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Peripheral blood lymphocyte subsets need to be determined in a large, urban, minority-predominant cohort of healthy children to serve as suitable control subjects for the interpretation of the appearance of these cells in several disease conditions, notably pediatric HIV-1 infection.We sought to determine the distribution of lymphocyte subsets in healthy urban-dwelling infants, children, and adolescents in the United States.Lymphocyte subsets were determined by means of 3-color flow cytometry in a cross-sectional study of 807 HIV-unexposed children from birth through 18 years of age.Cell-surface marker analysis demonstrated that age was an extremely important variable in 24 lymphocyte subset distributions measured as percentages or absolute counts--eg, the CD4 (helper) T cell, CD8 (cytotoxic) T cell, CD19 B cell, CD4CD45RACD62L (naive helper) T cell, CD3CD4CD45RO (memory helper) T cell, CD8HLA-DRCD38 (activated cytotoxic) T cell, and CD8CD28 (activation primed cytotoxic) T cell. The testing laboratory proved to be an important variable, indicating the need for using the same laboratory or group of laboratories to assay an individual's blood over time and to assay control and ill or treated populations. Sex and race-ethnicity were much less important.The results of this study provide a control population for assessment of the effects of HIV infection on the normal development and distribution of lymphocyte subsets in children of both sexes, all races, and all ethnic backgrounds from birth through 18 years of age in an urban population. This study's findings will also prove invaluable in interpreting the immune changes in children with many other chronic diseases, such as primary immunodeficiency, malignancy, rheumatoid arthritis, and asthma.

Objective. Streptococcus pneumoniae infections in the neonate (SPIN) are relatively unusual events (1%–11% of neonatal sepsis) but are associated with substantial morbidity and mortality. Previous reports suggest that invasive SPIN is associated with prolonged rupture of membranes, maternal colonization/illness, prematurity, early-onset pneumonia presentation (Methods. The US Pediatric Multicenter Pneumococcal Surveillance Group has been prospectively monitoring S pneumoniae infections since 1993 in 8 children’s hospitals. For this report, data were gathered retrospectively from the charts of neonates who were 30 days of age and younger and had SPIN from September 1993 to February 2001. All pneumococcal isolates were sent to a central laboratory for serogrouping/typing and susceptibility testing.Results. Twenty-nine cases of SPIN were identified from a total of 4428 episodes of S pneumoniae infection in children. Sixty-six percent were male, and 55% were white; the mean age was 18.1 day (±8.2). Ninety percent of infants were ≥38 weeks’ gestation. Two mothers had bacterial infections at delivery; 1 had S pneumoniae isolated from both blood and cervix, and 1 had clinical amnionitis. The primary diagnoses in the neonates were bacteremia (8), meningitis (8), bacteremic pneumonia (4), septic arthritis/osteomyelitis (1), and otitis media (8). Thirty percent of infants with invasive SPIN presented with leukopenia/neutropenia, but this did not predict poor outcome. The infecting pneumococcal serogroups were 19 (32%); 9 (18%); 3 and 18 (11% each); 1, 6, and 14 (7% each); and 5 and 12 (3.5% each). Twenty-six percent of invasive neonatal infections were caused by serogroups 1, 3, 5, and 12, which are not contained in the heptavalent pneumococcal vaccine. In contrast, 6% of invasive nonneonatal disease was caused by these same nonvaccine serogroups. Susceptibility testing demonstrated that 21.4% of isolates were penicillin nonsusceptible and 3.6% were ceftriaxone nonsusceptible. Three (14.3%) neonates with invasive SPIN died; all deaths occurred within 36 hours of presentation. Deaths did not appear to be related to pneumococcal serogroup or susceptibilities.Conclusions. Compared with previous studies of neonates with pneumococcal infection, this series showed that infants with SPIN were usually 2 to 3 weeks of age at presentation; likely to be full term; and ill with pneumonia, meningitis, and otitis media. This late-onset presentation was associated with an overall mortality rate of 10.3% (14.3% for invasive disease).

Streptococcus bovis is an uncommon cause of infection in neonates. However, S . bovis is capable of causing fulminant neonatal sepsis or meningitis that is indistinguishable clinically from that caused by group B streptococcus. S . bovis and S . bovis variant (sometimes referred to as S . bovis biotypes I and II, respectively) are phenotypically similar but may be differentiated by expanded testing. In adults, specific associations between disease states and different biotypes of S . bovis are apparent. No data exist on possible differences or clinical relevance of neonatal infection caused by different biotypes or newer species of S . bovis . We report a 3-day-old neonate with bacteremia and meningitis caused by S . bovis variant ( S . bovis biotype II/2) and review the literature.

Mycobacterium gordonae is historically viewed as an organism with low pathogenic potential, but it has increasingly become implicated in clinical disease in immunocompromised hosts. Illness related to M. gordonae infection ranges from localized infections to rare cases of disseminated disease. This report describes treatment of the first case of occult M. gordonae bacteremia in an adolescent with AIDS.

BACKGROUND An aggressive therapeutic approach for treatment of HIV in adults consists of combining five or more concurrent antiretrovirals. The clinical benefits of this regimen are often accompanied by increased toxicities. We report the safety and tolerance of multiple drug therapy in HIV-infected children. METHODS A retrospective chart review was performed to identify HIV-infected children who received > or =5 concurrent antiretrovirals or 4 antiretrovirals plus hydroxyurea. Treatment success was defined as > or =1 log(10) decrease in plasma HIV RNA from baseline any time during multiple drug therapy. Toxicities were defined as a >Grade 2 change from baseline in laboratory values. RESULTS Twelve patients received multiple drug therapy for 6 months, and 42% of patients continued to receive therapy for at least 1 year. No Grade 3 or 4 toxicities or laboratory abnormalities were reported. Treatment success occurred in 8 (83%) of 12 patients. Adherence was a determining factor in treatment success or failure. CONCLUSIONS Treatment of HIV-infected children with multiple drug therapy was well-tolerated in this cohort. Treatment success occurred in most patients, with adherence affecting patients' likelihood of success. Larger controlled clinical trials in this patient population are necessary to determine whether the benefit of this therapeutic approach outweighs potential risks.

Didanosine remains a cornerstone nucleoside analogue for the treatment of HIV infection. A potential problem with the buffered formulations of didanosine is the likelihood of interactions with other drugs that require an acidic pH for absorption or can be chelated by cations in the buffer. An encapsulated enteric-coated (EC) bead formulation of didanosine has been approved and is routinely used as an alternative to the chewable/dispersible buffered tablet formulation. The objective of this study was to evaluate the single-dose pharmacokinetics of didanosine EC at 240 mg/m2 in 10 HIV-infected children. Didanosine EC was administered at time 0 on an empty stomach with no other concomitant medications. Blood samples were collected at pre-dose, 0.5, 1, 2, 4, 8 and 12 h post-dose. Didanosine was measured in plasma using radioimmunoassay. Ten subjects completed the intensive pharmacokinetic evaluation; data are available for eight participants. Plasma concentrations of didanosine following EC administration were analysed using non-compartmental methods. Median (range) AUC∞, Cmax, Tmax and CL/F for didanosine following EC administration were 2385 (1291, 3966) ngxh/ml, 854 (300, 1799) ng/ml, 3.0 (1.0, 8.1) h and 3.3 (2.7–6.4) l/h/kg, respectively. Results from this study indicate that the didanosine Cmax is decreased and Tmax is prolonged, but total exposure of didanosine in plasma following didanosine EC administration appears similar to previous data collected in HIV-infected children following buffered didanosine administration.

Asplenia is associated with an increased risk of infections caused by Streptococcus pneumoniae. Overwhelming infection can be fulminate and lead to a fatal outcome.To review the epidemiology and clinical course of invasive S. pneumoniae infections in children with asplenia before the release of the conjugate pneumococcal vaccine.Children with S. pneumoniae infections from eight children's hospitals in the US were identified prospectively from September, 1993, to August, 1999. Further demographic, medical and microbiologic information was gathered retrospectively from the charts of patients with asplenia.Twenty-two asplenic patients with 26 episodes of invasive S. pneumoniae were identified. This represents 1% of the 2,581 episodes of invasive S. pneumoniae infections identified in our study. Twelve had congenital asplenia (CA), and 10 had undergone surgical splenectomy. Nine of the patients with CA had associated complex congenital heart disease. The median age at first infection was 12.5 months for CA patients as compared with 69 months in children with surgical splenectomy (P0.001). Seventy-five percent of those eligible had received the polysaccharide pneumococcal vaccine. The most common serotypes isolated were 6B (8), 23F (7), 18C (2) and 19A (2). Antimicrobial prophylaxis had been prescribed for 82% of the study cohort. Clinical presentations of the 26 episodes included fever (22), shock (7), petechiae or purpura (7), disseminated intravascular coagulation (5) and respiratory distress (5). Clinical illness included bacteremia alone (12), meningitis alone (8), bacteremia with otitis media-sinusitis (3), bacteremia with pneumonia (2) and meningitis with osteomyelitis (1). Five of the 6 patients who died had meningitis. Three of the survivors (19%) had significant morbidity, and all of them had meningitis. Two patients had 2 episodes each, and 1 patient had 3 episodes. All but 1 of the multiple episodes was with a different serotype. Forty-six percent of isolates were nonsusceptible to penicillin, and 19% were nonsusceptible to ceftriaxone. There was no association between antimicrobial resistance and mortality.Invasive pneumococcal disease in patients with asplenia has a high mortality, especially in those with meningitis. Even though the new conjugate vaccine might increase protection, 19% of patients had disease caused by serotypes not included in the current heptavalent vaccine. Clinicians should continue to be aggressive in evaluating asplenic patients with unexplained fevers.

In individuals infected with human immunodeficiency virus type 1 (HIV-1), specific immunity is associated with a more diverse viral repertoire and slower disease progression. Attempts to enhance antiviral immunity with therapeutic vaccination have shown that recombinant glycoprotein (RGP) vaccines are safe, well tolerated, and immunogenic, but the effect of RGP vaccines on the viral repertoire is unknown. We evaluated diversification of the viral envelope in 12 HIV-infected children who received placebo or RGP vaccines. At baseline, 11 of 12 patients had multiple viral variants. On follow-up 6 months later, children who had a strong vaccine-associated lymphoproliferative immune response showed less viral diversification than those in whom the immune response was weak or absent. These results suggest that the immune response elicited by RGP vaccines does not exert a significant selection pressure on the viral quasispecies and therefore may not be helpful in changing the course of the disease.

Stanford T. Shulman, MD, moderator: We now will discuss the human immunodefi ciency virus and AIDS. Ram Yogev, MD, is an international leader in HIV, specifi cally pediatric HIV. Ram Yogev, MD: This disease was fi rst noticed in 1981 in the United States, which is only 30 years ago. Interestingly, there is evidence that the disease originated in Africa. There is also a possibility that it had been identifi ed in the United States back in the 1960s, although we didn’t know too much about it at that time. It fi rst appeared in homosexual men and then in IV drug users, and unfortunately, that brought a lot of stigma to it. Many physicians were even reluctant to take care of these patients, and they even suggested that they should not be allowed in the hospital. The real breakthrough in this disease in pediatrics was about 5 or 6 years after it was discovered. The fi rst treatment was approved, which was azidothymidine (AZT). This drug was originally investigated for the treatment of cancer. However, it was not effective for cancer, and it was put on the shelf. Luckily enough, someone remembered it, and began suggesting its use. That really led to major changes to our approach to treatment. One of the biggest successes of all the funding in research is the study, conducted by the Pediatric AIDS Clinical Trials Group (PACTG), sponsored by the NIAIA/NIH, at several study sites, which showed that AZT reduces the risk of HIV transmission from infected mother to the children.1 The study showed that treatment with AZT alone can reduce mother-to-child transmission of the disease by two-thirds. Recently, a few states (eg, New York, Connecticut, Illinois) made it mandatory to test if the newborn is infected, and they reported close to 100% lack of transmission from mother to child. The next breakthrough was in the 1990s, when more drugs came to the market. These drugs attack the virus and when it enters the cell, or the way it comes out of the nucleus and when it replicates itself. The fi rst protease inhibitor was a major breakthrough. The availability of the family of protease inhibitors led to three different drugs from at least two different families, called HAART (Highly Active Antiretroviral Therapy). HAART made the difference between an acute disease, which in children had a 60% mortality rate by 6 years of age, to a life expectancy of 40 or 50 years. Obviously, there are side effects of these drugs. We have problems with patient adherence, but the future for those patients looks very bright compared with what it was 20 years ago. Dr. Shulman: Dr. Yogev wrote an editorial, which starts out by saying that when he started his career in treating patients with HIV, he attended their funerals.2 Now, he’s able to attend their grade school, high school, and college graduations. I think that encapsulates the incredible progress made in the treatment of pediatric HIV infection. Dr. Yogev: That editorial was written because there were small studies suggesting that at least in pediatrics, if we start treatment in the fi rst 3 months of life, we’re changing the course of the disease so much that the patients are losing their antibodies.3,4 A study published about 2 years ago showed that within 1 year you can see the difference in the outcomes of patients who started treatment before 3 to 4 months of age and those who started it later.5 Sharon B. Murphy, MD: I’m prompted to refl ect that, coincident with your recollections of the epiA note from the editors: To commemorate the 40th anniversary of Pediatric Annals, the publishing staff invited the Editorial Advisory Board and some experts to discuss important advances in the fi eld of pediatrics over the past 40 years. Excerpts from this discussion, held in March 2011, will be published in the next several issues of Pediatric Annals. roundtable • roundtable • • roundtable • roundtable roundtable

The CD40 ligand (CD154), expressed primarily on activated CD4-positive T cells, is a costimulatory molecule involved in B-cell proliferation, germinal center formation, and immunoglobulin class switching. Since B-cell abnormalities including hypergammaglobulinemia and abnormal antibody-specific immune responses are prominent and occur early during the course of pediatric human immunodeficiency virus (HIV) infection, we measured the baseline levels and the induced levels of expression of CD154 on CD3+CD8−(T helper cells) in HIV-infected children and uninfected children born to HIV-positive mothers. The percentage of CD154+T helper cells activated in vitro and the level of CD154 expressed per T helper cell (mean fluorescent channel [MFC]) were significantly lower in the HIV-infected children than in the uninfected control group (77% ± 3% versus 89% ± 1%, respectively [P< 0.002], and 261 ± 174 versus 415 ± 130 MFC, respectively [P< 0.03]). The levels of CD154 expressed on resting T helper cells in the HIV-infected group were not significantly different from the levels observed in the control group. In the HIV-infected children, the level of CD154 on activated T helper cells correlated with the level of immunodeficiency, as assessed by the CD4 T-cell levels (correlation coefficient [r] = 0.707,P= 0.003), but did not correlate with the viral load or with any of the serum immunoglobulin concentrations measured in this group of HIV-infected children. The baseline level of CD154 expressed on T helper cells did, however, correlate with the concentration of immunoglobulin A in serum. We conclude that HIV-infected children have impaired regulation of CD154 expression which may contribute to the immune dysregulation commonly observed.

Background Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. Methods We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration–time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. Results Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). Conclusion Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children. Clinical Pharmacology & Therapeutics (2001) 70, 24–32; doi: 10.1067/mcp.2001.115891

A phase 2 clinical trial was conducted to evaluate the antibody responses to bovine parainfluenza virus type 3 (bPIV3) vaccination in young infants. Three groups were tested as follows: placebo (n = 66) and 10 5 (n = 64) or 10 6 (n = 62) TCID 50 of bPIV3. The vaccine or placebo was administered intranasally at ages 2, 4, 6, and 12-15 months, and serum specimens were collected at ages 2, 6, 7, 12-15, and 13-16 months. Serum hemagglutination inhibition (HI) and IgA antibody titers against bPIV3 and human PIV3 (hPIV3) were measured. The results indicate that antibody responses to bPIV3 vaccination are more likely to be detected by the bPIV3 IgA and HI assays than by the hPIV3 IgA and HI assays, that bPIV3-induced antibody response can be differentiated from hPIV3-induced antibody response most reliably by comparing bPIV3 and hPIV3 HI titers, and that bPIV3 vaccine prevents vaccine recipients from developing antibody profiles of hPIV3 primary infection.

The placenta may play a critical role in inhibiting vertical transmission of HIV-1. Here we demonstrate that leukemia inhibitory factor (LIF) is a potent endogenous HIV-1-suppressive factor produced locally in placentae. In vitro, LIF exerted a potent, gp130-LIFRbeta-dependent, HIV coreceptor-independent inhibition of HIV-1 replication with IC50 values between 0.1 pg/ml and 0.7 pg/ml, depending on the HIV-1 isolate. LIF also inhibited HIV-1 in placenta and thymus tissues grown in ex vivo organ culture. The level of LIF mRNA and the incidence of LIF protein-expressing cells were significantly greater in placentae from HIV-1-infected women who did not transmit HIV-1 to their fetuses compared with women who transmitted the infection, but they were not significantly different from placentae of uninfected mothers. These findings demonstrate a novel pathway for endogenous HIV suppression that may prove to be an effective immune therapy for HIV infection.

Vitamin A administered to children infected with the human immunodeficiency virus before influenza vaccination in a double-blind randomized study did not enhance vaccine serologic responses but did dampen the increase in the human immunodeficiency virus viral load 14 days after immunization (vitamin A, decrease of 0.13 ± 0.09 log 10 copies/mL; placebo, increase of 0.14 ± 0.08, P =.02). (J Pediatr 2000;136:550-2)

Objective.To review the epidemiology and clinical course of facial cellulitis attributable toStreptococcus pneumoniae in children.Design.Cases were reviewed retrospectively at 8 children's hospitals in the United States for the period of September 1993 through December 1998.Results.We identified 52 cases of pneumococcal facial cellulitis (45 periorbital and 7 buccal). Ninety-two percent of patients were 15 000/mm3) were noted at presentation in 78% and 82%, respectively. Two of 15 patients who underwent lumbar puncture had cerebrospinal fluid with mild pleocytosis, which was culture-negative. All patients had blood cultures positive for S pneumoniae. Serotypes 14 and 6B accounted for 53% and 27% of isolates, respectively. Overall, 16% and 4% were nonsusceptible to penicillin and ceftriaxone, respectively. Such isolates did not seem to cause disease that was either more severe or more refractory to therapy than that attributable to penicillin-susceptible isolates. Overall, the patients did well; one third were treated as outpatients.Conclusions.Pneumococcal facial cellulitis occurs primarily in young children (

To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ’s area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower ( n = 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.

Plasma-soluble CD30 (sCD30) is the result of proteolytic splicing from the membrane-bound form of CD30, a putative marker of type 2 cytokine-producing cells. We measured sCD30 levels in children with tuberculosis, a disease characterized by prominent type 1 lymphocyte cytokine responses. We postulated that disease severity and nutritional status would alter cytokine responses and therefore sCD30 levels. Samples from South African children enrolled prospectively at the time of diagnosis of tuberculosis were analyzed. (Patients were originally enrolled in a randomized, double-blind placebo-controlled study of the effects of oral vitamin A supplementation on prognosis of tuberculosis.) Plasma samples collected at the time of diagnosis and 6 and 12 weeks later (during antituberculosis therapy) were analyzed. sCD30 levels were measured by enzyme immunoassay. The 91 children included in the study demonstrated high levels of sCD30 at diagnosis (median, 98 U/liter; range, 11 to 1,569 U/liter). Although there was a trend toward higher sCD30 levels in more severe disease (e.g., culture-positive disease or miliary disease), this was not statistically significant. Significantly higher sCD30 levels were demonstrated in the presence of nutritional compromise: the sCD30 level was higher in patients with a weight below the third percentile for age, in those with clinical signs of kwashiorkor, and in those with a low hemoglobin content. There was minimal change in the sCD30 level after 12 weeks of therapy, even though patients improved clinically. However, changes in sCD30 after 12 weeks differed significantly when 46 patients (51%) who received vitamin A were compared with those who had received a placebo. Vitamin A-supplemented children demonstrated a mean (± standard error of the mean) decrease in sCD30 by a factor of 0.99 ± 0.02 over 12 weeks, whereas a factor increase of 1.05 ± 0.02 was demonstrated in the placebo group ( P = 0.02). We conclude that children with tuberculosis had high sCD30 levels, which may reflect the presence of a type 2 cytokine response. Nutritional compromise was associated with higher sCD30 levels. Vitamin A therapy resulted in modulation of sCD30 levels over time.

The genetic diversity and molecular epidemiology of Mycobacterium avium complex (MAC) infections in children with and without human immunodeficiency virus (HIV) infection were evaluated. Isolates recovered from 136 children were subtyped by sequence analysis of a 360-bp region of the gene (hsp65) encoding a 65-kDa heat-shock protein. Twenty-one distinct hsp65 alleles were identified. On the basis of hsp65 genotype, 6 isolates were not MAC organisms. Of the remaining 130 samples, 61% were M. avium, 37% were Mycobacterium intracellulare, and 2% were species nonspecific MAC. Eighty-eight percent of the isolates obtained from HIV-infected children were M. avium. In contrast, only 38% of the isolates obtained from children without HIV infection were M. avium (chi2 test, P < .001). M. avium isolates were further subtyped by Southern blot analysis with insertion element IS1245. Taken together, no evidence for a single clonal M. avium strain causing infection was detected.

A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 μg/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 μg/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.

In Reply .— Since the publication of my commentary calling for a change in the influenza recommendations to include immunization of infants and children of child care/school age,1 the Advisory Committee on Immunization Practices revised its previous recommendation to include only children 6 to 23 months of age. They now recommend immunization of a wider group of children (ie, those 6–59 months of age).2 There was no explanation why older healthy children have not been included in the new recommendations, but the committee stated that it “is working toward the goal of annual universal …

To the Editor .— We fully concur with the assertion of Goldschmidt and Fogler that “pediatricians will be called on more and more to exercise their essential role in helping to eliminate perinatal HIV in the United States.”1 However, their commentary omitted the critical opportunity to prevent at least a third of mother-to-newborn HIV infection in vulnerable HIV-exposed newborns if they are started on anti-HIV prophylaxis within 48 hours after birth.2 With the advent of rapid HIV testing that is now available, we have the …

Objective: To address the special psychosocial and emotional needs and concerns of human immunodeficiency virus–infected children through a medical student–based Big Brother/Big Sister program. Design: A telephone survey of 9 medical students who participated in the program in the last 4 years was undertaken to assess their experiences and feelings about the program. Results: The experiences resulting from participation in the program were unanimously positive. The medical students stated that in no other medical setting were they able to develop a better understanding of the feelings and emotions of living with a terminal illness. The volunteers also believed that the program increased the benefits for the child and the medical student. Conclusions: Initial evaluation of the Big Brother/Big Sister program for human immunodeficiency virus–infected children suggests that it helped establish a strong, supportive relationship between the affected child and the medical student. A modified program in other medical schools may help to serve many other communities affected by the human immunodeficiency virus epidemic. Arch Pediatr Adolesc Med. 1997;151:189-192

Mycobacterium gordonae is historically viewed as an organism with low pathogenic potential, but it has increasingly become implicated in clinical disease in immunocompromised hosts. Illness related to M. gordonae infection ranges from localized infections to rare cases of disseminated disease. This report describes treatment of the first case of occult M. gordonae bacteremia in an adolescent with AIDS.

Rapid lysis of gram-negative bacteria is associated with considerable release of free endotoxin. Production of tumor necrosis factor (TNF) from adult whole blood ex vivo in response to bacterial products generated during antibiotic killing of Haemophilus influenzae type b (Hib) was investigated. Heparinized whole blood released TNF in a dose-dependent fashion in response to purified lipooligosaccharide of Hib. Bacteria (10(4)-10(7) cfu/mL) were placed into a Transwell filter insert (0.1 microns) and incubated with whole blood in the presence of various antibiotics. Exposure to ceftriaxone resulted in significantly greater release of TNF during killing of Hib than did exposure to imipenem, despite similar degrees of bacterial killing at 6 h. Polymyxin B inhibited the ceftriaxone-induced TNF release by 97%-99%, indicating that free endotoxin was the predominant stimulus for the increase in TNF release in this system. These observations suggest that ceftriaxone-induced killing of Hib results in bacterial cell wall products that are more proinflammatory than those produced by imipenem.

Ceftibuten (CFB), a new broad-spectrum cephalosporin for oral administration, possesses potent activity in vitro against a wide range of gram-negative and certain gram-positive pathogens frequently encountered in pediatric patients. Its antimicrobial spectrum and dosage formulation suggest a use for CFB in the treatment of otitis media and upper and lower respiratory and urinary tract infections in infants and children. To assess the pharmacokinetic characteristics of CFB in pediatric patients, we completed a multicenter investigation of 49 children (26 females) between the ages of 6 months and 17 years who had normal hepatic and renal functions and no evidence of chronic disease. Pharmacokinetic parameters were determined from repeated blood samples (n = 12) and, when possible, quantitative urine collections (n = 7) obtained over a 12- to 24-h period following a single oral CFB dose of either 4.5 or 9.0 mg/kg of body weight. CFB was quantitated from plasma and urine samples by using a sensitive, microanalytical high-pressure liquid chromatography method. The drug was rapidly absorbed (mean time to maximum concentration in serum = 140 min) and produced apparent peak concentrations in plasma (Cmax) ranging from 5.0 to 19.0 mg/liter. Average CFB pharmacokinetic parameters (+/- standard deviations) were as follows: apparent elimination half-life, 2.0 +/- 0.5 h; mean residence time, 3.9 +/- 1.1 h; apparent steady-state volume of distribution, 0.4 +/- 0.2 liter/kg; and apparent total plasma clearance (CL/F), 2.5 +/- 0.9 ml/min/kg. No significant differences in any of the pharmacokinetic parameters were observed between the two dosing groups. Significant (P < 0.05) negative correlations were found between patient age and CFB elimination half-life and CL/F and between the estimated creatinine clearance and renal clearance and CL/F. Apparent age dependence of CFB disposition was also reflected by a greater CL/F in children from 0.5 to less than or equal 5 years of age (3.1 +/- 1.1 ml/min/kg) than in children > 10 years of age (2.0 +/- 0.6 ml/min/kg; P < 0.005). The increased CL/f for CFB (3.0 +/- 0.5 ml/min/kg) was corroborated by a validation study performed with 11 infants (1.0 +/- 0.5 ml/min/kg) with CL/F for 19 subjects suggested that appreciable nonrenal clearance (1.3 +/- 0.6 ml/min/kg) of CFB occurred in children, a finding different from preliminary data for adults.

Because production of beta-lactamase by normal pharyngeal flora could account for penicillin treatment failure, we studied the effect of anaerobic and aerobic beta-lactamase-producing bacteria on bacteriologic outcome in acute group A beta-hemolytic streptococcal (GABHS) pharyngitis. We compared 10-day courses of orally administered phenoxymethyl penicillin and amoxicillin-clavulanic acid, using a randomized, single-blind treatment protocol. Eligible patients were 2 to 16 years of age and had culture-proven acute GABHS pharyngitis; 89 patients (43 penicillin, 46 amoxicillin-clavulanic acid) were compliant with therapy. beta-Lactamase-producing organisms were isolated before therapy from the throats of 67% of patients treated with penicillin and 63% treated with amoxicillin-clavulanic acid. Throat cultures after completion of therapy were positive for GABHS in 7 (7.9%) of 89 patients. The initial GABHS T type persisted (treatment failure) in only 4 (4.5%) of 89 patients, including 3 (6.5%) of 46 who received amoxicillin-clavulanic acid and in 1 (2.3%) of 43 who received penicillin (not statistically significant). Bacteriologic treatment failure was unrelated to recovery of beta-lactamase-producing bacteria at the time of enrollment or after treatment. We conclude that beta-lactamase production by normal pharyngeal flora does not fully explain the failure of penicillin therapy for acute streptococcal pharyngitis. Using an antibiotic effective against beta-lactamase-producing bacteria will not eliminate the problem of bacteriologic treatment failure.

Chemical mutagenesis techniques and genetic transformation methods were used to construct isogenic mutants of Haemophilus influenzae type b (Hib) defective in the ability to synthesize lipooligosaccharide (LOS). A mutant (17B) which expressed a LOS molecule with an altered oligosaccharide was less virulent than the wild-type parent strain, as determined by measurement of the ability of these strains to produce bacteremia in infant rats after intranasal challenge. Further mutagenesis of this mutant strain yielded two new mutants with different LOS phenotypes. Mutant 7A was slightly sensitive to the bactericidal activity present in normal infant rat serum and was even less virulent than its immediate parent strain (17B) in the intranasal challenge model. However, both mutants 17B and 7A could produce bacteremia and meningitis when introduced into infant rats by the intraperitoneal route. The other LOS mutant (14A) derived from mutant 17B exhibited a level of virulence equivalent to that of the original wild-type strain. Genetic transformation of wild-type chromosomal DNA into the essentially avirulent mutant 7A and selection of transformants on the basis of their LOS antigenic characteristics resulted in the sequential restoration of full virulence to this mutant. These findings suggest that LOS is involved on at least two different levels in the ability of Hib to produce invasive disease in the infant rat model. Changes in LOS phenotype can independently affect the ability of Hib to produce bacteremia after intranasal challenge and the sensitivity of Hib to killing by normal infant rat serum. These results reinforce the significance of Hib LOS in the expression of virulence by this pathogen.

The association between baseline drug resistance mutations and subsequent increase in viral failure has not been established for HIV-infected children. We evaluated drug resistance mutations at 39 codon sites (21 protease inhibitor (PI) resistant codons and 18 nucleoside reverse transcriptase inhibitor (NRTI) resistant codons) for 92 clinically stable NRTI-experienced, PI-naive HIV-infected children 2 to 17 years of age who were initiating new therapy with ritonavir plus zidovudine (ZDV) and lamivudine or plus stavudine. The association between baseline drug resistance mutations and subsequent viral failure after 12 and 24 weeks of highly active antiretroviral therapy (HAART) was studied. There were few primary PI associated mutations in this PI-naive population, but 84% had NRTI mutations – codons 215 (66%), 41 (42%), 67 (37%), 210 (33%) and 70 (32%). None of the specific baseline drug resistance mutations were associated with a higher rate of virologic failure after 12 or 24 weeks of HAART. Median week 12 viral load decreased as the total number of NRTI mutations at baseline increased (P = 0.006). Specifically, a higher level of baseline ZDV resistance mutation was associated with a decrease in viral failure after 12 weeks on a ZDV-containing HAART regimen (P = 0.017). No increase was seen in the rate of viral failure after HAART associated with the presence of resistance mutations at baseline. This paradoxical result may be due to adherence, replicative capacity, or ZDV hypersusceptibility to the new regimen.

Human immunodeficiency virus (HIV)-infected children often suffer from impaired growth. Highly active antiretroviral therapy (HAART) successfully reduces HIV 1 (HIV-1) RNA to 400 copies/mL or less in many children.To determine if age- and sex-adjusted growth z scores correlate with HIV-1 RNA level and if control of viral load for 48 and 96 weeks results in improved growth in children receiving highly active antiretroviral therapy.Secondary analysis of the cohort of children receiving ritonavir nested in a randomized, open-label, clinical trial.The Pediatric AIDS Clinical Trials Group Protocol 338 enrolled clinically stable, antiretroviral therapy-experienced, HIV-infected subjects aged 2 through 17 years. Using data from subjects randomized to ritonavir-containing regimens (n = 197), the association of growth z scores and HIV-1 RNA levels were examined.Age- and sex-adjusted weight and height z scores.Enrollment weights were comparable with age- and sex-adjusted norms, but subjects receiving ritonavir-containing antiretroviral therapy were significantly shorter (mean z score, -0.57 [29th percentile]; 95% confidence interval, -0.73 to -0.40). Higher HIV-1 RNA levels correlated with lower growth z scores (P.01). Subjects achieving and maintaining HIV-1 RNA of 400 copies/mL or less through 48 and 96 weeks experienced worse growth than subjects with a less controlled viral load.In this pediatric cohort, a significant decline in height and weight z scores was found despite control of viral replication. Further studies of growth are necessary to assess if nutritional and hormonal adjuvants to highly active antiretroviral therapy should be considered to improve growth in HIV-infected children.

Objectives.Newer combination antiretroviral therapies used to treat human immunodeficiency virus (HIV)-infected individuals have resulted in dramatic delays in HIV progression, with reduction in mortality and morbidity. However, adherence to highly active antiretroviral therapy (HAART) may be problematic, particularly in HIV-infected children. Reasons for nonadherence include refusal, drug tolerability, and adverse reactions. We assess: 1) the potential benefits of gastrostomy tube (GT) for the improvement of adherence to HAART in HIV-infected children, and 2) the factors that may result in improved viral suppression after GT placement.Methods.The medical records of 17 pediatric HIV-infected patients, in whom GT was used to improve HAART adherence, were retrospectively reviewed for clinical and laboratory parameters. Each record was reviewed for the period of 1 year before and after GT insertion. The main outcome parameters were virologic (plasma HIV RNA polymerase chain reaction quantification) and immunologic (CD4 cell counts). Documentation of adherence to medications in medical records was also assessed during the study. Parental questionnaires were used to determine GT satisfaction and medication administration times. The Wilcoxon rank sum test was used to assess change in viral load (VL) and CD4 cell percentages.Results.GT was well-tolerated with minor complications, such as local site tenderness, reported by 4 patients (23%). Before GT insertion, only 6 patients (35%) were documented as being adherent, compared with all patients after GT insertion. Ten patients (58%) had ≥2 log10 VL decline after GT insertion (median: 3.2 log10), compared with 7 patients (42%) who had ≤2 log10 VL decline (median: 1.27 log10). Both groups of patients (responders and nonresponders) did not differ significantly in baseline parameters, such as VL, CD4 cell percentages, or previous drug therapy. However, in all 10 patients with ≥2 log10 VL decline, therapy was changed at the time of or soon after GT insertion (median: .8 months; range: 0–6 months), compared with 7 patients with 5 minutes before GT, compared with 0% after GT. Questionnaires indicated satisfaction with GT, with perceived benefits being reduced medication administration time and improved behavior surrounding taking medications.Conclusions.GT is well-tolerated in pediatric HIV-infected patients and should be considered for selected patients to overcome difficulties with medication administration and to improve adherence. For maximal virologic response, combination therapy should be changed at the time of GT insertion.

ContextAlthough protease inhibitors are used routinely in adults with human immunodeficiency virus (HIV) infection, the role of these drugs in the treatment of clinically stable HIV-infected children is not clear.ObjectiveTo evaluate the safety, tolerance, and virologic response produced by a change in antiretroviral therapy in HIV-infected children who were clinically and immunologically stable while receiving previous therapy.DesignThe Pediatric AIDS Clinical Trials Group 338, a multicenter, phase 2, randomized, open-label controlled trial conducted from February 6 to April 30, 1997 (patient entry period); patients were followed up for 48 weeks.SettingPediatric HIV research clinics in the United States and Puerto Rico.PatientsTwo hundred ninety-seven antiretroviral-experienced, protease inhibitor–naive, clinically stable HIV-infected children aged 2 to 17 years.InterventionsChildren were randomized to receive zidovudine, 160 mg/m2 3 times per day, plus lamivudine, 4 mg/kg 2 times per day (n = 100); the same regimen plus ritonavir, 350 mg/m2 2 times per day (n = 100); or ritonavir, 350 mg/m2 2 times per day, and stavudine, 4 mg/kg 2 times per day (n = 97).Main Outcome MeasurePlasma HIV-1 RNA levels at study weeks 12 and 48, compared among the 3 treatment groups.ResultsAt study week 12, 12% of patients in the zidovudine-lamivudine group had undetectable plasma HIV RNA levels (