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Guidelines for Prophylaxis Against Pneumocystis carinii Pneumonia for Children Infected with Human Immunodeficiency Virus

The Working Group on PCP Prophylaxis in Children was convened by the National Pediatric HIV Resource Center at Children's Hospital of New Jersey, New Jersey Medical School Newark, New Jersey. The Working Group was supported in part by Project # BPH PRC021-01-0 Maternal and Child Health Bureau Program Health Resources and Services Administration U.S. Department of Health and Human Services. Participants

Edward Connor, MD, Chairman

Children's Hospital of New Jersey University of Medicine and

Dentistry-New Jersey Medical School (UMDNJ) Newark, NJ

Walter Hughes, MD, Co-Chairman

St Jude Children's Research Hospital Memphis, TN

Carolyn Burr, RN, MS

National Pediatric HIV Resource Center Children's Hospital of New Jersey Newark, NJ

Clemente Diaz, MD

University of Puerto Rico University Children's Hospital San Juan, PR

Carol DiPaolo

Consumer Parent Brooklyn, NY

Gerald Fischer, MD

Uniformed Services University of Health Sciences Bethesda, MD

Earlene Hollaway

Consumer Parent Newark, NJ

Deborah Katz, RN, MS

National Institute of Allergy and

Infectious Diseases Bethesda, MD

Aditya Kaul, MD

New York University Medical Center New York, NY

Andrea Kovacs, MD

Los Angeles County/University of Southern California Medical Center Los Angeles, CA

Kenneth McIntosh, MD

The Children's Hospital Harvard Medical School Boston, MA George McSherry, MD

Children's Hospital of New Jersey UMDNJ Medical School Newark, NJ

Lynne Mofenson, MD

National Institute of Child Health

and Human Development Rockville, MD

James Oleske, MD, MPH

Children's Hospital of New Jersey UMDNJ Medical School Newark, NJ

Margaret Oxtoby, MD

Centers for Disease Control Atlanta, GA

Philip Pizzo, MD Pediatric Branch, National Cancer

Institute Bethesda, MD

Gwendolyn Scott, MD

University of Miami School of Medicine Miami, FL

Anne Willoughby, MD, MPH

National Institute of Child Health and

Human Development Rockville, MD

Catherine Wilfert, MD

Duke University Medical Center Durham, NC

Ram Yogev, MD

Children's Memorial Hospital Chicago, IL *************************************************************

INTRODUCTION

Although guidelines have been established for prophylaxis against Pneumocystis carinii pneumonia (PCP) for adults with human immunodeficiency virus (HIV) infection, they have not been available for children (1). Experts in pediatric HIV infection (convened by the Pediatric HIV Resource Center) independently reviewed recent data and provided recommendations to the U.S. Public Health Service for PCP prophylaxis for HIV-infected or -exposed children. This report summarizes these deliberations and details the consensus guidelines.

BACKGROUND Impact of PCP on HIV-Infected Children

Pneumocystis carinii pneumonia is the most common serious HIV-associated opportunistic infection among children. PCP was diagnosed for 1,080 (39%) of the 2,786 pediatric AIDS patients reported to CDC through 1990. In medical centers caring for large numbers of children with perinatally acquired HIV infection, PCP has been the initial HIV-related illness for 8%-12% of all children and for greater than 50% of those children who progress to AIDS within the first year of life (2-6).

Although PCP can occur at any age, among children it is most commonly diagnosed between 3- 6 months of age (Figure 1). A population-based study in Massachusetts found the minimum incidence of PCP during the first year of life to be 2.3% among all infants born to seropositive mothers, or an estimated 7.7% among HIV-infected infants (7).

PCP is often the initial clinical sign of HIV infection, particularly among infants. Of the children described in the literature, at least half who developed PCP were not recognized as HIV-infected before they were diagnosed as having PCP, although some had had earlier HIV-associated symptoms (3-8).

Despite the availability of effective antimicrobial therapy, mortality from PCP among infants and children is high; the median survival time from the first episode is only 1-4 months (2-11). Among AIDS cases reported to CDC, 35% of children with PCP died within 2 months of diagnosis, compared with 13% of children with other AIDS diagnoses. Infants and young children may be more seriously affected than older children and adults because for the former, Pneumocystis carinii pneumonia may represent primary infection rather than reactivation disease, and because an infant's or young child's immune defenses may be immature. Considering the common occurrence and high mortality associated with PCP among HIV-infected children and the demonstrated efficacy of prophylaxis in other immunosuppressed populations, prevention is a high priority.

Problems in Defining the Pediatric Population Appropriate for Prophylaxis

Ideally, prophylaxis should be administered only to those children with proven HIV infection and those at highest risk of PCP. Practically, this is difficult for the youngest patients since definitive diagnosis of HIV infection in the first year of life is problematic due to maternal antibody acquired transplacentally (12). Although many of the truly infected infants can be identified from among seropositive infants by 6 months of age using HIV culture and other research-based tests (e.g., p24 antigen assay, HIV-specific IgA antibody, in vitro antibody production assays, polymerase chain reaction), this technology may not be available in all communities. To prevent most effectively the morbidity and mortality resulting from PCP among children with perinatally acquired HIV infection, prophylaxis must be initiated in the first few months of life, and, therefore, often before HIV can be definitively diagnosed.

Although no data from prospective studies are available to define the predictors of PCP among HIV-infected children, information is available regarding correlates of PCP. The strongest of these appear to be age less than 1 year, HIV-related symptoms, and reduction of CD4+ lymphocyte number or function (5,8,13).

CD4+ Cell Count and PCP Among HIV-Infected Children

Typically, T-helper lymphocyte (CD4+ cell) counts decline as HIV disease progresses, for children as well as adults. Among HIV-infected adults, a CD4+ cell count less than 200/mm3 is highly predictive of increased risk for PCP (1,14). Recent studies of lymphocyte phenotypes among healthy infants and young children have demonstrated that total lymphocytes and absolute CD4+ cell counts are much higher than among healthy adults (15,16). Consequently, HIV-infected children can have marked depletion of CD4+ cells but have values that would fall within the normal range for CD4+ cell counts for adults. A study of HIV-uninfected, healthy infants and children (16) (Table 1) demonstrated that normal median CD4+ cell counts were 3,200/mm3 during the first 6 months of life, with a progressive decline to 2,600/mm3 between 13-24 months of age, and to 1,700/mm3 by 2-6 years of age. Thus, the CD4+ cell count clinically useful for identifying young children at risk for PCP or other AIDS complications is likely to be higher than that for HIV-infected adults.

Several small studies have investigated the relationship between the CD4+ cell count and the subsequent development of PCP among children (4,8,9,17-19). Most information is available on children less than 1 year of age. Of published PCP episodes for which CD4+ cell counts were known shortly preceding or accompanying the development of PCP, greater than 50% were in the first year of life. Ninety percent of HIV-infected infants had counts less than 1,500/mm3 (only 73% had counts less than 1,000/mm3) (Table 2). In comparison, in one study of adults with PCP, a similar proportion (93%) had a CD4+ lymphocyte count less than 200/mm3 (14). Although fewer data are available on children greater than or equal to 12 months, children greater than or equal to 12 months with PCP had relatively lower CD4+ cell counts, compared with infants.

The CD4+ percentage threshold under which prophylaxis is recommended for adults (20%) (1) may also not be applicable to young children at risk for PCP. In one study, only 40% of infants less than 1 year with PCP had a CD4+ percentage less than 20%, compared with 75% of children 1-4 years of age and 93% of children greater than 4 years of age (8). Although the normative data confirm that a CD4+ percentage less than 20% is clearly abnormal for children of all ages (Table 1), this threshold appears to have a lower sensitivity for PCP risk among young HIV-infected children compared with HIV-infected adults. Hence, CD4+ percentages must be considered in conjunction with absolute CD4+ cell enumeration for adequate interpretation.

Regimens for PCP Prophylaxis for HIV-Infected or -Exposed Children

Although no studies of chemoprophylactic regimens for PCP among HIV-infected children have been performed, extrapolations may be made from experience with drugs used for PCP prophylaxis for children with other diseases, from clinical trials of PCP prophylaxis completed among HIV-infected adults, and from pediatric dosage and safety information regarding prophylactic drugs that have been used for children who have diseases other than PCP.

Trimethoprim-Sulfamethoxazole

Trimethoprim-sulfamethoxazole (TMP-SMX) has been demonstrated to be effective for prophylaxis against PCP for children with cancer and for adults with HIV infection. It is systemically active against Pneumocystis carinii, and there is longstanding experience with the drug for prophylaxis for children. TMP-SMX is currently one of the two drugs recommended by the U.S. Public Health Service for PCP prophylaxis for adults with HIV infection (1).

In 1988, one report indicated that adults with Kaposi's sarcoma who received TMP-SMX had fewer episodes of PCP and longer survival than did untreated patients (20). None of 30 patients given TMP-SMX developed PCP, compared with 16 of 30 patients without prophylaxis. A study of immunocompromised children with cancer clearly demonstrated that daily or intermittent (3 consecutive days per week) oral administration of 150 mg/M2 (square meter of body surface area) TMP and 750 mg/M2 SMX in two divided doses is effective in preventing PCP (21,22). No episodes of PCP occurred among TMP-SMX- treated patients, whereas 21% of those given placebo developed PCP.

Information regarding adverse reactions associated with long-term administration of TMP-SMX to children has come from studies of prophylaxis against recurrent urinary tract infection and otitis media, and from studies of PCP prophylaxis among children with leukemia. Fatal reactions to TMP-SMX are rare, occurring among less than 1/100,000 children (23). Dermatologic and hematologic abnormalities are the most common adverse reactions to TMP-SMX. Mild cutaneous reactions, consisting of an erythematous maculopapular rash, were noted among 16% of children with leukemia who received TMP-SMX 3 times weekly for PCP prophylaxis (22). Stevens-Johnson syndrome and exfoliative dermatitis occur rarely--in about 1/200,000 courses of therapy (23,24).

The incidence of hematologic reactions, principally leukopenia and thrombocytopenia, has varied in published reports from extremely low ( less than 0.1% in a study of greater than 1,000 hospitalized patients) to relatively high (12%-34% in a study of 50 children receiving outpatient therapeutic courses of drug) (25-27). Although the potential for induction of hemolytic anemia (as a consequence of the sulfonamide component) exists for patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, it has only rarely been reported (26). Because of concerns about bilirubin displacement as well as rapidly changing drug metabolism during the first month of life, TMP-SMX is not recommended for neonates.

Adverse reactions to TMP-SMX appear to be more frequent and severe among HIV-infected adults than among HIV-infected children. In several studies, 40%-65% of adults with AIDS had adverse reactions to TMP-SMX, occasionally requiring discontinuation of the drug (20,28,29). In contrast, a retrospective chart review of 75 HIV-infected children who received TMP-SMX--the majority for prophylaxis against PCP, recurrent otitis media, or urinary tract infections--identified only 15% with an adverse reaction (30). The majority (82%) of reactions were cutaneous (maculopapular or urticarial skin rash), followed by hematologic (18%). Serious reaction rates seemed to be dependent on dose, with patients who received a prophylaxis dosage having the lowest rate of reactions. Hematologic toxicity due to TMP-SMX theoretically could be increased for children treated with zidovudine, which also can cause bone marrow suppression.

Aerosolized Pentamidine

The potential use of aerosolized pentamidine (AP) for young children is limited by their ability to use the nebulizer. Theoretically, aerosol delivery of pentamidine offers the advantage of targeting the drug to the alveolar site of the Pneumocystis organisms while reducing the systemic toxicity noted with parenteral drug. Published reports of experience with AP, including establishment of an effective dosage and delivery system, have related only to adult patients (31). Currently, 300 mg of AP delivered by Respirgard II jet nebulizer (Marquest, Englewood, CO) once a month is recommended as standard PCP prophylaxis for HIV-infected adults (1).

The most common minor adverse effects associated with AP administration to adults have been limited to fatigue, burning sensation in the back of the throat, and unpleasant taste (32). Bronchospasm has been noted among up to 15% of treated patients and cough among 38% of treated patients (33). Pneumothorax has also been reported among HIV-infected patients receiving AP prophylaxis (34). Other reported adverse reactions are rash, chemical conjunctivitis, pancreatitis, renal insufficiency, and hypoglycemia (35-40). Breakthrough PCP has been reported among 5%-25% of patients receiving AP (41). Atypical clinical signs have been described among patients who develop PCP while receiving AP prophylaxis, including upper-lobe infiltrates and extrapulmonary disease (42-47). Other issues to be addressed when considering the use of AP are the potential for transmission of pulmonary pathogens such as Mycobacterium tuberculosis and the unknown long-term effects of AP on lung tissue, especially that of the developing lung of the child (48,49).

Dapsone

No data have been published regarding the use of dapsone for PCP prophylaxis for children. For HIV-infected adults, several small comparative trials have shown PCP recurrence rates comparable with those for TMP-SMX or AP, when daily, twice weekly, or weekly regimens are followed (50-53). In one study of greater than 200 HIV-infected adults, daily administration of 100 mg dapsone for secondary PCP prophylaxis was associated with a less than 1% PCP recurrence rate over a follow-up period of 16 months (50). The long half-life of dapsone (1-2 days) may permit less frequent doses. Recently, a regimen of 100 mg or 200 mg once weekly for 61 HIV-infected adults was noted to have a failure rate of zero when used for primary prophylaxis and 8% PCP recurrence when used for secondary prophylaxis (54).

The overall incidence of toxicity among HIV-infected patients treated with dapsone has been reported as approximately 10%-13%, and has consisted principally of reversible hematologic effects (anemia, methemoglobinemia, neutropenia) (54). Rash has been noted; however, approximately 60% of patients who are unable to tolerate TMP-SMX have been able to tolerate dapsone administration. Nausea, vomiting, and reversible increases in liver transaminases have been noted among a small percentage of patients.

Dapsone has been used as the primary drug for the treatment of children for leprosy and dermatitis herpetiformis. The pediatric dosage for the treatment for leprosy is 1-2 mg/kg divided by ay. Dapsone has not been noted to have adverse effects on growth and development when used for children (55). Dose-related hemolysis is the most common adverse effect, and is seen among patients with and without G6PD deficiency; hemolysis is most often noted when daily doses exceed 200 mg. As noted with other sulfonamide drugs, rare cases of agranulocytosis and other blood dyscrasias have been associated with dapsone administration. Other rare but reported adverse reactions include a reversible hypersensitivity syndrome ("sulfone syndrome," characterized by fever, exfoliative dermatitis, hepatic dysfunction, and methemoglobinemia beginning 1-4 weeks into therapy) and peripheral neuropathy predominantly involving motor function (55,56).

Parenteral Pentamidine

Little information has been published regarding the use and toxic effects of parenteral (intravenous or intramuscular) pentamidine for PCP prophylaxis for HIV-infected adults. Parenteral pentamidine can produce drug levels in lung tissue that can persist for weeks (57); however, four or five parenteral doses are required before achieving therapeutic levels of 30 ug/gm tissue.

Several abstracts have been published regarding the use of intravenous pentamidine for secondary PCP prophylaxis among small numbers of HIV-infected adults. Monthly administration of 4 mg/kg for secondary prophylaxis resulted in a recurrence rate of zero to 28.5%, with follow-up periods ranging from 5-24 months (58-60). In one study, twice monthly administration was associated with a 5.5% recurrence rate (61). Hypoglycemia and hypotension during infusion have been noted, and the use of intramuscular administration has been associated with the development of sterile abscesses (32,61). The limited data regarding efficacy (even for adults) and the need for repeated intravenous infusions or intramuscular injections make parenteral pentamidine a less desirable choice for routine PCP prophylaxis for children.

RECOMMENDATIONS

The Working Group has constructed guidelines for initiation of PCP prophylaxis for HIV-infected children (Figure 2). The guidelines were based on the age distribution of PCP among children, the rapid onset of PCP (especially among infants), the high mortality rate associated with the primary episode, and recent data regarding the CD4+ cell counts among HIV-infected children with PCP and among healthy children of various ages. The various regimens for PCP prophylaxis have not been approved as labelling indications by the U.S. Food and Drug Administration. In addition, the doses have not been tested specifically among infants and children with HIV infection.

Patient Evaluation

Because PCP may be the initial manifestation of HIV infection among infants and young children, an optimal prophylaxis program will involve identification of HIV-exposed infants as soon as possible so that prophylaxis can be initiated, when indicated, to prevent PCP. Diagnosing maternal HIV infection during the pregnancy is the best way to accomplish this goal. If this is not possible, it is important for the pediatric health-care provider to identify the HIV-exposed infant as soon as possible after birth. PCP prophylaxis should be only one part of a comprehensive program of medical and social services, which includes HIV education, counseling and voluntary HIV antibody testing (with consent) in the obstetric prenatal setting, and access to care for both the HIV-infected woman and her newborn (62). A strong tracking and follow-up system is essential to the effectiveness of such a program.

Currently, CD4+ counts provide the most practical way to distinguish HIV-infected children at risk of early PCP disease. Most uninfected children and infected children with more intact immunity will have normal CD4+ cell counts, whereas children with HIV-induced immunosuppression will usually have lower CD4+ counts before developing HIV disease.

On the basis of currently available pediatric CD4+ cell normative data and the available data regarding age-related changes in CD4+ cell values that are correlated with PCP among HIV-infected children, the following age-adjusted CD4+ cell count indicator levels for the initiation of prophylaxis are recommended:

  • less than 1,500 for children 1-11 months

  • less than 750 for children 12-23 months

  • less than 500 for children 24 months through 5 years

  • less than 200 for children 6 years and older.

A CD4+ percentage less than 20% is also abnormally low, and if present, should be used as indication for prophylaxis regardless of the absolute count.

Primary PCP prophylaxis should begin after the first month of life, because of the potential for adverse drug effects among neonates, and because PCP rarely occurs among infants less than 1 month of age. However, if an infant less than 1 month of age is recognized to be at risk for HIV infection (i.e., born to an HIV-infected mother), an initial CD4+ cell count at that time can assist in patient evaluation. If the CD4+ cell count is less than 1,500/mm3, the infant should be carefully monitored, and prophylaxis begun at 1 month of age. If the CD4+ cell count is greater than or equal to 1,500/mm3, the count should be repeated 1 month later to evaluate the need to institute prophylaxis at that time.

Whenever a child is found to be HIV seropositive, an initial CD4+ count should be measured at that time to rapidly evaluate the child's need for PCP prophylaxis. Cell counts should be repeated at least every 3-4 months for HIV-infected children (and those of uncertain infection status) during the first 2 years of life. If the CD4+ cell count is approaching the age-adjusted threshold level for initiation of prophylaxis, the CD4+ lymphocyte count should be assessed more frequently (at 1-month intervals) to evaluate the rate of decline and the need to initiate prophylaxis. For children greater than or equal to 2 years of age, CD4+ cell counts should be monitored at least every 6 months, as recommended for HIV-infected adults.

Other clinical and laboratory assessments are also appropriate in the evaluation of HIV-infected or -exposed children. Every attempt should be made to diagnose HIV infection definitively as soon as possible so that children may receive antiretroviral treatment if indicated. In addition, depending on clinical findings, other diagnostic evaluation or treatment may be needed. Prophylaxis can also be considered for a young infant who is thought to be at particularly high risk of PCP because of the presence of a constellation of HIV-related symptoms, even if a CD4+ count is not yet available.

Some children initially placed on prophylaxis will not subsequently warrant continuation of prophylaxis based on HIV-infection status or CD4+ lymphocyte count. Discontinuation of prophylaxis is recommended for infants who were initially seropositive (as a result of transplacentally acquired antibody) but who are later shown not to be infected with HIV. Also, prophylaxis can be discontinued for HIV-infected or seropositive children who have CD4+ cell counts above indicated prophylaxis thresholds on two sequential measurements at least 1 month apart, unless there are special clinical circumstances--for instance if children are receiving medications that could alter the CD4+ cell count (corticosteroids, cytotoxic agents or antiretroviral therapy).

Regardless of symptoms or CD4+ cell counts, children with a previous episode of PCP should continue on lifelong prophylaxis to prevent recurrence.

Recommended Chemoprophylaxis Regimen

Because of its safety profile, proven efficacy in PCP prophylaxis for children with cancer and adult AIDS patients, and relative ease of administration, trimethoprim-sulfamethoxazole is recommended as the drug of choice for PCP prophylaxis of HIV-infected or -exposed children greater than or equal to 1 month of age (Table 3). To minimize toxicity, an intermittent regimen of 150 mg TMP with 750 mg SMX /M2 divided by ay, 3 days per week, is recommended. Doses should be adjusted upward as the child grows. The total daily dose should not exceed 320 mg TMP with 1600 mg SMX.

If life-threatening toxicity (anaphylaxis, Stevens-Johnson syndrome, or hypotension) occurs, the drug should be permanently discontinued. If other potentially drug-related reactions are noted (i.e., rash, neutropenia), the drug should be temporarily discontinued, and tried again within 2 weeks. Some patients with documented adverse reactions to TMP-SMX have been successfully desensitized. If desensitization is done, administration of TMP-SMX should then be given daily because of the potential for serious adverse reaction upon reintroduction of the drug after any interruption of dosing.

Complete blood counts with differential and platelet count should be performed at initiation of TMP-SMX prophylaxis and at monthly intervals to assess hematologic toxicity, as is recommended for HIV-uninfected children receiving TMP-SMX for recurrent otitis media or urinary tract infection (63).

Alternative Regimens

If TMP-SMX is not tolerated, aerosolized pentamidine is recommended for HIV-infected children greater than or equal to 5 years of age. The dose and delivery system recommended for adults is 300 mg every 4 weeks via the Respirgard II jet nebulizer; this dose has also been used for children, although no pharmacokinetic or efficacy data are available. The dose is diluted in 6 ml of sterile water and delivered at 6 L/min from a 50-pounds per square inch (PSI) compressed air source until the reservoir is dry (1). If cough or bronchospasm occurs, therapy is interrupted and a bronchodilator administered; for mild cough, in some instances lowering the flow rate of the nebulizer has helped (32). Although routine pulmonary function tests are not recommended, clinical awareness of the potential for pulmonary compromise is warranted.

Dapsone can be considered for patients who cannot tolerate TMP-SMX. The suggested dose is 1 mg/kg of body weight per day given orally to minimize toxicity. The total daily dose should not exceed 100 mg per day. Although dapsone is not available as a liquid preparation, the tablets (25 mg or 100 mg) are crushable so that an appropriate dose can be administered and the drug may be given with or in food. As noted for TMP-SMX, monthly complete blood counts with differential and platelet count should be performed for those children receiving dapsone prophylaxis to assess hematologic toxicity.

For HIV-infected children who cannot tolerate TMP-SMX, AP, or dapsone, some clinicians use intravenous pentamidine (4 mg/kg of body weight) given every 2 or 4 weeks.

FUTURE NEEDS

The guidelines in this consensus statement have been formulated using available data regarding PCP among children and in recognition of the urgent need to provide guidance to the practitioner in this area. However, it is also recognized that the knowledge base is incomplete and that additional information is needed to optimize PCP prophylaxis. Although it is unlikely that placebo-controlled studies of PCP prophylaxis for HIV-infected children will be performed given the proven efficacy of primary prophylaxis for HIV-infected adults and for children with other immunosuppressive conditions, research questions of high priority remain. These include the impact of PCP prophylaxis on the frequency and characteristics of PCP among HIV-infected children, the side effects of the recommended (and alternative) regimens, the rates of breakthrough PCP, the impact of TMP-SMX prophylaxis on the frequency of bacterial infections and the natural history of HIV infection, and comparison of regimens for PCP prophylaxis.

These guidelines on prophylaxis may need to be modified as more information becomes available. In particular, with advances in HIV diagnosis in infancy and with further data from ongoing prospective studies, it may be possible to better define those children at most risk for development of PCP, using other clinical or laboratory parameters in addition to CD4+ counts. Further refinement of the CD4+ thresholds for prophylaxis may also be possible.

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