Pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection.

Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (approximately 12.5 mg/kg of body weight [BW] for children weighing < 40 kg and 500 mg for children weighing > or = 40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to < 6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW(0.696). An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.

Elaboration of type b capsule by Haemophilus influenzae as a determinant of pathogenicity and impaired killing by trimethoprim-sulfamethoxazole.

In vitro, Haemophilus influenzae strains have two distinct patterns of susceptibility to trimethoprim-sulfamethoxazole (TMP/SMZ); strains with low minimum inhibitory concentration and high minimum bactericidal concentration (tolerant) and those with both low minimum inhibitory concentration and minimum bactericidal concentration (kill-sensitive). Tolerant H. influenzae strains were found to elaborate significantly more type b capsular polysaccharide, a linear polymer of ribosyl ribose phosphate (PRP), than kill-sensitive strains. Tolerant strains became susceptible to killing by TMP/SMZ when type b capsule was physically removed, but reacquired tolerance following growth and reversion to original (mucoid) phenotype. Susceptibility of wild (type a, b, c), isogenic (type b and untypable), and transformed (type b and d) strains indicated that elaboration of type b capsule was associated with TMP/SMZ tolerance. In a second series of studies, virulence of H. influenzae in the infant rat model was correlated with in vitro tolerance. Tolerant strains (13/13) caused systemic disease while none (0/7) of kill-sensitive strains were pathogenic. The efficacy of TMP/SMZ in the treatment of invasive infection was evaluated in rats with established bacteremia and meningitis. TMP/SMZ failed to eradicate H. influenzae b from the blood in 85% (17/20) or from the cerebrospinal fluid in 95% (19/20) of infected animals. Thus, in vitro tolerance correlated with therapeutic failure in vivo.

Leukemia inhibitory factor inhibits HIV-1 replication and is upregulated in placentae from nontransmitting women.

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.

High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema.

OBJECTIVE: To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND: Although noninvasive ventilation is increasingly used in the treatment of pulmonary edema, its efficacy has not been compared prospectively with newer treatment modalities. METHODS: We enrolled 40 consecutive patients with severe pulmonary edema (oxygen saturation <90% on room air prior to treatment). All patients received oxygen at a rate of 10 liter/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Thereafter patients were randomly allocated to receive 1) repeated boluses of IV isosorbide-dinitrate (ISDN) 4 mg every 4 min (n = 20), and 2) BiPAP ventilation and standard dose nitrate therapy (n = 20). Treatment was administered until oxygen saturation increased above 96% or systolic blood pressure decreased to below 110 mm Hg or by more than 30%. Patients whose conditions deteriorated despite therapy were intubated and mechanically ventilated. All treatment was delivered by mobile intensive care units prior to hospital arrival. RESULTS: Patients treated by BiPAP had significantly more adverse events. Two BiPAP treated patients died versus zero in the high dose ISDN group. Sixteen BiPAP treated patients (80%) required intubation and mechanical ventilation compared to four (20%) in the high dose ISDN group (p = 0.0004). Myocardial infarction (MI) occurred in 11 (55%) and 2 (10%) patients, respectively (p = 0.006). The combined primary end point (death, mechanical ventilation or MI) was observed in 17 (85%) versus 5 (25%) patients, respectively (p = 0.0003). After 1 h of treatment, oxygen saturation increased to 96 +/- 4% in the high dose ISDN group as compared to 89 +/- 7% in the BiPAP group (p = 0.017). Due to the significant deterioration observed in patients enrolled in the BiPAP arm, the study was prematurely terminated by the safety committee. CONCLUSIONS: High dose ISDN is safer and better than BiPAP ventilation combined with conventional therapy in patients with severe pulmonary edema.

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

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.

Treatment of pediatric infections with amikacin as first-line aminoglycoside.

Because of increased aminoglycoside resistance of hospital bacterial isolates, aminoglycoside sensitivity patterns of isolates in a large children's hospital were assessed before and during a 33-month period of almost exclusive amikacin use. There was no significant change in overall resistance rates of gram-negative enteric bacteria to gentamicin (4.8 percent and 4.6 percent), tobramycin (2.5 percent and 3.6 percent), and amikacin (1.2 percent and 1.8 percent) from the pre-amikacin period to the amikacin usage period, respectively. No significant differences were observed for isolates of Escherichia coli, Klebsiella, Serratia, Acinetobacter, and Pseudomonas species. In contrast, significant decreases in gentamicin and tobramycin resistance rates for Enterobacter, Citrobacter, and Pseudomonas aeruginosa and in gentamicin resistance of Proteus were found. Very little change in resistance of staphylococcal isolates was seen during a shorter evaluation period. Pediatric aminoglycoside usage includes therapy of neonatal infections, cystic fibrosis, febrile neutropenic episodes in patients with cancer, abdominal surgery, bacterial endocarditis, and gram-negative central nervous system infections. Amikacin has also been used successfully as single-dose therapy of urinary tract infections, and acceptable cerebrospinal fluid levels of amikacin have been documented in hydrocephalic patients with ventriculitis. In vitro studies of 22 bacterial isolates demonstrated synergy between amikacin and penicillin or newer cephalosporins in 13, an additive effect in seven and indifference in two. No antagonism was found. In addition, in vivo synergy between imipenem and amikacin was found in neutropenic infant rats with P. aeruginosa sepsis using a strain with which no synergy was demonstrable in vitro. Amikacin is effective in pediatric infections and is well tolerated by children. Because excessive or inadequate levels are frequent with usually recommended doses, particularly in neonates and patients with compromised renal function or cystic fibrosis, serum levels should be monitored to minimize risk and to ensure therapeutic levels.

Combination antibiotic therapy in pediatrics.

Combinations of beta-lactam and aminoglycoside antibiotics are frequently used in the treatment of pediatric infections. At our institution, amikacin has been the sole aminoglycoside utilized for the past five years. Such regimens are used empirically in specific patient populations to treat the pathogens most likely to be responsible for a symptom complex, e.g., sepsis in the immunocompromised host, pneumonitis in patients with cystic fibrosis, neonatal infections such as sepsis or meningitis, and infections in patients with intestinal perforations. Beta-lactam and aminoglycoside combinations are employed as definitive therapy when synergistic interactions can be predicted, such as in systemic Pseudomonas infections, viridans streptococcal endocarditis, or enterococcal infections. In all of these circumstances, we have utilized amikacin extensively as the sole aminoglycoside, with highly satisfactory results. In vitro antibiotic synergy studies, including those employing aminoglycosides such as amikacin, may be used to predict in vivo antibiotic interactions. However, definitions of in vitro synergy vary with the laboratory method used to evaluate synergy. Furthermore, recent data from our laboratory suggest that the absence of demonstrated in vitro synergy between amikacin and imipenem may not correlate with improved survival of neutropenic rats with gram-negative sepsis that are treated with both agents. Thus, in vitro studies of synergy may underestimate the frequency of improved outcomes with combination antibiotics, especially with amikacin and imipenem. There are potential risks associated with the use of multiple, broad-spectrum antibiotics, including fungal or bacterial superinfection and increased drug toxicity. Although the former is common in pediatric patients, aminoglycoside (amikacin) toxicity has rarely been a problem. Combination antibiotic regimens that include an aminoglycoside such as amikacin continue to have an important role in pediatrics and should be used empirically or definitively for the specific indications discussed.

Nasopharyngeal carriage of Haemophilus influenzae type b: attempted eradication by cefaclor or rifampin.

The efficacy of cefaclor and rifampin in eradicating Haemophilus influenzae type b (HITB) from the nasopharynx of day care center and household contacts of children with HITB meningitis was evaluated. In 38/50 children treated with cefaclor, the carrier state persisted, a failure rate of 76%. Although cefaclor failed to eradicate HITB from many carriers, an appreciable reduction in the intensity of colonization following treatment was noticed. When rifampin was used in 17 children who had failed to respond to cefaclor, persistence of the carrier state with HITB was found in only two children, a failure rate of only 12%. During the study, two episodes of invasive HITB disease were documented to be acquired from sources other than the index cases or from children who were screened, which suggested the need to reevaluate the usually recommended strategy to screen for carriage and to treat only the immediate contacts 6 years of age and younger. Furthermore, the most appropriate agent for eradicating nasopharyngeal carriage of HITB awaits additional studies.

Pharmacokinetic comparison of intravenous and oral chloramphenicol in patients with Haemophilus influenzae meningitis.

The pharmacokinetics of chloramphenicol following intravenous and oral administration were studied in 14 infants with Haemophilus influenzae meningitis. Following five days of treatment with intravenous chloramphenicol (100 mg/kg/day every six hours), oral chloramphenicol was substituted at the same dose. Multiple serum levels of chloramphenicol were determined after an intravenous dose on day 4 and after an oral dose on day 10. CSF levels were measured six hours after intravenous or oral chloramphenicol dose on those days (CSF trough). Following intravenous administration, the mean peak serum level of 15.0 micrograms/ml was reached at 45 minutes. In comparison, after oral chloramphenicol in the same dosage, the mean peak serum level of 18.5 micrograms/ml was achieved at two to three hours. The mean serum half-life of the drug (6.5 hours) was significantly longer after oral administration than after intravenous chloramphenicol (4.0 hours) (P less than .001). The increased serum half-life following orally administered chloramphenicol was occasionally associated with drug accumulation. In addition, mean trough CSF levels were somewhat higher when the patient received oral medication (6.6 micrograms/ml) compared to intravenous administration (4.2 micrograms/ml) (P less than .001). For any treatment regimen for H influenzae meningitis that includes a period of oral chloramphenicol therapy the patient should be hospitalized to ensure compliance. Because of the wide range of individual variation in serum half-life that may result in accumulation, periodic monitoring of serum chloramphenicol levels is also recommended.

Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures.

The recent pattern of immigration from Indochina and Latin America to the United States suggests that tuberculosis will remain a significant public health problem. Two infants recently seen with probable congenital tuberculosis prompted critical evaluation of the 24 cases of congenital tuberculosis reported in the English literature since the introduction of isoniazid in 1952. Failure to thrive, jaundice, and central nervous system involvement, all reported in previous reviews and textbooks to be very common, were unusual presenting manifestations. In contrast, hepatomegaly, a finding not mentioned in the recent literature, was common. Diagnostic procedures previously underutilized but found in this review to be useful included liver biopsy, biopsy of skin lesions when present, and cultures of gastric aspirates. Factors which enable differentiation of congenital from early postnatally acquired tuberculosis include (1) the presence of known maternal tuberculosis at delivery, (2) whether infant and mother were separated from birth until the onset of illness, and (3) whether other tuberculous exposure of the infant can be determined. Insufficient data prevent recommendation of a preferred regimen of drugs in addition to isoniazid for the treatment of congenital tuberculosis. However, the responses of our patients suggest that streptomycin can be omitted without hazard. Information regarding the long-term prognosis of survivors is lacking, but early diagnosis and institution of appropriate therapy has markedly decreased the mortality of this previously fatal disorder.

Pulmonary paragonimiasis in Laotian refugee children.

Three Laotian refugee children with chronic pulmonary complaints and findings were found to have pulmonary paragonimiasis during a one-year period in Chicago. These patients ranged from 8 to 11 years of age and the diagnosis was delayed five to six months in two children because of the unfamiliarity of American physicians with signs and symptoms of this disorder. Clinical manifestations included chronic cough for up to two years, apparent hemoptysis in two patients, lack of fever or sweats, and family history negative for tuberculosis. Physical findings included rales and dullness to percussion, clubbing (one patient), and lack of fever or respiratory distress. All three patients showed interstitial infiltrates on chest roentgenogram whereas two had multiple small cystic areas. Moderate eosinophilia was present. Paragonimus westermani ova were found in stools of two patients, in sputum of two patients, and in bronchoscopic specimens in one patient. All patients demonstrated striking clinical and radiologic improvement following treatment with bithionol (50 mg/kg every other day for 15 doses), which was well tolerated. Lung fluke infestation must be considered in Indochinese refugee children with apparent hemoptysis or chronic pulmonary symptoms, and sputum and stool should be examined for P westermani ova.

Fatal hepatitis B in early infancy: the importance of identifying HBsAg-positive pregnant women and providing immunoprophylaxis to their newborns.

Infants born to women who are asymptomatic hepatitis B surface antigen (HBsAg) carriers frequently acquire hepatitis B virus infection in infancy. The spectrum of disease in such affected infants includes mild transient acute hepatitis B, chronic active hepatitis with or without cirrhosis, chronic persistent hepatitis, chronic asymptomatic HBsAg carriage, and, rarely, fulminant fatal hepatitis B. Recently, the administration of hepatitis B immunoglobulin has been demonstrated to reduce the risk of infantile acquisition of hepatitis B virus; hepatitis B vaccine may also be preventive in this setting. Three young infants, aged 8 to 16 weeks, who died of acute fulminant hepatitis were studied. In each instance, the mother was found, retrospectively, to be asymptomatic but HBsAg positive. One of these mothers was hepatitis B e-antigen-negative but hepatitis B e-antibody positive. All three babies were HBsAg positive; two who were tested for hepatitis B core antibody were positive. These three fatalities serve to dramatize both the importance of HBsAg screening of pregnant women, particularly those with demographic factors that place them at increased risk for HBsAg carriage, as well as the significance of effective immunoprophylaxis for hepatitis B in all offspring of women with HBsAg seropositivity.

Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate): immunogenicity and safety at various doses.

The Haemophilus influenzae vaccine consisting of purified type b capsular polysaccharide (polyribosylribitol-phosphate [PRP]) was shown in Finland to be protective, with 90% efficacy in children older than 18 to 23 months of age. However, a wide range of estimates of vaccine efficacy has been reported in the United States after its licensure in 1985. These estimates range from -55% to +89%. In addition, the PRP vaccine was not effective in children younger than 18 months of age, in whom 70% to 80% of meningitis cases occur. A further development was the introduction of H influenzae type b polysaccharide-protein conjugate vaccines such as the PRP-D. These conjugate vaccines were found to be more immunogenic than PRP vaccine in children of all ages. Two doses of PRP-D in infants 7 months of age and older induced antibody levels equal to or greater than levels in infants 24 months of age who received the PRP vaccine alone. Recently, Eskola et al reported that repeat vaccinations with PRP-D at 3, 4, 6, and 14 months of age was 83% protective (95% confidence interval, 26% to 96%). Yet PRP-D vaccine elicits only low serum antibody levels in infants younger than 7 months of age. Because of the discrepancy in efficacy results for the PRP vaccine in the United States and Finland and the lack of data about the protective efficacy of PRP-D vaccine in infants in the United States, the PRP-D vaccine is currently recommended only for children 18 months of age or older.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemophilus influenzae type b immunization of children with sickle cell diseases.

Haemophilus influenzae type B vaccine is recommended for children 1.5 to 6 years of age with sickle cell anemia, but the adequacy of their response is unknown. A total of 69 children with sickle cell syndromes, 1.5 to 5.6 years of age, were immunized with two vaccines alternatively, single blind. PRP vaccine was given to 36 children and a diphtheria toxoid conjugated vaccine, PRP-D, was given to 36. Coded pre- and postvaccine sera were tested by radioimmunoassay for anti-PRP antibody. The groups did not differ in age distribution or type of sickle hemoglobinopathy. Preexisting antibody levels were low in both vaccine groups; 65% were less than 0.15 microgram/mL. The vaccines were safe but associated with frequent minor reactions. PRP-D gave higher geometric mean titers and mean fold titer increase than PRP in all children (15.58 micrograms/mL [234-fold] v 2.63 micrograms/mL [29-fold]) and in the subgroups 1.5 to 2.5 years of age or with pretiter values less than 0.15 microgram/mL. Titers for 64% of children receiving PRP and 94% receiving PRP-D were greater than or equal to 1.0 microgram/mL. Thus, both vaccines were useful in this population, but PRP-D was more immunogenic. Duration of antibody levels postvaccination, booster responses, and PRP-D immunogenicity in younger children with sickle cell syndromes all require further study.

Enterobacter aerogenes primary bacteremia in pediatric patients.

Enterobacter aerogenes bacteremia associated with the infusion of contaminated admixed intravenous (IV) fluid occurred in seven patients in a pediatric hospital over a five-day period. Clinical illness was characterized by spiking fever in all patients. The temporal clustering of cases allowed for rapid recognition of the problem. The primary control measure was the prompt replacement of the IV fluids, although IV antibiotics were also administered. Hospital pharmacy practices for admixing IV solutions should follow published recommendations to minimize this source of potential contamination of fluids.

Three-year multicenter surveillance of systemic pneumococcal infections in children.

OBJECTIVE: To track antibiotic susceptibility of Streptococcus pneumoniae isolates obtained from children with systemic infections and determine outcome of treatment. DESIGN: A 3-year (September 1993 through August 1996) prospective surveillance study of all invasive pneumococcal infections in children. PATIENTS: Infants and children cared for at eight children's hospitals in the United States with culture-proven systemic pneumococcal infection. RESULTS: One thousand two hundred ninety-one episodes of systemic pneumococcal infection were identified in 1255 children. An underlying illness was present in the children for 27% of the episodes. The proportion of isolates that were nonsusceptible to penicillin or ceftriaxone increased annually and nearly doubled throughout the 3-year period; for the last year the percentages of isolates nonsusceptible to penicillin and ceftriaxone were 21% and 9.3%, respectively. There was no difference in mortality between patients with penicillin-susceptible or nonsusceptible isolates. Only 1 of 742 patients with bacteremia had a repeat blood culture that was positive > 1 day after therapy was started. All 24 normal children with bacteremia attributable to isolates resistant to penicillin had resolution of their infection; the most common treatment regimen was a single dose of ceftriaxone followed by an oral antibiotic. CONCLUSIONS: The percentage of pneumococcal isolates nonsusceptible to penicillin and ceftriaxone increased yearly among strains recovered from children with systemic infection. Because empiric antibiotic therapy already has changed for suspected pneumococcal infections, antibiotic resistance has not been associated with increased mortality. Careful monitoring of antibiotic susceptibility and outcome of therapy is necessary to continually reassess current recommendations for treatment.

Suppurative intracranial complications of upper respiratory tract infections.

Suppurative intracranial complications of respiratory infections are relatively rare in children. These complications occur more often in association with chronic sinusitis and chronic otitis media. Because symptoms and signs of the intracranial complications can be nonspecific, a high index of suspicion by the physician is important for early diagnosis. The routine cerebrospinal fluid examination often does not distinguish between the various complications, and radiologic procedures such as radionuclide brain scan, arteriography and computer-assisted tomographic scan should be used. Computer-assisted tomographic scan is very useful in detecting early complications allowing trial with medical treatment alone. Appropriate selection of antibiotics must be made on the basis of the likely pathogens in the particular setting and the ability of the antibiotic to penetrate the affected area. Appropriate early management of suppurative intracranial complications should result in a favorable outcome.

Serum tumor necrosis factor alpha, interleukin 1-beta, p24 antigen concentrations and CD4+ cells at various stages of human immunodeficiency virus 1 infection in children.

We measured the serum concentrations of tumor necrosis factor (TNF-alpha), interleukin 1-beta (IL-1-beta), p24 antigen, CD4+/CD8+ cells and immunoglobulins in 35 children at various stages of human immunodeficiency virus infection. Serum TNF-alpha concentrations were significantly higher in children with lymphocytic interstitial pneumonitis and in children with mildly symptomatic illness than in asymptomatic children or children with acquired immunodeficiency syndrome. In addition serum IL-1 concentrations were significantly higher in patients with lymphocytic interstitial pneumonitis than in asymptomatic, mildly symptomatic, or acquired immunodeficiency syndrome patients. Children with lymphocytic interstitial pneumonitis had the highest serum TNF-alpha and IL-1 concentrations. Among symptomatic children serum TNF-alpha concentrations correlated positively with those of IL-1, and both were inversely related to the amount of p24 antigen. TNF-alpha values in excess of 50 pg/ml were observed more frequently among patients with CD4+ cell count greater than 400/mm3 than in those with CD4+ cell count less than 400/mm3. We did not find any association between elevated TNF-alpha concentrations and cachexia, opportunistic infections or progressive encephalopathy.

CD8+ T cell-mediated suppression of human immunodeficiency virus replication in older children with acquired immunodeficiency syndrome.

BACKGROUND: Suppression of HIV replication by CD8+ T cells and/or their products correlated with the survival of infants. We sought to elucidate the role of CD8+ T cell-mediated suppression in seven older children with AIDS. METHODS: After separation of each child's CD4+ and CD8+ T cells, three different HIV culture assays were performed: (1) patient CD4+ T cells and phytohemagglutinin (PHA)-stimulated donor peripheral blood mononuclear cells (PBMC); (2) patient CD8+ T cells added to the CD4+ T cells and the PHA-stimulated donor PBMC (to test for CD8-mediated T cell suppression of HIV); (3) patient CD8+ cells added across a semipermeable membrane to the CD4+ T cells and the PHA-stimulated donor PBMC [to determine whether the CD8 cells secreted a soluble factor(s) that suppressed HIV]. RESULTS: Cultures from four of seven children showed greater HIV replication with CD4 cells alone than with CD4 and CD8 cells together, demonstrating CD8 suppression; evidence of soluble suppression was also seen. Cultures from two of the seven children showed HIV replication and no evidence of CD8 cell suppression. Cultures from one of the seven children had no appreciable replication of HIV even after removal of CD8 cells. CONCLUSIONS: CD8-mediated suppression is present in at least some children with AIDS. Additional mechanisms may be operating to slow the progression of the disease.

Serologic response to standard inactivated influenza vaccine in human immunodeficiency virus-infected children.

We compared the serologic response of 46 human immunodeficiency virus (HIV)-infected children and adolescents and 61 age-matched controls to standard trivalent inactivated influenza vaccine (A/Taiwan (H1N1), A/Shanghai (H3N2), B/Yamagata). Children were immunized according to the package insert recommendations before the 1990 to 1991 influenza season. Serum antibody titers to influenza A were determined before and 1 month after each vaccination and compared for study and control subjects. Serologic responses of HIV-infected participants were correlated with absolute CD4 counts and stage of HIV disease. Regardless of age or HIV status, all groups responded with significant increases in antibody to the influenza A strains (range, 2.1-fold to 11.8-fold), with the exception that antibody to H3N2 rose only 1.5-fold (P = 0.058) among HIV-positive subjects > or = 9 years old. Pre- and postimmunization antibody titers were significantly higher for controls than for HIV-positive subjects. There was no correlation between serologic responses and CD4 counts among HIV-infected subjects, but those with Centers for Disease Control and Prevention-defined acquired immunodeficiency syndrome responded significantly less well to vaccine. We conclude that HIV-infected children and adolescents produce significant antibody rises after inactivated influenza A vaccination but that their absolute antibody concentrations are lower than those seen in age-matched controls.