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HIV-infected children may have clinical, virologic, and immunologic characteristics that account for their varying patterns of disease progression. Approximately 20% of infants and children who contracted HIV from their mothers will have rapid disease progression. Children who develop AIDS manifestations within the first year of life, particularly encephalopathy or Pneumocystis carinii pneumonia, have poorer prognoses than other HIV-infected children. Children who contract HIV during the fetal period may have more rapid disease progression than children infected during birth. High blood levels of HIV and strains of HIV that cause infected lymphocytes to clump together may be markers of rapid disease progression. High blood levels of free p24 or immune-complex dissociated p24 and low levels of p24 antibodies may be a viral marker associated with a poor prognosis. The foremost immunological marker of increased disease activity is low age-adjusted CD4 counts.

HIV-infected children may have clinical, virologic, and immunologic characteristics that account for their varying patterns of disease progression. Approximately 20% of infants and children who contracted HIV from their mothers will have rapid disease progression. Children who develop AIDS manifestations within the first year of life, particularly encephalopathy or Pneumocystis carinii pneumonia, have poorer prognoses than other HIV-infected children. Children who contract HIV during the fetal period may have more rapid disease progression than children infected during birth. High blood levels of HIV and strains of HIV that cause infected lymphocytes to clump together may be markers of rapid disease progression. High blood levels of free p24 or immune-complex dissociated p24 and low levels of p24 antibodies may be a viral marker associated with a poor prognosis. The foremost immunological marker of increased disease activity is low age-adjusted CD4 counts.

The Western blot assay measures the presence of antibodies against virus-associated proteins and is used as a means of diagnosing viral infections from blood samples. Use of Western blot in infants is complicated by the passage and persistence of maternal antibodies. If the mother is infected with HIV (the causative virus of AIDS), the infant may have anti-HIV antibodies from the mother for as long as 18 months, but not be infected with HIV. One study reported that 58 percent of infants lose maternal antibody by 12 months of age, and 78 percent by 15 months. However, HIV-infected infants may produce antibodies distinct from those of the mother as early as three months of age, but some infected infants may not do so for prolonged periods. These complexities of Western blots are frequently not appreciated. The significance of Western blot analysis in 36 HIV-infected children is discussed. Western blot immunoassays were positive in 25 children. Nine of the children had indeterminate Western blot results, and two had negative results. Two children with indeterminate blots were symptom-free, while the other seven had symptoms of HIV infection. The asymptomatic children with indeterminate results were under 15 months of age; both had positive HIV cultures. The children with indeterminate results tended to have higher levels of viral proteins and a poorer prognosis than children with positive Western blot results. The study suggests that in children under 18 months, thorough medical history and examination and full laboratory testing, of which Western blot analyses are only one component, are necessary to diagnose or rule out HIV infection. Other laboratory tests are essential, including ELISA (enzyme-linked immunosorbent assay), determination of specific HIV viral antigens, and culturing to isolate the HIV virus. (Consumer Summary produced by Reliance Medical Information, Inc.)

Zidovudine (ZDV, also called azidothymidine, or AZT) is the only known effective treatment for AIDS. It has been used safely in adults. The major side effect is suppression of blood cell production by bone marrow and other tissue. The effects of three escalating dosage regimens of ZDV on clinical and laboratory measures of 35 children with AIDS or severe AIDS-related complex are reported. The children were between 5 months and 14 years old, with an age of 3.5 years. ZDV was administered intravenously and, then, orally. During the clinical trial, none of the children were taken off ZDV. Side effects were generally related to anemia and neutropenia (low numbers of red and white blood cells), causing 13 children to receive lower doses of ZDV. The other major side effect was staphylococcus-associated phlebitis (vein inflammation due to bacterial infection). Children and parents reported an improved sense of well-being; children gained weight rapidly. There was a decrease in liver and/or spleen enlargement in most of the children who began the study with an enlarged liver and/or spleen. In many of the children, there was a decline in elevated levels of immunoglobulins (blood proteins which act as antibodies), particularly in children with the highest immunoglobulin levels. Neutropenia could have caused an increased susceptibility to infection, but only two infections were linked to this condition, and all infections (many related to catheters) were relatively minor and inconsistent with AIDS-linked opportunistic infections. Indications of HIV (which causes AIDS), as isolated from blood samples, did not change in response to ZDV treatment. The group of children receiving the highest dose of ZDV (160 milligrams/meter squared) required more transfusions for anemia. Neutropenia was greater in this group and the lowest dose (80 mg/meter squared) group. More patients in the lowest dose group needed dose reductions. These results indicate that ZDV is safe in children with HIV if they are closely monitored for blood disorders; continued investigation is needed. (Consumer Summary produced by Reliance Medical Information, Inc.)

EDITOR'S NOTE: Although curative therapy for HIV infection remains an elusive goal, a number of advances have occurred that can improve the quality and duration of life for HIV-infected infants and children. This includes both antiretroviral therapy and general supportive care. It is certainly hoped and exected that, in the years ahead, improvements and refinements will make treatments more successful. For now, however, standards of care can be defined and should be made available to the pediatric community. Accordingly, the National Pediatric HIV Resource Center brought together a multidisciplinary group of health care providers and parents to define what could and should be done now for all HIV-infected children. It is recognized that these recommendations can (and will) be improved in the future. However, they provide a common ground and basis for dialogue and intervention now and they should be read and considered by all who engaged in the care of children.

The majority of children infected with human immunodeficiency virus live in resource-constrained settings and die without an established diagnosis. Definitive laboratory diagnosis in children younger than 12–18 months requires virologic testing; however, antibody testing is often the only option available. Antibody testing provides a definitive diagnosis in older children but is frequently not used. Children meeting clinical criteria should be treated regardless of availability of laboratory diagnoses.

To evaluate the prognostic value of surrogate markers (HIV RNA copy number, CD4 counts and CDC clinical and immunologic categories) in HIV-infected children through a 2-year period.

Summary Plaque purified Coxsackie B4 virus (CB4) caused a persistent infection of rat insulinoma (RIN) cells which lasted for the 70 day observation period. Infectious virus was produced and no cytopathic effect was observed. Indirect immunofluorescence and infectious center assays demonstrated that a majority of RIN cells were infected. Defective interfering particles were not demonstrated. Despite persistent infection, insulin synthesis by RIN cells was not altered.

• We studied blood transfusion variables and cytomegalovirus (CMV) infection in 385 infants admitted to the Duke University Medical Center, Durham, NC, neonatal intensive care unit over 14 months. Cytomegalovirus antibody titers were measured at birth and monthly thereafter. Urine cultures for CMV were performed regularly. Infants admitted in the first six months (n=197) received conventionally prepared blood. Infants admitted in the remaining eight months (n=188) were given frozen, deglycerolized blood. Of the 105 infants weighing 1250 g or less (low birth weight [LBW]), 90 (86%) received transfusions. Two hundred eighty infants weighed more than 1250 g (non-LBW), and 111 (40%) of these were given blood. In the first six months of the study, three infants had CMV viruria. One case was congenital; two were acquired. Both infants who acquired infection were antibody-positive at birth and received multiple transfusions. In the remaining eight months, five infants had CMV viruria. Two cases were congenital; three were acquired. The three infants who acquired infection were antibody-positive at birth and received multiple transfusions. Our study demonstrates that infants with an LBW are more likely to receive blood transfusion and to be given significantly more blood than non-LBW infants. There was no difference in the number of infants acquiring CMV in the two periods despite the use of different preparations of blood.(AJDC 1988;142:1188-1193)

A total of 465 healthy infants and adolescents ages 12 months to 17 years without a known history of varicella or recent exposure to varicella-zoster virus VZV were immunized with live attenuated Oka/Merck varicella vaccine from November, 1984, through April, 1989. The vaccine administered was from 1 of 7 production lots containing from 950 to 3265 plaque-forming units and was well-tolerated with few side effects. The seroconversion rate for seronegative subjects was 94.6 (403 of 426). This varied by lot from 85 (950 plaque-forming units) to 100 (3010 and 3265 plaque-forming units). Breakthrough disease after exposure to varicella in seroconverters during 5 to 10 years of follow-up was 18.6 (75 of 403). The breakthrough disease was characterized by a maculopapular rash with a median of 35 lesions, most of which were macules. Breakthrough disease lasted a median of 5 days and the median temperature was 99°F; 65.3 (49 of 75) of subjects were afebrile and 2.7 (2 of 75) of subjects had temperatures of > 102.9°F. Varicella vaccine provides excellent (94.6) seroconversion, and most children who developed breakthrough disease (18.6) experienced a modified, milder form of illness than has been observed with natural varicella in unvaccinated subjects.

In order to provide the opportunity for women delivering newborns to have human immunodeficiency virus (HIV) testing we piloted a hospitalbased voluntary HIV testing program during the newborn period using the Guthrie card. During the study period 789 women were offered newborn HIV antibody testing. Test acceptance during the newborn period (61.0) was comparable to that reported for the prenatal period (60.6). Overall 77.4 of women were tested in the newborn period or reported being tested in the prenatal period. Prenatal test acceptance best predicted newborn HIV test acceptance (odds ratio, 3.37; 95 confidence interval, 2.40 to 4.74). When compared to HIV testing during the newborn period prental HIV testing is preferable because it enables the recognition of HIV infection early during pregnancy and allows the mother the option to elect zidovudine therapy and potentially prevent infection in her newborn. However, when prenatal HIV testing is not routinely made available or cannot be assured, women should be offered the opportunity to be tested during the newborn period.

Although the numbers of human immunodeficiency virus-infected children in the United States are among the most rapidly growing populations, pediatric patients still comprise only approximately 2 of the acquired immunodeficiency syndrome cases in developed countries. In developing nations, however, children comprise 5 to 20 of the people with acquired immunodeficiency syndrome and the impact of human immunodeficiency virus infection on infant and childhood morbidity and mortality in these countries is astounding. As the global community evolves, it is important for pediatricians to be aware of the seriousness of acquired immunodeficiency syndrome on the world's community of children. Drs. Quinn, Ruff and Halsey present a well-informed and sobering perspective on the incidence, patterns of transmission, clinical manifestations, medical management, social impact and preventive considerations regarding human immunodeficiency virus-infected children in developing nations. There are many important lessons and insights to be gained from the experiences in Africa and Haiti and we would encourage all physicians to read and think about this important article.

We evaluated the responses of HIV-infected children to a single dose of split-virus influenza vaccine and the relationship to viral load and other characteristics.

Twelve amniotic fluid samples were examined for immunoglobulin content, specific viral antibodies, and the presence of viral agents. Amniotic fluid cells were established in culture from 8 amniotic fluid samples, and 4 cell lines were found to be susceptible to infection by 9 animal viruses. These techniques are of potential value in assesment of a pregnancy for intrauterine viral infection.

A study of antibiotic use at Duke University Medical Center in June 1973 showed that 34.2% of all patients received antibiotics (43.6% surgical, 21.4% medical patients). Cephalothins were most frequently ordered for surgical patients, ampicillin sodium and penicillin G or penicillin V with potassium for other patients.A retrospective analysis of 50 randomly selected patients, according to the Kunin's categories of use, showed 64% of total antibiotic therapy as not indicated or inappropriately administered in terms of drug or dosage.These results are similar to previous reports of antibiotic surveillance and further establish the need for continuing education of prescribing physicians.(JAMA 237:2819-2822, 1977)

Echovirus 14 was isolated from the liver of a newborn infant with fatal hepatic necrosis. It appeared likely that the infection was acquired in utero. Ultrastructurally, the findings in the liver cells were consistent with a viral infection. In cell cultures the viral isolate was found to produce crystalline inclusions in the nucleus and cytoplasm. Negative stained virions measured approximately 30.3 mμ in diameter. To our knowledge, the electron microscopy of echovirus 14 has not been previously reported.

FROM THE first reports1,2 of data obtained in careful clinical investigations of susceptible children to whom live HPV-77 African green monkey kidney (GMK) rubella vaccine was administered, several characteristics of the attenuated infection became apparent. As other investigators confirmed and extended, these initial results over a three-year period, the original features have been strikingly consistent.3-5 They include the successful establishment of an infection which is usually occult, the intermittent shedding of vaccine virus from the pharynx during the period from one to three weeks after immunization, the absence of communicability to susceptible contacts, a failure to develop detectable viremia, and the appearance in two to four weeks postinoculation of type-specific serum antibody with both hemagglutination-inhibiting (HI) and virus-neutralizing (VN) activities but no measurable complement-fixing antibody. In collaborating with Drs. Parkman and Meyer to enlarge the experience with this experimental vaccine, our continuing interest in the patterns of interaction

Answers why an HIV infection is particularly difficult to combat in children. HIV's aggressiveness in children; The problem of drug companies waiting to test medications on children until the agents proved effective in adults; Suggestion that beginning a combination therapy promptly after diagnosis is better for limiting viral replication and for establishing immunity; The efforts in the developing world to assess new preventative approaches.

• An 8-month-old male infant with severe combined immunodeficiency syndrome was admitted to the hospital with pneumonitis and, subsequently, died at 21 months of age. During his lengthy hospitalization, parainfluenza virus type 3 (PIV-3) was isolated from respiratory secretions and unusual sites, such as pericardial fluid, CSF, and WBCs. A postmortem examination showed apparent viral pancreatitis, and PIV-3 was isolated from the lung, brain, and pericardial fluid. To our knowledge, this is the first reported case of disseminated parainfluenza infection identified during life. We speculated that a mutant fusion protein may have been elaborated by the virus, allowing dissemination beyond the respiratory tract.(Am J Dis Child 1983;137:1172-1174)

A prospective study of 70 mother-infant pairs was designed to evaluate vertical transmission of group B Streptococcus (GBS) in relation to the use of intrauterine fetal monitors (IUFMs). Multiple-site cultures obtained from mothers during the intrapartum interval and those obtained from infants on day 1 and at discharge or day 4 were plated on a selective medium. Thirteen (27.1%) of 48 IUFM-exposed women vs seven (31.8%) of 22 non-IUFM-exposed women had GBS at one or more sites. The GBS colonization with maternally concordant serotypes occurred in eight (61.5%) of 13 infants born to GBS-colonized, IUFM-exposed women vs two (28.6%) of seven infants born to GBS-colonized, non-IUFM-exposed women. While this suggests that vertical transmission of GBS is enhanced by IUFM placement, the differences in these infant rates were not statistically significant.(JAMA 242:42-44, 1979)

A 15-month-old infant observed at Duke University Medical Center for his final six months of life died with infectious complications of lymphopenic agammaglobulinemia. Parainfluenza virus type II was present in four specimens of respiratory secretions obtained during the terminal three months of life. Autopsy findings disclosed multinucleate giant cells in his lungs.

Dr Finley's comments are appreciated. The 50 patients whose records were reviewed were selected in a completely random manner. The appraisal of the antibiotic management was accomplished individually by three physicians prior to the assignment of the terms "inappropriate" or "appropriate." Examples of the criteria employed are (1) no evidence of infection and no indicated reason for prophylaxis, and (2) no bacterial cultures obtained, or an organism isolated but resistant to the drug employed.Antibiotics are one of the most frequently prescribed groups of drugs, and in the best interests of patient management, we must continue to use antimicrobial agents wisely to achieve effective therapy, to try to minimize the development of resistant organisms, and to reduce costs of treatment if two equally effective antimicrobial agents are available. These problems have been carefully considered in the report by Kunin et al.1 In 1977 the ad hoc

Reports on Duke University researcher Catherine M. Wilfert's assertion that AIDS testing of pregnant women could prevent the transmission of HIV in babies. Call for mandatory AIDS testing of pregnant women; Study by the AIDS Clinical Trial Group (ACTG) which found that HIV-positive women who are given zidovudine during pregnancy are less likely to pass HIV on to their babies.

WIN 51,711 is an antiviral agent with demonstrated in vitro activity against a number of Picornaviruses, including Coxsackievirus A9 (CA9). The drug has proved to be effective in animal model studies against Echovirus 9 and Poliovirus 2 infection in mice. This study used white Swiss mice which were infected with CA9 when they were between 24 and 48 hours of age. The LD50for these mice was established as 1.8 × 105TCID, and this quantity of virus was injected intraperitoneally (ip). Several routes of delivery of the drug have been tested. Giving 100 mg/kg/day of the drug in a 1% gum tragacanth suspension as a single daily ip injection led to significent delay in weight gain and mortality approaching 50%. Reducing this dose to 50 mg/kg/day ip appeared to alleviate this problem, as did delivering 100 mg/kg/day subcutaneously instead of ip. In the limited numbers of mice studied to date, protection against mortality using the latter two routes is 100%. Administering 100 mg/kg/day po once daily in a 1% gum tragacanth suspension had no effect on animal growth, but also provided no protection against mortality or symptomatology. It is hypothesized that this lack of effect reflects either poor absorption via the po route in suckling mice, or the shorter half-life of the drug when administered in oral boluses instead of ip or subcutaneous deposition. The toxicity of the 100 mg/kg/day dose ip appeared to be mechanical, since eventually crystals could be seen to accumulate in the peritoneum.

56 children, including nephrotic syndrome (NS) patients, renal transplant (TX) recipients and normals, aged 2 to 15 years; were given a pneumococcal vaccine containing 14 polysaccharide (PS) types. Vaccine A with 50ug of each PS type was compared to Vaccine B with 25ug of each type. Study divisions were: Group 1)16 NS patients, Vaccine A; Group 2)10NS patients, Vaccine B; Group 3)3 TX patients, A; Group 4)10 TX patients, B; Group 5)10 normals A; Group 6)7 normals, B. Antibodies were determined for each PS type before, and 1, 3, 12 and 24 months after vaccination. At 1 month: a)the two vaccines produced comparable geometric mean titers (GMT) for 7/12 PS types in normals, 2/14 in NS patients, and 2/14 in TX patients. b)Vaccine B produced higher GMT's for 4/12 PS types in normals and for 11/14 in NS patients. c)Vaccine A produced a greater GMT for 12/14: types in TX patients. The sero-conversion rates were similar within paired groups. By 24 months the GMT was ≤ the pre-vaccine level for 9/12 types in Group 1, 7/12 Group 2, 11/12 Group 3, 6/12 Group 4, 6/12 Group 5, and 3/12 Group 6. The GMT was greater than the assumed protective level of 300 ng antibody N/ml for 4/12 types in Group 1, 5/12 Group 2, 4/12 Group 3, 4/12 Group 4, 5/12 Group 5, and 10/12 Group 6 at 24 months. 25ug of PS provided a similar immune response to that induced by the currently employed 50ug dose. Waning antibody titers suggest that longitudinal assessment of protection is essential and the possible need for booster doses remains to be determined.

In this AIDS Commentary, Dr. Catherine Wilfert addresses the issue of vertical transmission of the human immunodeficiency virus type 1 (HIV-1). She reviews the results of the recently completed trial conducted by the AIDS Clinical Trials Group that evaluated the effectiveness of administering zidovudine to pregnant women in reducing the incidence of vertical transmission. In view of the success of this trial, Dr. Wilfert addresses the problem of the efficacy of voluntary counseling and testing of pregnant women. Identification and treatment of HIV-1 infected women could potentially reduce the incidence of pediatric HIV-1 infection and increase the number of women receiving appropriate therapy. She makes the point that legislative mandates have been necessary to produce rates of childhood immunization that are effective in reducing the occurrence of vaccine-preventable diseases. This suggests that such mandates are an option to consider in the effort to control vertical transmission of HIV-1 infection. Her cost-benefit analysis indicates that universal screening of pregnant women for HIV infection would result in enormous overall savings for the health care system. Obviously, making the testing of pregnant women mandatory raises a number of difficult issues and is controversial. Dr. Wilfert has provided a service by raising this issue; further discussion is needed.

The first reported outbreak of echovirus 18 meningitis in the United States occurred during the summer of 1972 in Durham, North Carolina. One hundred three cases of aseptic meningitis were seen at Duke University Medical Center over a period of four months. Most of the patients were less than 25 years old, black, and residents of Durham County or nearby counties. Symptoms included headache (92%), fever (76%), nuchal rigidity (67%), and nausea and/or vomiting (51 % ). In contrast to previously published reports of echovirus 18 infection, diarrhea and rash were infrequent (6 % and 5%, respectively). There were no deaths. Counts of white blood cells in the cerebrospinal fluid ranged from 0 to 1,540 cells/mm3, but 90% of the patients had < 500 cells/mm3. Echovirus 18 was recovered from the cerebrospinal fluid of 55 of 78 patients, and echovirus 11 was isolated from two patients. Virus was recovered from the cerebrospinal fluid of 12 patients despite white blood cell counts in cerebrospinal fluid of < 10 cells/mm3.

This discussion of the pathogenesis of infant human immunodeficiency virus (HIV) type 1 infection emphasizes features unique to pediatric disease and provides general insights into HIV Illness 10 all populations. Therapies designed to interrupt transmission of HIV can be most efficiently addressed through studies of maternal-infant transmission. The rapid progression of disease in children constantly emphasizes the urgent need for continued progress in treatment of HIV infectionandpresentsaunique opportunityoptimallytoassesseffectsofearlyintervention.