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A national survey on the care of infants and children with human immunodeficiency virus infection
CURRENT LITERATURE AND CLINICAL ISSUES
We are not partial to surveys of current practice because it often is not possible to determine whether the diagnostic criteria are uniform, decisions regarding treatment have been made with similar considerations, and the respondents have similar experience or qualifications. Moreover, it is not certain that a consensus is necessarily correct. We have made an exception in this instance because only experts were surveyed, the field is changing rapidly, and more readers will be sharing the responsibility for caring for pediatric patients with HIV infection. We hope that this status report will be helpful for at least the immediate future.--J.M.G., Editor
A national survey on the care of infants and children with human immunodeficiency virus infection The number of infants and children with recognized human immunodeficiencyvirus infection and acquired immun0deficiency syndrome is increasing at an alarming rate. Many Pediatric Care givers lack training or experience in the management of patients with the complex problems encountered. Furthermore, the medical literature is either lacking or in a state of flux with regard to many important issues in pediatric HIV infection. We surveyed pediatric specialists nationally on selected topics relevant to the care of infants and children with HIV infection. The goal of this survey was to gain insight into the current management of selected problems that affect these patients, and to provide practical information that other pediatric care givers might find useful in their own practices. The survey does not, and cannot, address the potential superiority of any particular treatment regimen over any other. It merely serves to highlight currently prevalent clinical practices. METHODS A questionnaire was mailed on about Dec. 1, 1990, to 72 people nationally. All National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group pediatric Supported in part by grant No. AI-27551 from the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group, contract No. HD-72925 from the National Institute of Child Health and Human Development, and contract No. HR96040 from the National Heart, Lung, and Blood Institute. Reprint requests: Mark W. Kline, MD, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. 9/34/28188
principal investigators and lead subunit investigators received copies of the questionnaire by mail, as did selected pediatric infectious disease specialists at other institutions known to care for substantial numbers of HIV-infected infants and children. The questionnaire was mailed to only one person at any given institution. Addressees were asked to pass the questionnaire along to the person at their institution whom they deemed most appropriate for answering the survey questions. Questionnaires returned to us by Jan. 18, 1991, were used in the tabulation of results. Survey questions Could be categorized broadly as pertaining to zidovudine therapy, routine immunologic and virologic monitoring, prophylaxis and treatment of Pneumo, cystis carinii infection, and intravenous administration of immune globulin to infants and children with HIV infection. AIDS HIV IVIG
Acquired immunodeficiencysyndrome Human immunodeficiencyvirus Intravenously administered immune globulin
RESULTS Of 72 surveys, 40 (56%) were returned. Not all respondents answered every question, so the number of responses to each question frequently did not total 40. Respondents work in 18 different states. Every geographic region of the continental United States was represented. Multiple questionnaires were received from seven states: California (nine), New York (six), Texas (five), and Florida, Illinois, New Jersey, and Pennsylvania (two each). Thirty-one respondents identified their medical specialty as pediatric infectious diseases. Three pediatric infectious
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The Journal of Pediatrics May 1991
Table I. Respondents answering yes or no to the
Table II. Recommendations for initial zidovudine dosing
question of whether various patient characteristics are indications for zidovudine therapy in HIV-infected infants and children
of infants and children
Patient characteristic-Indication for zldovudine?
No. of respondents Yes
No
Asymptomatic infection, CD4 >500/#1 8 Asymptomatic infection, CD4 <500//A 36 Symptomatic infection, CD4 >500/~1 36 Symptomatic infection, CD4 <500//~1 38 HIV culture positive 13 p24 antigen positive 17 Unexplained CSF abnormalities 17 Unexplained failure to thrive 23 Unexplained developmental delay 22 CD4. CD4 lymphocytecount: CSF. cerebrospinalfluid.
30 2 2 0 25 22 21 15 16
disease specialists also listed pediatric immunology as a specialty, as did five other respondents. Four respondents listed pediatrics as their specialty. Respondents work in university-affiliated private hospitals (28), university-affiliated public hospitals (10), or non-university-affiliated hospitals or clinics (2). Thirty-four respondents reported that they are responsible for the day-to-day outpatient and inpatient management of HIV-infected infants and children: four provide intermittent, consultative care only. Sixteen of the respondents reported that each of their institutions provides care to more than 100 infants and children with suspected or proven HIV infection (Centers for Disease Control classes P0, P1, P2, and P3), 15 care for between 21 and 100 of these infants and children, and only two care for fewer than 10. Twenty-six of the respondents work at member institutions of the AIDS Clinical Trials Group; 14 do not. Twenty-seven respondents Participate in other studies of pediatric HIV infection; 11 do not. Zidovudine therapy. Table I lists some of the clinical characteristics of HIV-infected infants and children that would cause respondents to consider initiation of zidovudine therapy. Almost all respondents said that they would consider zidovudine therapy for infants and children with symptomatic HIV infection, regardless of CD4 lymphocyte count, and for symptom-free infants and children with CD4 lymphocyte counts less than 500 cells/gl. Most respondents would not consider zidovudine therapy for symptom-free infants and children with CD4 lymphocyte counts greater than 500 eells//zl. Opinion was divided as to whether HIVinfected infants and children with a positive culture for HIV, a positive p24 antigen test result~ unexplained cerebrospinal fluid pleocytosis or elevated protein levels in the cerebrospinal fluid, unexplained failure to thrive, or devel-
Dose ( m g / m 2 every 6 hr)
For asymptomatic infection 90 120 180 For symptomatic inaction 90 120 180
No. of respondents
4 5 28 2 2 27
opmental delay should be considered for zidovudine therapy in the absence of, other indications for use of the drug. Thirty-one respondents said that they would consider zidovudine therapy for infants and children of any age; seven would not administer the drug to infants less than 3 months of age. Zidovudine dosing was somewhat controversial (Table II). Most respondents suggested an initial dosage of 180 m g / m 2 per dose, given four times daily, but a substantial number of respondents favored a lower initial dose for symptom-free infants and children. In addition, there was disagreement on the appropriate maximum dose of zidovudine for larger children (Table III). There was virtual unanimity of opinion in two areas: none of the respondents suggested any clinical scenario in which they would consider administration of a zidovudine loading dose, and only 3 of 36 respondents would administer larger doses of zidovudine to infants and children with evidence of central nervous system involvement by the HIV. Most respondents (30/37) monitor the complete blood cell count every 2 weeks during the initial 6 weeks of zidovudine therapy and every 4 weeks thereafter (31/39). Three respondents also recommended the routine monitoring of liver function. Almost all respondents reduce the dose of zidovudine when the patient's blood hemoglobin concentration falls; 26 of 34 would do so by the time the hemoglobin concentration reaches 8.0 gm/dl. One respondent recommends transfusion rather than reduction in the dose of zidovudine. All respondents reduce the zidovudine dose for neutropenia, most often (29/37) at an absolute neutrophil count of 750 cells/#l. Routine immunologic and virologic monitoring. Almost all the specialists surveyed (37/38) routinely obtain CD4 lymphocyte counts from HIV-infected infants and children, generally every 3 months (23 respondents) or 6 months (13 respondents). Other immunologic and virologic studies were recommended less consistently. Nine respondents ob-
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National survey on care o f HIV-infected children
Table III. Maximum daily dose of zidovudine for children Dose (rag)
For asymptomatic infection 500 600 800 1200 None For symptomatic infection 500 800 1200 None
No. of respondents
11 5 2 6 I 8 1 7 1
tain serum immunoglobulin levels every 3 months, 13 every 6 months, 2 every 12 months, and 14 not routinely. Only 6 of 37 respondents routinely perform delayed hypersensitivity skin tests, generally every 12 months, The.respondents obtain serum p24 antigen test results every 3 months (9 respondents) or 6 months (10 respondents), or not routinely (18 respondents). Prophylaxis and treatment of Pneumocystis carinii infection. Table IV shows the various threshold CD4 lymphocyte counts and other criteria that are being employed by respondents in decisions concerning the institution of P. carinii prophylaxis. Various oral regimens of trimethoprimsulfamethoxazole are used. Twenty-two respondents prescribe twice-daily dosing of the drug for 3 days each week (either consecutive days or alternating days), whereas 10 respondents prescribe a single dose given every day and 6 prescribe twice-daily dosing every day. Of 39 respondents, 9 suggested a minimum age ranging from 1 to 3 months for the institution of prophylaxis with trimethoprim-sulfamethoxazole. Aer0solized pentamidine has been used for pediatric P. carinii prophylaxis by 28 of 39 respondents. Sixteen of the respondents who have used the drug have administered it to five or fewer patients. The usual indications listed by respondent s for use of this form of prophylaxis include hypersensitivity to trimethoprim-sulfamethoxazole (26 respondents), granulocytopenia (16 respondents), and problems of compliance with oral prophylactic regimens (four respondents). Of 28 respondents, 21 listed a minimum patient age (generally 4 to 6 years) for administration of this drug or noted that the patient must be old enough to cooperate with its administration. Of 21 respondents, 15 prescribe aerosolized pentamidine in a dose of 300 rag, three prescribe 150 rag, and one each prescribes 200 mg, 400 rag,
8 19
T a b l e IV. Indications for P. carinii prophylaxis Indication
Age <1 yr CD4 <500 cells/#l CD4 <1000 cells/tzl CD4 <1500 cells/izl Any patient with symptomatic or documented H1V infection Age > 1 yr CD4 <200 cells/#l CD4 <400 cells/~l CD4 <500 cells/#l CD4 <1000 cells/~l Any patient with symptomatic or documented HIV infection CD4, CD4 lymphocytecount.
No. of respondents
7 8 3 20 2 1 23 8 3
and 8 mg/kg. Of 22 respondents, 20 administer t h e d r u g every 28 days, one prescribes a dose of 150 mg every 14 days, and One prescribes a dose of 8 mg/kg every 21 days. Of 37 respondents, 28 recommend corticosteroid therapy for at least some infants and children with HIV infection and P. carinii pneumonia. Eight respondents administer corticosteroid therapy to all these patient s, 11 only to those patients with severe pneumonia or respiratory failure, and three only to patients with mild or moderate pneumonia. Numerous corticosteroid preparations and dosing regimens were recommended. Methylprednisolone, in a dose of 0.5 to 1 m g / k g given intravenously every 6 to 12 hours for 5 to 14 days, was recommended most frequently (9 of 16 respondents). Intravenous immune globulin administration. Of 39 respondents, 13 report that they routinely use IVIG to treat HIV-infected infants and children. The usual indications cited for its use include recurrent bacterial infections and inability of the patient to form functional antibody. Most respondents (17/20) recommend a dose of 400 mg/kg, given every 4 weeks. Fourteen respondents alter routine immunization schedules for infants and children receiving IVIG; 13 do not. Six respondents administer immunizations during the middle part of the period between doses of immune globulin or immediately before administration of a close of immune globulin; three respondents withhold immunizations altogether; and one respondent administers only measles vaccine to these infants and children. DISCUSSION Our survey revealed uniformity of opinion on some aspects of the care of HIV-infected infants and children but divergence of opinion in other areas. As experience in the care of HIV-infected infants and children accrues and the
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medical literature grows, standard clinical practices are destined to evolve. For example, recently published studies of corticosteroid therapy for adults with P. carinii pneumonia,I, 2 and the recently announced beneficial effects of IVIG therapy for infants and children with symptomatic HIV infection (National Institute of Child Health and Human Development [NICHD] IVIG Clinical Trial Study Group, unpublished data) undoubtedly have altered the clinical practices of many respondents to our survey. Zidovudine therapy. The survey results reflect in part the demonstrated efficacy of zidovudine therapy in slowing HIV disease progression among adults with symptomatic 3 and asymptomatic4 infection, and among infants and children with symptomatic infection, 5 when CD4 lymphocyte counts are less than 500 cells//A. There are no published studies directly addressing the efficacy of zidovudine therapy for symptom-free infants and children with CD4 lymphocyte counts less than 500 cells/#l; however, almost all respondents recommend therapy for this group of patients. The treatment of HIV-infected patients with CD4 lymphocyte counts greater than 500 cells/#l is more controversial. The efficacy of zidovudine therapy for this group of patients has not been demonstrated. 3 Some infants and children with CD4 lymphocyte counts greater than 500 cells/#l were included in the study of McKinney et al., 5 but outcome measures were not examined separately for this group of patients. Nevertheless, it appears that most respondents would initiate zidovudine therapy for infants and children with symptoms and with CD4 lymphocyte counts greater than 500 cells/#l, and a substantial number recommend therapy for symptom-free patients as well. Indications for antiretroviral therapy in infants and children, including the use of CD4 lymphocyte counts and other markers, will be the subject of future studies. An ongoing AIDS Clinical Trials Group study is comparing two dosages of zidovudine for infants and children with HIV infection: 90 and 180 m g / m 2 per dose, given every 6 hours. At present, most of the respondents are employing the larger dose both for infants and children with symptomatic and for those with asymptomatic HIV infection. Studies among adults with asymptomatic HIV infection indicate that total daily zidovudine doses of 500 mg and 1500 mg have equivalent efficacy, and that the lower dose is less toxic. 4 Similarly, total daily doses of 300 mg for adults with AIDS-related complex,6 and 600 mg for adults with AIDS, 7 appear to be as effective as, and less toxic than, larger doses of zidovudine. In spite of these findings, several respondents recommend a maximum daily zidovudine dose of 1200 mg for larger children. Recently a National Institutes of Health ( N I H ) Consensus Conference panel s recommended that among adults re-
The Journal of Pediatrics May 1991
ceiving zidovudine, the complete blood cell count should be monitored monthly for the first 3 months of therapy and, if stable, every 3 months thereafter. Survey respondents had similar recommendations for infants and children receiving zidovudine. The N I H Consensus Conference panel recommended reduction of the zidovudine dose once the hemoglobin concentration and absolute neutrophil count fall to 8.0 gm/dl and 750 cells/~l, respectively. This recommendation is shared by most of the respondents to our survey. Routine immunologic and virologic monitoring, The CD4 lymphocyte count appears to be the surrogate HIV disease marker used most consistently by the respondents to our survey. The value of this marker in assessing disease progression and predicting the risk of opportunisti c disease has been recognized in many studies. The N I H Consensus Conference Panels recommended monitoring the CD4 lymphocyte count every 6 months in adults with HIV infection, or every 3 months if the count is at a level where critical therapeutic decisions are necessary (e.g., 500 cells/#l for the institution of antiretroviral therapy or 200 cells//A for the institution of P. carinii prophylaxis). Most of the survey respondents recommend somewhat more frequent routine monitoring (every 3 months), and this schedule may be appropriate because of the more rapid progression of HIV infection in infants and children compared with that in adults. The appropriate use of other surrogate immunologic and virologic markers in infants and children with HIV infection requires definition. Prophylaxis and treatment of P. carinii infection. Adults infected with HIV who have the highest risk of P. carinH infection are those with CD4 lymphocyte counts less than 200 cells/#l. 9 The potential hazard of reserving prophylaxis for HIV-infected infants with low CD4 lymphocyte counts is highlighted by reports of P. carinii pneumonia among infants with counts well over 1000 ceils/~l.l~ Most survey respondents report that they provide prophylaxis to all infants with symptomatic or documented HIV infection, regardless of CD4 lymphocyte count. After a patient's first year of life, most respondents employ arbitrary threshold CD4 lymphocyte counts for decisions regarding prophylaxis. Additional data on normal CD4 lymphocyte counts in infants and young children, and correlations of counts with the risk of P. carinii infection, are needed. Aerosolized pentamidine is effective prophylaxis against P. carinii pneumonia in HIV-infected adults. 9 The usual dose employed is 300 rag, given every 4 weeks. The majority of respondents to our survey prescribe a similar dosing schedule. Pediatric studies of aerosolized pentamidine are ongoing. Problems of administering the drug to young children, noted by many respondents, should be addressed by future studies.
Volume 118 Number 5
Corticosteroid therapy for P. carinii pneumonia has been a controversial subject. Recent studies of adults with A I D S and moderate or severe P. carinii pneumonia have shown a reduced risk of respiratory failure and death with corticosteroid therapy. 1, 2 A recent N I H Consensus Conference panel 11 recommended adjunctive corticosteroid therapy for HIV-infected adults and adolescents with P. carinii pneumonia and moderate or severe pulmonary dysfunction. These three publications on the subject of corticosteroid therapy for P. carinii pneumonia were published shortly before our questionnaire was mailed, so most respondents probably were aware of the papers' findings and recommendations. Controlled studies of infants and children are lacking. Most survey respondents appear to be using guidelines similar to those used for adults with A I D S and P. carinii pneumonia. Intravenous immune globulin administration. A recently completed (Jan. 10, 199i) N I C H D collaborative study demonstrates the efficacy of I V I G in the prevention of laboratory-diagnosed bacterial infections and clinically diagnosed infections in infants and children with symptomatic H I V infection who have CD4 lymphocyte counts of at least 200 cells/~l ( N I C H D I V I G Clinical Trial Study Group, unpublished data). The results of this study were announced after the compilation of our survey results. This study is certain to expand the use of I V I G for HIV-infected infants and children. The appropriate use of this preparation requires further definition. Mark W. Kline, MD William T. Shearer, MD, PhD Department o f Pediatrics Section o f Allergy and Immunology Baylor College o f Medicine and Texas Children's Hospital Houston, TX 77030 We thank the physicians who responded to the survey. We also thank Drs. Ralph D. Feigin and Sheldon L. Kaplan for their helpful advice.
National survey on care o f HIV-infected children
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REFERENCES 1. Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Vole L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo-controlled trial. N Engl J Med 1990;323:1444-50. 2. Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1451-7. 3. Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection: a double-blind, placebo-controlled trial. Ann Intern Med 1990;112:727-37. 4. Volberding PA, Lagokos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990;322:941-9. 5. McKinney RE Jr, Pizzo PA, Scott GB, et al. Safety and tolerance of intermittent intravenous and oral zidovudine therapy in human immunodeficieney virus-infected pediatric patients. J PEDIATR 1990;116:640-7. 6. Collier AC, Bozzette S, Coombs RW, et al. A pilot study of low-dose zidovudine in human immunodeficiency virus infection. N Engl J Med 1990;323:1015-21. 7. Fischl MA, Parker CB, Pettinelli C, et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1009-14. 8. National Institutes of Health. State-of-the-art conference on azidothymidine therapy for early HIV infection. Am J Med 1990;89:335-44. 9. Leoung GS, Feigal DW Jr, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis against Pneumocystis earinii pneumonia: the San Francisco community prophylaxis trial. N Engl J Med 1990;323:769-75. 10. 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. 11. National Institutes of Health. Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1500-4.
We are not partial to surveys of current practice because it often is not possible to determine whether the diagnostic criteria are uniform, decisions regarding treatment have been made with similar considerations, and the respondents have similar experience or qualifications. Moreover, it is not certain that a consensus is necessarily correct. We have made an exception in this instance because only experts were surveyed, the field is changing rapidly, and more readers will be sharing the responsibility for caring for pediatric patients with HIV infection. We hope that this status report will be helpful for at least the immediate future.--J.M.G., Editor
A national survey on the care of infants and children with human immunodeficiency virus infection The number of infants and children with recognized human immunodeficiencyvirus infection and acquired immun0deficiency syndrome is increasing at an alarming rate. Many Pediatric Care givers lack training or experience in the management of patients with the complex problems encountered. Furthermore, the medical literature is either lacking or in a state of flux with regard to many important issues in pediatric HIV infection. We surveyed pediatric specialists nationally on selected topics relevant to the care of infants and children with HIV infection. The goal of this survey was to gain insight into the current management of selected problems that affect these patients, and to provide practical information that other pediatric care givers might find useful in their own practices. The survey does not, and cannot, address the potential superiority of any particular treatment regimen over any other. It merely serves to highlight currently prevalent clinical practices. METHODS A questionnaire was mailed on about Dec. 1, 1990, to 72 people nationally. All National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group pediatric Supported in part by grant No. AI-27551 from the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group, contract No. HD-72925 from the National Institute of Child Health and Human Development, and contract No. HR96040 from the National Heart, Lung, and Blood Institute. Reprint requests: Mark W. Kline, MD, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. 9/34/28188
principal investigators and lead subunit investigators received copies of the questionnaire by mail, as did selected pediatric infectious disease specialists at other institutions known to care for substantial numbers of HIV-infected infants and children. The questionnaire was mailed to only one person at any given institution. Addressees were asked to pass the questionnaire along to the person at their institution whom they deemed most appropriate for answering the survey questions. Questionnaires returned to us by Jan. 18, 1991, were used in the tabulation of results. Survey questions Could be categorized broadly as pertaining to zidovudine therapy, routine immunologic and virologic monitoring, prophylaxis and treatment of Pneumo, cystis carinii infection, and intravenous administration of immune globulin to infants and children with HIV infection. AIDS HIV IVIG
Acquired immunodeficiencysyndrome Human immunodeficiencyvirus Intravenously administered immune globulin
RESULTS Of 72 surveys, 40 (56%) were returned. Not all respondents answered every question, so the number of responses to each question frequently did not total 40. Respondents work in 18 different states. Every geographic region of the continental United States was represented. Multiple questionnaires were received from seven states: California (nine), New York (six), Texas (five), and Florida, Illinois, New Jersey, and Pennsylvania (two each). Thirty-one respondents identified their medical specialty as pediatric infectious diseases. Three pediatric infectious
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The Journal of Pediatrics May 1991
Table I. Respondents answering yes or no to the
Table II. Recommendations for initial zidovudine dosing
question of whether various patient characteristics are indications for zidovudine therapy in HIV-infected infants and children
of infants and children
Patient characteristic-Indication for zldovudine?
No. of respondents Yes
No
Asymptomatic infection, CD4 >500/#1 8 Asymptomatic infection, CD4 <500//A 36 Symptomatic infection, CD4 >500/~1 36 Symptomatic infection, CD4 <500//~1 38 HIV culture positive 13 p24 antigen positive 17 Unexplained CSF abnormalities 17 Unexplained failure to thrive 23 Unexplained developmental delay 22 CD4. CD4 lymphocytecount: CSF. cerebrospinalfluid.
30 2 2 0 25 22 21 15 16
disease specialists also listed pediatric immunology as a specialty, as did five other respondents. Four respondents listed pediatrics as their specialty. Respondents work in university-affiliated private hospitals (28), university-affiliated public hospitals (10), or non-university-affiliated hospitals or clinics (2). Thirty-four respondents reported that they are responsible for the day-to-day outpatient and inpatient management of HIV-infected infants and children: four provide intermittent, consultative care only. Sixteen of the respondents reported that each of their institutions provides care to more than 100 infants and children with suspected or proven HIV infection (Centers for Disease Control classes P0, P1, P2, and P3), 15 care for between 21 and 100 of these infants and children, and only two care for fewer than 10. Twenty-six of the respondents work at member institutions of the AIDS Clinical Trials Group; 14 do not. Twenty-seven respondents Participate in other studies of pediatric HIV infection; 11 do not. Zidovudine therapy. Table I lists some of the clinical characteristics of HIV-infected infants and children that would cause respondents to consider initiation of zidovudine therapy. Almost all respondents said that they would consider zidovudine therapy for infants and children with symptomatic HIV infection, regardless of CD4 lymphocyte count, and for symptom-free infants and children with CD4 lymphocyte counts less than 500 cells/gl. Most respondents would not consider zidovudine therapy for symptom-free infants and children with CD4 lymphocyte counts greater than 500 eells//zl. Opinion was divided as to whether HIVinfected infants and children with a positive culture for HIV, a positive p24 antigen test result~ unexplained cerebrospinal fluid pleocytosis or elevated protein levels in the cerebrospinal fluid, unexplained failure to thrive, or devel-
Dose ( m g / m 2 every 6 hr)
For asymptomatic infection 90 120 180 For symptomatic inaction 90 120 180
No. of respondents
4 5 28 2 2 27
opmental delay should be considered for zidovudine therapy in the absence of, other indications for use of the drug. Thirty-one respondents said that they would consider zidovudine therapy for infants and children of any age; seven would not administer the drug to infants less than 3 months of age. Zidovudine dosing was somewhat controversial (Table II). Most respondents suggested an initial dosage of 180 m g / m 2 per dose, given four times daily, but a substantial number of respondents favored a lower initial dose for symptom-free infants and children. In addition, there was disagreement on the appropriate maximum dose of zidovudine for larger children (Table III). There was virtual unanimity of opinion in two areas: none of the respondents suggested any clinical scenario in which they would consider administration of a zidovudine loading dose, and only 3 of 36 respondents would administer larger doses of zidovudine to infants and children with evidence of central nervous system involvement by the HIV. Most respondents (30/37) monitor the complete blood cell count every 2 weeks during the initial 6 weeks of zidovudine therapy and every 4 weeks thereafter (31/39). Three respondents also recommended the routine monitoring of liver function. Almost all respondents reduce the dose of zidovudine when the patient's blood hemoglobin concentration falls; 26 of 34 would do so by the time the hemoglobin concentration reaches 8.0 gm/dl. One respondent recommends transfusion rather than reduction in the dose of zidovudine. All respondents reduce the zidovudine dose for neutropenia, most often (29/37) at an absolute neutrophil count of 750 cells/#l. Routine immunologic and virologic monitoring. Almost all the specialists surveyed (37/38) routinely obtain CD4 lymphocyte counts from HIV-infected infants and children, generally every 3 months (23 respondents) or 6 months (13 respondents). Other immunologic and virologic studies were recommended less consistently. Nine respondents ob-
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National survey on care o f HIV-infected children
Table III. Maximum daily dose of zidovudine for children Dose (rag)
For asymptomatic infection 500 600 800 1200 None For symptomatic infection 500 800 1200 None
No. of respondents
11 5 2 6 I 8 1 7 1
tain serum immunoglobulin levels every 3 months, 13 every 6 months, 2 every 12 months, and 14 not routinely. Only 6 of 37 respondents routinely perform delayed hypersensitivity skin tests, generally every 12 months, The.respondents obtain serum p24 antigen test results every 3 months (9 respondents) or 6 months (10 respondents), or not routinely (18 respondents). Prophylaxis and treatment of Pneumocystis carinii infection. Table IV shows the various threshold CD4 lymphocyte counts and other criteria that are being employed by respondents in decisions concerning the institution of P. carinii prophylaxis. Various oral regimens of trimethoprimsulfamethoxazole are used. Twenty-two respondents prescribe twice-daily dosing of the drug for 3 days each week (either consecutive days or alternating days), whereas 10 respondents prescribe a single dose given every day and 6 prescribe twice-daily dosing every day. Of 39 respondents, 9 suggested a minimum age ranging from 1 to 3 months for the institution of prophylaxis with trimethoprim-sulfamethoxazole. Aer0solized pentamidine has been used for pediatric P. carinii prophylaxis by 28 of 39 respondents. Sixteen of the respondents who have used the drug have administered it to five or fewer patients. The usual indications listed by respondent s for use of this form of prophylaxis include hypersensitivity to trimethoprim-sulfamethoxazole (26 respondents), granulocytopenia (16 respondents), and problems of compliance with oral prophylactic regimens (four respondents). Of 28 respondents, 21 listed a minimum patient age (generally 4 to 6 years) for administration of this drug or noted that the patient must be old enough to cooperate with its administration. Of 21 respondents, 15 prescribe aerosolized pentamidine in a dose of 300 rag, three prescribe 150 rag, and one each prescribes 200 mg, 400 rag,
8 19
T a b l e IV. Indications for P. carinii prophylaxis Indication
Age <1 yr CD4 <500 cells/#l CD4 <1000 cells/tzl CD4 <1500 cells/izl Any patient with symptomatic or documented H1V infection Age > 1 yr CD4 <200 cells/#l CD4 <400 cells/~l CD4 <500 cells/#l CD4 <1000 cells/~l Any patient with symptomatic or documented HIV infection CD4, CD4 lymphocytecount.
No. of respondents
7 8 3 20 2 1 23 8 3
and 8 mg/kg. Of 22 respondents, 20 administer t h e d r u g every 28 days, one prescribes a dose of 150 mg every 14 days, and One prescribes a dose of 8 mg/kg every 21 days. Of 37 respondents, 28 recommend corticosteroid therapy for at least some infants and children with HIV infection and P. carinii pneumonia. Eight respondents administer corticosteroid therapy to all these patient s, 11 only to those patients with severe pneumonia or respiratory failure, and three only to patients with mild or moderate pneumonia. Numerous corticosteroid preparations and dosing regimens were recommended. Methylprednisolone, in a dose of 0.5 to 1 m g / k g given intravenously every 6 to 12 hours for 5 to 14 days, was recommended most frequently (9 of 16 respondents). Intravenous immune globulin administration. Of 39 respondents, 13 report that they routinely use IVIG to treat HIV-infected infants and children. The usual indications cited for its use include recurrent bacterial infections and inability of the patient to form functional antibody. Most respondents (17/20) recommend a dose of 400 mg/kg, given every 4 weeks. Fourteen respondents alter routine immunization schedules for infants and children receiving IVIG; 13 do not. Six respondents administer immunizations during the middle part of the period between doses of immune globulin or immediately before administration of a close of immune globulin; three respondents withhold immunizations altogether; and one respondent administers only measles vaccine to these infants and children. DISCUSSION Our survey revealed uniformity of opinion on some aspects of the care of HIV-infected infants and children but divergence of opinion in other areas. As experience in the care of HIV-infected infants and children accrues and the
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Kline and Shearer
medical literature grows, standard clinical practices are destined to evolve. For example, recently published studies of corticosteroid therapy for adults with P. carinii pneumonia,I, 2 and the recently announced beneficial effects of IVIG therapy for infants and children with symptomatic HIV infection (National Institute of Child Health and Human Development [NICHD] IVIG Clinical Trial Study Group, unpublished data) undoubtedly have altered the clinical practices of many respondents to our survey. Zidovudine therapy. The survey results reflect in part the demonstrated efficacy of zidovudine therapy in slowing HIV disease progression among adults with symptomatic 3 and asymptomatic4 infection, and among infants and children with symptomatic infection, 5 when CD4 lymphocyte counts are less than 500 cells//A. There are no published studies directly addressing the efficacy of zidovudine therapy for symptom-free infants and children with CD4 lymphocyte counts less than 500 cells/#l; however, almost all respondents recommend therapy for this group of patients. The treatment of HIV-infected patients with CD4 lymphocyte counts greater than 500 cells/#l is more controversial. The efficacy of zidovudine therapy for this group of patients has not been demonstrated. 3 Some infants and children with CD4 lymphocyte counts greater than 500 cells/#l were included in the study of McKinney et al., 5 but outcome measures were not examined separately for this group of patients. Nevertheless, it appears that most respondents would initiate zidovudine therapy for infants and children with symptoms and with CD4 lymphocyte counts greater than 500 cells/#l, and a substantial number recommend therapy for symptom-free patients as well. Indications for antiretroviral therapy in infants and children, including the use of CD4 lymphocyte counts and other markers, will be the subject of future studies. An ongoing AIDS Clinical Trials Group study is comparing two dosages of zidovudine for infants and children with HIV infection: 90 and 180 m g / m 2 per dose, given every 6 hours. At present, most of the respondents are employing the larger dose both for infants and children with symptomatic and for those with asymptomatic HIV infection. Studies among adults with asymptomatic HIV infection indicate that total daily zidovudine doses of 500 mg and 1500 mg have equivalent efficacy, and that the lower dose is less toxic. 4 Similarly, total daily doses of 300 mg for adults with AIDS-related complex,6 and 600 mg for adults with AIDS, 7 appear to be as effective as, and less toxic than, larger doses of zidovudine. In spite of these findings, several respondents recommend a maximum daily zidovudine dose of 1200 mg for larger children. Recently a National Institutes of Health ( N I H ) Consensus Conference panel s recommended that among adults re-
The Journal of Pediatrics May 1991
ceiving zidovudine, the complete blood cell count should be monitored monthly for the first 3 months of therapy and, if stable, every 3 months thereafter. Survey respondents had similar recommendations for infants and children receiving zidovudine. The N I H Consensus Conference panel recommended reduction of the zidovudine dose once the hemoglobin concentration and absolute neutrophil count fall to 8.0 gm/dl and 750 cells/~l, respectively. This recommendation is shared by most of the respondents to our survey. Routine immunologic and virologic monitoring, The CD4 lymphocyte count appears to be the surrogate HIV disease marker used most consistently by the respondents to our survey. The value of this marker in assessing disease progression and predicting the risk of opportunisti c disease has been recognized in many studies. The N I H Consensus Conference Panels recommended monitoring the CD4 lymphocyte count every 6 months in adults with HIV infection, or every 3 months if the count is at a level where critical therapeutic decisions are necessary (e.g., 500 cells/#l for the institution of antiretroviral therapy or 200 cells//A for the institution of P. carinii prophylaxis). Most of the survey respondents recommend somewhat more frequent routine monitoring (every 3 months), and this schedule may be appropriate because of the more rapid progression of HIV infection in infants and children compared with that in adults. The appropriate use of other surrogate immunologic and virologic markers in infants and children with HIV infection requires definition. Prophylaxis and treatment of P. carinii infection. Adults infected with HIV who have the highest risk of P. carinH infection are those with CD4 lymphocyte counts less than 200 cells/#l. 9 The potential hazard of reserving prophylaxis for HIV-infected infants with low CD4 lymphocyte counts is highlighted by reports of P. carinii pneumonia among infants with counts well over 1000 ceils/~l.l~ Most survey respondents report that they provide prophylaxis to all infants with symptomatic or documented HIV infection, regardless of CD4 lymphocyte count. After a patient's first year of life, most respondents employ arbitrary threshold CD4 lymphocyte counts for decisions regarding prophylaxis. Additional data on normal CD4 lymphocyte counts in infants and young children, and correlations of counts with the risk of P. carinii infection, are needed. Aerosolized pentamidine is effective prophylaxis against P. carinii pneumonia in HIV-infected adults. 9 The usual dose employed is 300 rag, given every 4 weeks. The majority of respondents to our survey prescribe a similar dosing schedule. Pediatric studies of aerosolized pentamidine are ongoing. Problems of administering the drug to young children, noted by many respondents, should be addressed by future studies.
Volume 118 Number 5
Corticosteroid therapy for P. carinii pneumonia has been a controversial subject. Recent studies of adults with A I D S and moderate or severe P. carinii pneumonia have shown a reduced risk of respiratory failure and death with corticosteroid therapy. 1, 2 A recent N I H Consensus Conference panel 11 recommended adjunctive corticosteroid therapy for HIV-infected adults and adolescents with P. carinii pneumonia and moderate or severe pulmonary dysfunction. These three publications on the subject of corticosteroid therapy for P. carinii pneumonia were published shortly before our questionnaire was mailed, so most respondents probably were aware of the papers' findings and recommendations. Controlled studies of infants and children are lacking. Most survey respondents appear to be using guidelines similar to those used for adults with A I D S and P. carinii pneumonia. Intravenous immune globulin administration. A recently completed (Jan. 10, 199i) N I C H D collaborative study demonstrates the efficacy of I V I G in the prevention of laboratory-diagnosed bacterial infections and clinically diagnosed infections in infants and children with symptomatic H I V infection who have CD4 lymphocyte counts of at least 200 cells/~l ( N I C H D I V I G Clinical Trial Study Group, unpublished data). The results of this study were announced after the compilation of our survey results. This study is certain to expand the use of I V I G for HIV-infected infants and children. The appropriate use of this preparation requires further definition. Mark W. Kline, MD William T. Shearer, MD, PhD Department o f Pediatrics Section o f Allergy and Immunology Baylor College o f Medicine and Texas Children's Hospital Houston, TX 77030 We thank the physicians who responded to the survey. We also thank Drs. Ralph D. Feigin and Sheldon L. Kaplan for their helpful advice.
National survey on care o f HIV-infected children
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REFERENCES 1. Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Vole L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo-controlled trial. N Engl J Med 1990;323:1444-50. 2. Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1451-7. 3. Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection: a double-blind, placebo-controlled trial. Ann Intern Med 1990;112:727-37. 4. Volberding PA, Lagokos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990;322:941-9. 5. McKinney RE Jr, Pizzo PA, Scott GB, et al. Safety and tolerance of intermittent intravenous and oral zidovudine therapy in human immunodeficieney virus-infected pediatric patients. J PEDIATR 1990;116:640-7. 6. Collier AC, Bozzette S, Coombs RW, et al. A pilot study of low-dose zidovudine in human immunodeficiency virus infection. N Engl J Med 1990;323:1015-21. 7. Fischl MA, Parker CB, Pettinelli C, et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1009-14. 8. National Institutes of Health. State-of-the-art conference on azidothymidine therapy for early HIV infection. Am J Med 1990;89:335-44. 9. Leoung GS, Feigal DW Jr, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis against Pneumocystis earinii pneumonia: the San Francisco community prophylaxis trial. N Engl J Med 1990;323:769-75. 10. 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. 11. National Institutes of Health. Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1500-4.