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1995 Revised Guidelines for Prophylaxis Against Pneumocystis carinii Pneumonia for Children Infected with or Perinatally Exposed to Human Immunodeficiency Virus

Date: April 28, 1995
Source: Centers for Disease Control and Prevention (CDC)

Summary
Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection in children who have acquired immunodeficiency syndrome (AIDS). Despite the publication of guidelines for prophylaxis against PCP for children infected with human immunodeficiency virus (HIV) in 1991 (1), ongoing AIDS surveillance has detected no substantial decrease in PCP incidence among HIV-infected infants. Studies indicate that this continued incidence is associated with failure to identify HIV-infected children before PCP occurs and with limitations in the ability of CD4+ measurements to identify children at risk for PCP. In March 1994, the National Pediatric & Family HIV Resource Center,* in collaboration with CDC, convened a working group to review additional data about the occurrence of PCP among HIV-infected children and to reevaluate the 1991 PCP prophylaxis guidelines for children. This report summarizes these new data and presents revised PCP prevention guidelines that recommend a) promptly identifying children born to HIV-infected women and initiating regular diagnostic and immunologic monitoring of such children; b) beginning PCP prophylaxis at 4-6 weeks of age for all children who have been perinatally exposed to HIV; c) continuing prophylaxis through 12 months of age for HIV-infected children; and d) making decisions regarding prophylaxis for HIV-infected children greater than or equal to 12 months of age based on CD4+ measurements and whether PCP previously has occurred.
INTRODUCTION
In 1991, guidelines for prophylaxis against Pneumocystis carinii pneumonia (PCP) for children infected with human immunodeficiency virus (HIV) were developed by a working group convened by the National Pediatric & Family HIV Resource Center (1). These guidelines addressed the need for prompt identification of infants born to HIV-infected women (i.e., HIV-exposed infants), measurement of such infants' CD4+ T-lymphocyte counts (CD4+ counts) and percentage of total lymphocytes (CD4+ percentage) first upon identification and then serially thereafter, and initiation of PCP prophylaxis based on age-associated CD4+ measurement values. In addition, the guidelines recommended that all children who had had a previous episode of PCP be maintained on prophylaxis, regardless of their CD4+ measurement values.
Since publication of these guidelines, additional data have been collected that address a) the specificity and sensitivity of CD4+ count thresholds for indicating risk for PCP, b) changes in CD4+ counts preceding an episode of PCP, c) correlation of CD4+ counts with CD4+ percentages, d) medications used for prophylaxis, and e) factors underlying the continued incidence of PCP among children. In March 1994, the National Pediatric & Family HIV Resource Center, in collaboration with CDC, convened a working group to review this new information and to reevaluate the 1991 PCP prophylaxis guidelines for children. This report summarizes that information and presents the group's recommendations for PCP prophylaxis for children less than 13 years of age.
BACKGROUND
Identification of Children at Risk for PCP Among children with perinatally acquired HIV infection, PCP occurs most often in infants 3-6 months of age (2). PCP in infants (i.e., children less than 12 months of age) is often acute in onset and results in a poor prognosis. Effective prevention of PCP among HIV-infected infants requires that exposure to HIV be identified either before or immediately following birth so that prophylaxis can be initiated before 2 months of age (the age at which the risk for PCP begins to increase dramatically) (2). The recent demonstration of the efficacy of zidovudine in lowering the rate of perinatal HIV transmission emphasizes the importance of identifying pregnant women with HIV infection as early as possible (3). Thus, through prenatal HIV counseling and voluntary testing, pregnant women who are infected with HIV can be offered interventions to a) maintain or improve their own health, b) reduce the risk for transmitting HIV infection to their children, and c) prevent PCP in their children if they also become infected.
At present, however, many HIV-exposed children are not identified early enough to be offered prophylaxis before the period of highest risk for PCP. Studies have indicated that only 35%-55% of HIV-exposed children have been identified by their health-care providers (4-6). A study of HIV-infected children diagnosed with PCP in the United States during 1991-1993 indicated that 59% of the children who had not received prophylaxis had not been identified as being at risk for HIV infection soon enough for prophylaxis to be initiated (7). Failure to identify and evaluate pregnant women with HIV infection and HIV-exposed children by early infancy substantially limits the effectiveness of any PCP prophylaxis strategy in preventing PCP among HIV-infected children.
CD4+ Count and PCP Among HIV-Infected Children
Data available when the 1991 prophylaxis guidelines were published indicated that approximately 10% of children diagnosed with PCP at less than 12 months of age had CD4+ counts of greater than or equal to 1,500 cells/uL, the threshold for prophylaxis in this age group as defined in the 1991 guidelines. Recently published data, however, suggest that this percentage may be even higher among HIV-infected infants diagnosed with PCP at less than or equal to 6 months of age, the age at which most cases of PCP occur (7-9). Moreover, CD4+ counts can drop rapidly in infants during the few months preceding PCP diagnosis. For example, in one study of children with PCP, 26% of children less than 6 months of age had CD4+ counts of greater than or equal to 1,500 cells/uL at the time of PCP diagnosis (Table 1) (7). In the same study, among 129 infants less than 1 year of age who had CD4+ counts measured before or at the time of PCP diagnosis, the estimated decline of CD4+ counts during the 3 months preceding the PCP diagnosis was 967 cells/uL (95% confidence interval=724-1,210 cells/uL) (7). Because HIV-infected infants less than 1 year of age are at risk for PCP even with CD4+ counts of greater than or equal to 1,500 cells/uL and because these infants might have counts that drop to this level or lower between measurements, the usefulness of CD4+ counts in determining the need for prophylaxis among infants in this age group is limited.
Few data are available regarding CD4+ counts at the time of PCP diagnosis for children greater than 1 year of age. In three previously published studies of children who had PCP, one (5%) of 18 children 1-5 years of age had a CD4+ count of greater than or equal to 500 cells/uL, and two (22%) of nine children 6-12 years of age had counts of greater than or equal to 200 cells/uL (10-12). In a recent study, three (16%) of 19 children 1-5 years of age had CD4+ counts of greater than or equal to 500 cells/uL at the time of PCP diagnosis; each of these three children had CD4+ counts that declined rapidly at approximately the time of PCP diagnosis (Table 1) (7). Also, all seven of the children greater than or equal to 6 years of age who developed PCP had CD4+ counts of less than 200 cells/uL (Table 1).
Correlation of CD4+ Counts with CD4+ Percentages
Measurements of CD4+ percentages may be subject to less variation than those of CD4+ counts (13); thus, some clinicians prefer using CD4+ percentage to monitor immunosuppression in HIV-infected children. In the 1991 guidelines (1), the prophylaxis threshold of less than 20% that had been recommended previously for adolescents and adults (14) was also recommended for children. However, the potentially low sensitivity of this threshold for the risk for PCP among young children was recognized. Recently revised recommendations for PCP prophylaxis among adolescents and adults no longer include CD4+ percentage as a criterion for prophylaxis (15). Data correlating CD4+ counts and percentages among HIV-infected children have been collected since 1991. These data have been used to develop a revised classification system for HIV infection among children that utilizes both CD4+ counts and percentages to categorize children by their level of immunosuppression (16) (Table 2). Correlation of these measurements has also allowed for determination of a CD4+ percentage level that is more indicative of severe immunosuppression in children.
Diagnosis of HIV Infection Among Children
HIV infection can be diagnosed among children greater than or equal to 18 months of age by using standard HIV IgG antibody tests. However, because maternal IgG can be present in children less than 18 months of age, standard HIV-IgG serologic assays cannot be used to diagnose HIV infection in this age group. Advances in the development of viral detection assays, however, have made diagnosing HIV infection possible in nearly all infants by 4-6 months of age (17). The sensitivity of HIV culture or polymerase chain reaction (PCR) among infants is less than or equal to 50% during the first week after birth, but increases to greater than 90% by age 3 months and to nearly 100% by 6 months of age (17-20). The use of these assays has been recommended for HIV-exposed children who are greater than or equal to 1 month of age (21) because results of these assays can be used to diagnose HIV infection among infants (16).
Both the standard p24 antigen-capture assay and the immune-complex-dissociated, p24 antigen-capture assay are highly specific and can be used to diagnose HIV infection among infants (16). The sensitivity of the standard p24 antigen-capture assay, however, is low (i.e., less than 50%) in all age groups and therefore cannot be used to exclude HIV infection. Modification of the p24 antigen-detection assay by pretreating serum samples to dissociate antigen-antibody complexes has increased the sensitivity of this assay (21,22). However, because data concerning the sensitivity of this assay in early infancy are limited, use of this assay alone is not currently recommended to exclude HIV infection.
RECOMMENDATIONS
The revised guidelines for PCP prophylaxis for children who are infected with or perinatally exposed to HIV are based on similar considerations as the 1991 guidelines, including the age distribution of PCP among children, the rapid onset of PCP (especially among infants), the high mortality rate associated with PCP, and data regarding CD4+ counts and percentages among HIV-infected children. Based on these considerations and more recent data, the following guidelines are recommended for PCP prophylaxis among children less than 13 years of age.
Identifying Infants at Risk for HIV Infection
o Infants born to HIV-infected women should be identified promptly so that prophylaxis can be initiated before these infants are at risk for PCP. Diagnosing HIV infection among women before or during pregnancy is the most beneficial way to accomplish this goal. Early diagnosis not only allows for prompt evaluation of the need for PCP prophylaxis among the infants of HIV-infected women, but also gives such women the opportunity to access interventions that could a) maintain or improve their own health status and b) reduce the risk for transmitting HIV infection to their children (e.g., through antiretroviral therapy and avoidance of breastfeeding).
o If maternal HIV infection is not identified prenatally, pediatric health-care providers should identify infants born to HIV-infected women as soon as possible after birth so that PCP prophylaxis can begin promptly. Availability of and access to health care for both HIV-infected women and their newborns are essential to the implementation of an effective PCP prophylaxis strategy.
Diagnostic and Immunologic Monitoring of HIV-Exposed Infants
o All infants born to HIV-infected women should be monitored to determine their HIV infection status; the use of HIV culture or PCR is the preferred method for diagnosing HIV infection among infants (21). These assays should be performed at least twice: once at less than or equal to 1 month of age and once at less than or equal to 4 months of age. If the result of any test is positive, testing should be repeated to confirm diagnosis of HIV infection.
o Although the use of CD4+ counts and percentages is no longer recommended for determining the need for PCP prophylaxis among HIV-exposed infants less than 1 year of age (see Initiating PCP Prophylaxis Among HIV-Exposed Infants), other clinical considerations for such infants rely on these measurements. These include the assessment of such infants' immune status, risk for disease progression, and need for continued PCP prophylaxis after 1 year of age (see PCP Prophylaxis for HIV-Infected Children less than or equal to 12 Months of Age). Therefore, CD4+ counts and percentages should be measured in all HIV-exposed infants at 1 and 3 months of age (Table 3). CD4+ monitoring is not necessary after HIV infection has been reasonably excluded (see PCP Prophylaxis for Infants 4-12 Months of Age). For infants who have been diagnosed as HIV-infected and for those whose infection status has not yet been determined, CD4+ values should be monitored at 6, 9, and 12 months of age.
Initiating PCP Prophylaxis Among HIV-Exposed Infants
* All infants born to HIV-infected women should be started on PCP prophylaxis at 4-6 weeks of age, regardless of their CD4+ count (Table 3). Infants who are first identified as being HIV-exposed after 6 weeks of age should be started on prophylaxis at the time of identification. These recommendations are based on the following considerations: a) most cases of PCP among HIV-infected children occur in the first year of life; b) the risk for PCP begins to increase dramatically at age 2 months (when HIV infection cannot yet be reasonably excluded) (see PCP Prophylaxis For Infants 4-12 Months of Age); and c) the reliability of CD4+ counts in predicting which infants are at risk for PCP is relatively low during infancy particularly among infants less than or equal to 6 months of age, the age at which the peak incidence of PCP occurs.
PCP prophylaxis should not be administered to infants less than 4 weeks of age because a) they are at low risk for PCP and b) the use of sulfa drugs among infants at this age is not advised because of the potential for adverse drug effects resulting from immature bilirubin metabolism. Additionally, the concurrent use of sulfa drugs among HIV-exposed infants who are receiving zidovudine during the first 6 weeks of life to prevent perinatal HIV transmission could potentially exacerbate the anemia that some children receiving zidovudine experience (3). Therefore, to avoid the potential for additional toxicity in such children, prophylaxis should be started at 6 weeks of age, the age at which zidovudine is discontinued.
PCP Prophylaxis for Infants 4-12 Months of Age
* All HIV-infected infants and infants whose infection status has not yet been determined should continue prophylaxis until 12 months of age.
* PCP prophylaxis should be discontinued among infants in whom HIV infection has been reasonably excluded on the basis of two or more negative viral diagnostic tests (i.e., HIV culture or PCR), both of which are performed at greater than or equal to 1 month of age and one of which is performed at greater than or equal to 4 months of age. In some clinical centers, these viral diagnostic tests are not available. For children who do not have access to such testing, prophylaxis should be continued until 12 months of age unless HIV infection has been excluded on the basis of two or more negative HIV-antibody tests performed at greater than or equal to 6 months of age (16).
PCP Prophylaxis for HIV-Infected Children greater than or equal to 12 Months of Age
* All HIV-infected children greater than or equal to 12 months of age should continue to have regular CD4+ monitoring to determine their need for PCP prophylaxis (Table 3).
* HIV-infected children and children whose infection status has not been determined should be evaluated at 12 months of age to determine their need for continued PCP prophylaxis. PCP prophylaxis should be continued after 12 months of age for HIV-infected children who have had any CD4+ measurement during the first 12 months of life indicating severe immunosuppression (i.e., a CD4+ count of less than 750 cells/uL or a CD4+ percentage of less than 15%). Prophylaxis should be discontinued at 12 months of age for HIV-infected children whose CD4+ measurements have been adequately monitored (Table 3) and have remained higher than these levels. PCP prophylaxis should also be discontinued for any child who is diagnosed as not being infected with HIV (16).
* Children who have received PCP prophylaxis from 12 to 24 months of age should be evaluated again at 24 months of age, and prophylaxis should be continued for those children who have had any CD4+ measurement indicating severe immunosuppression (i.e., a CD4+ count of less than 500 cells/uL or a CD4+ percentage of less than 15%). Prophylaxis should be discontinued at 24 months of age for HIV-infected children whose CD4+ measurements have been adequately monitored (Table 3) and have remained higher than these levels.
* HIV-infected children greater than or equal to 12 months of age who are not receiving prophylaxis (e.g., those children whose infection was not identified previously or whose PCP prophylaxis was discontinued) should begin PCP prophylaxis if their CD4+ measurement indicates severe immunosuppression (Table 2).
* Initiation or continuation of prophylaxis should also be considered on a case-by-case basis for HIV-infected children greater than or equal to 12 months of age who might otherwise be at risk for PCP, such as children with rapidly declining CD4+ counts or percentages or children with severely symptomatic HIV disease (i.e., Category C conditions [16 ]).
Prophylaxis Against PCP Recurrence
o HIV-infected children who have had an episode of PCP should receive lifelong PCP prophylaxis to prevent recurrence -- regardless of CD4+ measurement or clinical status.
Recommended Chemoprophylaxis Regimens
* The recommended PCP chemoprophylaxis regimen for children is trimethoprim/sulfamethoxazole (TMP-SMX) (Box 1). When initiating TMP-SMX prophylaxis, a baseline complete blood count, differential count, and platelet count should be obtained. These measurements should be repeated monthly while the child is receiving prophylaxis. If TMP-SMX is not tolerated, alternative regimens should be followed. On the basis of recently compiled pharmacokinetics data, the revised recommended dosage of dapsone as an alternative regimen is 2 mg/kg/day. These data indicate that peak serum concentrations for children receiving chronic dosing of dapsone at 1 mg/kg/dose average 1.84 ug/mL, compared with average peak concentrations of 4.65 ug/mL for adults receiving the standard dose of 100 mg/day (23,24). The increased dose of dapsone is recommended so that peak concentrations will approach concentrations achieved at dosages recommended for adults (15).
PCP prophylaxis is an approved labeling indication by the U.S. Food and Drug Administration for oral TMP-SMX but not for the various other alternative regimens for PCP prophylaxis. TMP-SMX has been shown to substantially reduce the risk for PCP among HIV-infected children (25). However, clinicians should be aware that some children have developed PCP despite the use of recommended prophylaxis (26).
Education and Counseling
* Providing HIV counseling and voluntary testing to all pregnant women and providing comprehensive pediatric care for infants born to HIV-infected women are likely to be the most effective steps toward preventing PCP in children. The U.S. Public Health Service is recommending voluntary HIV counseling and testing of all pregnant women because of the prevention opportunities these services provide for women and their infants (27). For uninfected women, such counseling is intended to initiate or reinforce HIV risk-reduction behavior. For infected women, knowledge of their HIV infection status allows for more informed reproductive decisions, opportunities to reduce the risk for perinatal HIV transmission, and early diagnosis and treatment for themselves and their HIV-exposed infants. Early identification of HIV-exposed infants also allows for education of parents or other caregivers regarding treatment considerations, including PCP prophylaxis.
* An optimal PCP prophylaxis strategy requires consistent adherence to the chemoprophylaxis regimen by the child's parent or other caregiver. Such adherence is likely to be enhanced if the caregiver is knowledgeable about PCP and its prevention. Therefore, parents and other caregivers of HIV-exposed children should be provided information that addresses -- how HIV infection is diagnosed among infants, including types and sensitivities of available tests; -- the relatively high risk for PCP among young infants; -- the frequently sudden onset and high mortality of PCP among infants; -- drug regimens for PCP chemoprophylaxis, including efficacy and the frequency and nature of potential adverse effects; -- the importance of starting prophylaxis in all HIV-exposed infants at 4-6 weeks of age, even when the diagnosis of HIV infection has not been established; and -- the rationale for having different prophylaxis strategies for adults and children. -- Additionally, health-care providers should review the various acceptable alternative dosing schedules with the child's caregiver and make every effort to tailor the dosing regimen to fit the caregiver's schedule.
FUTURE NEEDS
These recommendations were developed on the basis of currently available data. Other strategies for prophylaxis might need to be considered in the future. Factors that might influence the need to modify these guidelines include the extent to which a) the incidence of PCP decreases following implementation of these recommendations and those for HIV counseling and testing of pregnant women; b) improvements in the sensitivity and availability of HIV diagnostic tests allow for diagnosis and exclusion of HIV infection in most HIV-exposed infants before the age of greatest risk for PCP; and c) reduction in mother-to-infant HIV transmission through zidovudine therapy results in an increased number of HIV-exposed but uninfected infants receiving PCP prophylaxis.
References
1. CDC. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR 1991;40(No. RR-2):1-13.
2. Simonds RJ, Oxtoby MJ, Caldwell MB, Gwinn ML, Rogers MF. Pneumocystis carinii pneumonia among U.S. children with perinatally acquired HIV infection. JAMA 1993;270:470-3.
3. CDC. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR 1994;43(No. RR-11):1-20.
4. Hsu HW, Moye J, Kunches L, et al. Perinatally acquired human immunodeficiency virus infection: extent of clinical recognition in a population-based cohort. Pediatr Infect Dis J 1992;11:941-5.
5. Simonds R, Malecki J, Cioffi P, Bigler W, Oxtoby M, Witte J. Evaluating a tracking system for infants born to HIV-infected mothers in Palm Beach County, Florida [Abstract]. 121st Annual Meeting of the American Public Health Association, San Francisco, October 1993.
6. Maldonado YA, Wang NE, Caldwell B, et al. Factors associated with early clinical recognition of children with perinatal human immunodeficiency virus infection. J Infect Dis 1995;171:689-92.
7. Simonds RJ, Lindegren ML, Thomas P, et al. Prophylaxis against Pneumocystis carinii pneumonia among children with perinatally acquired HIV infection in the United States. N Engl J Med 1995;332:786-90.
8. Israele V, Wittek A, Courville T, Srugo I, Brunell P. Pneumocystis carinii pneumonia (PCP) in infants with CD4 counts greater than 2000 cells/mm3 [Abstract]. VIII International Conference on AIDS, Amsterdam, July 1992.
9. European Collaborative Study Group. CD4 T cell count as predictor of Pneumocystis carinii pneumonia in children born to mothers infected with HIV. Br Med J 1994;308:437-40.
10. Connor E, Bagarazzi M, McSherry G, et al. Clinical and laboratory correlates of Pneumocystis carinii pneumonia in children infected with HIV. JAMA 1991;265:1693-7.
11. Kovacs A, Frederick T, Church J, Eller A, Oxtoby M, Mascola L. CD4 T-lymphocyte counts and Pneumocystis carinii pneumonia in pediatric HIV infection. JAMA 1991;265:1698-703.
12. Leibovitz E, Rigaud M, Pollack H, et al. Pneumocystis carinii pneumonia in infants infected with the human immunodeficiency virus with more than 450 CD4 T lymphocytes per cubic millimeter. N Engl J Med 1990;323:531-3.
13. Raszka WV Jr, Meyer GA, Waecker NJ, et al. Variability of serial absolute and percent CD4+ lymphocyte counts in healthy children born to human immunodeficiency virus 1-infected parents. Pediatr Infect Dis J 1994;13:70-2.
14. CDC. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989;38(No. S-5):1-9.
15. CDC. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR 1992;41(No. RR-4):1-11.
16. CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994;43(No. RR-12):1-10.
17. Report of a consensus workshop, Siena, Italy, January 17-18, 1992. Early diagnosis of HIV infection in infants. J Acquir Immune Defic Syndr 1992;5:1169-78.
18. McIntosh K, Pitt J, Brambilla D, et al. Blood culture in the first 6 months of life for the diagnosis of vertically transmitted human immunodeficiency virus infection. J Infect Dis 1994;170:996-1000.
19. Burgard M, Mayaux MJ, Blanche S, et al. The use of viral culture and p24 antigen testing to diagnose human immunodeficiency virus infection in neonates. N Engl J Med 1992;327:1192-7.
20. Borkowsky W, Krasinski K, Pollack H, Hoover W, Kaul A, Ilmet-Moore T. Early diagnosis of human immunodeficiency virus infection in children less than 6 months of age: comparison of polymerase chain reaction, culture, and plasma antigen capture techniques. J Infect Dis 1992;166:616-9.
21. El-Sadr W, Oleske JM, Agins BD, et al. Evaluation and management of early HIV infection. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, January 1994; DHHS publication no. (AHCPR)94-0572. (Clinical Practice Guideline no. 7).
22. Quinn TC, Kline R, Moss MW, Livingston RA, Hutton N. Acid dissociation of immune complexes improves diagnostic utility of p24 antigen detection in perinatally acquired human immunodeficiency virus infection. J Infect Dis 1993;167:1193-6.
23. Mirochnick M, Michaels M, Clarke D, et al. Pharmacokinetics of dapsone in children. J Pediatr 1993;122:806-9.
24. Garg SK, Kumar B, Bakaya V, Lal R, Shukla VK, Kaur S. Plasma dapsone and its metabolite monoacetyldapsone levels in leprotic patients. Int J Clin Pharmacol Ther Toxicol 1988;26:552-4.
25. Thea DM, Lambert G, Weedon J, et al. Benefit of primary prophylaxis prior to 18 months of age in reducing the incidence of Pneumocystis carinii pneumonia and early death in a cohort of 112 HIV-infected infants. Pediatrics 1995 (in press).
26. Mueller BU, Butler KM, Husson RN, Pizzo PA. Pneumocystis carinii pneumonia despite prophylaxis in children with human immunodeficiency virus infection. J Pediatr 1991;119:992-4.
27. CDC. Availability of draft U.S. Public Health Service recommendations for HIV counseling and testing for pregnant women. Federal Register 1995;60(36):10086-7.
* Until September 1994, this organization was named the National Pediatric HIV Resource Center.

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