration. Liver enzymes may increase briefly. No serious toxicity or fatality has been demonstrated from the use of atovaquone in adults or children. Adverse reactions to clindamycin/primaquine include skin rash, nausea, and diarrhea. |
| | Management of Treatment Failure | | An inflammatory reaction to antibiotic-induced killing of the organism in the lungs can result in an initial early and reversible deterioration during the first 3-5 days of therapy, so an adequate trial of therapy is needed before switching drugs because of lack of clinical improvement. Clinical failure is defined by lack of improvement or worsening of respiratory function documented by arterial blood gases after at least 4-8 days of anti-PCP treatment. Other concomitant infections need to be excluded as causees of clinical failure. With evidence of treatment failure after the use of TMP-SMX, drugs can be changed. If tolerated, pentamidine isethionate is the drug of next choice (BII). No evidence exists for synergistic or additive therapeutic effects; therefore, because of potential increased toxicity, their combination is not recommended. |
| | Prevention of Recurrence | | None of the drugs administered to treat and prevent PCP completely eliminates Pneumocystis, and prophylaxis is effective
only while the selected drug is administered. Patients who have experienced an episode of PCP should have prophylaxis administered
continuously after completion of treatment (AI). |
| | Prophylaxis to prevent first episode of opportunistic infections among HIV-exposed and HIV-infected infants and children, United States*†: Pneumocystis pneumonia§ | | | Preventive regimen |
|---|
Excerpted from Table 1 * Abbreviations: HIV = human immunodeficiency virus; PCP = Pneumocystis pneumonia; TMP-SMX = trimethoprim-sulfamethoxazole; TST = tuberculin skin test; TB = tuberculosis; IM = intramuscularly; IVIG = intravenous immune globulin; IgG = immunoglobulin G; CMV = cytomegalovirus; VZV = varicella-zoster virus; FDA = Food and Drug Administration. † Information in these guidelines might not represent FDA approval or FDA-approved labeling for products or indications. Specifically, the terms “safe” and “effective” might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendation and the quality of the evidence supporting it (see Box). §§ Daily trimethoprim-sulfamethoxazole (TMP-SMX) reduces the frequency of certain bacterial infections. TMP-SMX, dapsone-pyrimethamine, and possibly atovaquone (with or without pyrimethamine) protect against toxoplasmosis; however, data have not been prospectively collected. Compared with weekly dapsone, daily dapsone is associated with lower incidence of PCP but higher hematologic toxicity and mortality. Patients receiving therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected against PCP and do not need TMP-SMX. ¶ Substantial drug interactions can occur between rifamycins (i.e., rifampin and rifabutin) and protease inhibitors and non-nucleoside reverse transcriptase inhibitors. A specialist should be consulted. ** Children routinely being administered intravenous immune globulin (IVIG) should receive VariZIG if the last dose of IVIG was administered >21 days before exposure. †† As of 2007, VariZIG can be obtained only under a treatment Investigational New Drug protocol (1-800-843-7477, FFF Enterprises, Temecula, California.) §§ Protection against toxoplasmosis is provided by the preferred anti-Pneumocystis regimens and possibly by atovaquone. | | Strongly recommended as standard of care | | HIV-infected or HIV- indeterminate infants aged 1-12 mos; HIV-infected children aged 1-5 yrs with CD4 count of <500 cells/mm3 or CD4 percentage of <15%; HIV-infected children aged 6-12 yrs with CD4 count of <200 cells/mm3 or CD4 percentage of <15% | |  | TMP-SMX, 150/750 mg/m2 body surface area per day (max: 320/1600 mg) orally divided into 2 doses daily and administered 3 times weekly on consecutive days (AI) | |
| | Acceptable alternative dosage schedules for same dose (AI): single dose orally 3 times weekly on consecutive days; 2 divided doses orally daily; or 2 divided doses orally 3 times weekly on alternate days | |
| | | Dapsone: children aged ≥1 mo, 2 mg/kg body weight (max 100 mg) orally daily; or 4 mg/kg body weight (max 200 mg) orally weekly (BI) | |
| | Atovaquone: children aged 1-3 mos and >24 mos,
30 mg/kg body weight orally daily; children aged
4-24 mos, 45 mg/kg body weight orally daily (BI) | |
| | Aerosolized pentamidine: children aged ≥5 yrs,
300 mg every mo by Respirgard II™ (Marquest,
Englewood, CO) nebulizer (BI) | |
|
|
| | Prophylaxis to prevent recurrence of opportunistic infections, after chemotherapy for acute disease, among HIV-exposed and HIV-infected infants and children, United States*†: Pneumocystis pneumonia§ | | | Preventive regimen |
|---|
Excerpted from Table 2 * Information in these guidelines might not represent FDA approval or FDA-approved labeling for products or indications. Specifically, the terms “safe”and “effective” might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations
and the quality of evidence supporting it (see Box). † Abbreviations: HIV—human immunodeficiency virus; FDA—Food and Drug Administration; PCP—Pneumocystis pneumonia; TMP-SMX—trimethoprim-sulfamethoxazole; HAART—highly active antiretroviral treatment; IV—intravenous; IVIG—intravenous immune globulin. §§ Pyrimethamine plus sulfadiazine, and possibly atovaquone, confers protection against PCP as well as against toxoplasmosis. Although the clindamycin-plus-pyrimethamine or atovaquone-with/without-pyrimethamine regimens are recommended for adults, they have not been tested in children. However, these drugs are safe and are used for other infections in children. ¶ Substantial drug interactions might occur between rifabutin and protease inhibitors and non-nucleoside reverse transcriptase inhibitors. A specialist should be consulted. ** Antimicrobial prophylaxis should be chosen on the basis of microorganism identification and antibiotic susceptibility testing. TMP-SMX, if used, should be administered daily. Health-care providers should be cautious about using antibiotics solely for this purpose because of the potential for development of drug-resistant microorganisms. IVIG might not provide additional benefit to children receiving daily TMP/SMX but might be considered for children who have recurrent bacterial infections despite TMP-SMX prophylaxis. Choice of antibiotic prophylaxis versus IVIG also should involve consideration of adherence, ease of IV access, and cost. If IVIG is used, respiratory syncytial virus (RSV) IVIG (750 mg/kg body weight), not monoclonal RSV antibody, can be substituted for IVIG during the RSV season to provide broad anti-infective protection, if this product is available. | | Recommended as standard of care after completion of initial therapy | | Prior PCP | TMP-SMX, 150/750 mg/m2 body surface area daily (max: 320/1600 mg) orally divided into 2 doses and administered 3 times weekly on consecutive days (AI) Acceptable alternative dosage schedules for same dosage: single dose orally 3 times
weekly on consecutive days; 2 divided doses orally daily; or 2 divided doses orally 3 times
weekly on alternate days (AI) | Dapsone: children aged ≥1 mos, 2 mg/kg body weight (max 100 mg) orally daily or 4 mg/kg body weight (max 200 mg) orally weekly (BI) Atovaquone: children aged 1-3 mos and >24 mos, 30 mg/kg body weight orally daily;
children aged 4-24 mos, 45 mg/kg body weight orally daily (BI) Aerosolized pentamidine: children aged ≥5 yrs, 300 mg every mo by Respirgard II™ (Marquest,Englewood, CO) nebulizer (BI) |
|
| | Criteria for discontinuing and restarting prophylaxis for opportunistic infections among HIV-exposed and HIV-infected infants and children, United States*: Pneumocystis pneumonia | | |
| | Recommendations for treatment of opportunistic infections in HIV-exposed and HIV-infected infants and children, United States*†: Pneumocystis pneumonia | | | Preferred therapies and duration | Alternative therapies | Other options or issues |
|---|
Excerpted from Table 4 * HIV=human immunodeficiency virus; PCP=Pneumocystis pneumonia; TB=tuberculosis; IV=intravenous; IV=intravenous; IM=intramuscularly; CSF=cerebrospinal fluid;CNS=central nervous system; TMP/SMX=trimethoprim-sulfamethoxazole; HAART=highly active antiretroviral therapy; CMV=cytomegalovirus. HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HCV=hepatitis C virus; IRIS=immune reconstitution inflammatory syndrome; PCR=polymerase chain reaction; HSV=herpes simplex virus; HPV=human papillomavirus † Information in these guidelines might not represent Food and Drug Administration (FDA) approval or approved labeling for products or indications. Specifically, the terms safe and effective might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box). | TMP-SMX, 15-20 mg/kg body weight TMP; PLUS 75-100 mg/kg body weight SMX daily IV or orally in 3-4 divided doses (AI) (after acute pneumonitis resolved in mild to moderate disease, IV TMP-SMX may be changed to oral) Treatment duration (followed by chronic suppressive therapy): 21 days (AII) | Alternative therapeutic regimens (if patient is TMP-SMX intolerant or clinical treatment fails after 5-7 days of TMP-SMX therapy): | | Pentamidine, 4 mg/kg body weight IV once daily is first choice alternative regimen (AI) (pentamidine may be changed to atovaquone after 7-10 days IV therapy (BIII) | |
| | Atovaquone, 30-40 mg/kg body weight (max 1500 mg/day) daily orally in 2 divided doses with food for patients from birth to 3 mos and ≥24 mos of age (BI). For infants aged 3-24 mos, an increased dose of 45 mg/kg body weight daily in 2 divided doses with food is needed (AII) | |
| Dapsone, 2 mg/kg body weight orally once daily (max 100 mg/day) PLUS TMP, 15 mg/kg body weight orally per day divided into 3 doses has been used in adults (BI), but data in children are limited (CIII). Primaquine base, 0.3 mg/kg body weight orally once daily (max 30 mg/day), PLUS clindamycin, 10 mg/kg body weight IV or orally
(max 600 mg IV and 300 - 450 mg orally) every 6 hrs has been used in adults (BI), but data in children are not available (CIII). Indications for corticosteroids (AI): | | PaO2 <70 mmHg at room air or alveolar-arterial oxygen gradient >35 mm Hg. | |
| | Prednisone dose: 1 mg/kg body weight orally twice daily for 5 days, then 0.5-1.0 mg/kg body weight orally twice daily for 5 days, then 0.5 mg/kg body weight orally once daily for days 11-21. | |
Chronic suppressive therapy (secondary prophylaxis) with TMP/SMX is recommended for children and adults after initial therapy (Table 2) (AI). |
|
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