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Introduction: Children with nephrotic syndrome are susceptible to invasive bacterial infections. In this study, we aimed to: (1) determine the pathogens associated with infections in children with nephrotic syndrome and (2) describe antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae to guide evidence-based treatment and prevention policies., Methods: From June 2013 to March 2015, we collected blood and/or ascitic fluid from children hospitalized with nephrotic syndrome and suspected bacterial disease in the largest pediatric hospital of Bangladesh. We cultured all samples and performed polymerase chain reaction (PCR) and immunochromatographic test on ascitic fluid for detection of S. pneumoniae. Pneumococcal isolates were tested for antibiotic susceptibility using disc diffusion and serotyped using Quellung reaction and PCR., Results: We identified 1342 children hospitalized with nephrotic syndrome. Among them, 608 children had suspected bacterial disease from whom blood and/or ascitic fluid were collected. A pathogen was identified in 8% (48/608) of cases, 94% (45/48) of which were S. pneumoniae. Most (73%, 33/45) pneumococcal infections were identified through culture of blood and ascitic fluid and 27% (12/45) through immunochromatographic test and PCR of ascitic fluid. In total, 24 different pneumococcal serotypes were detected; 51% are covered by PCV10 (+6A), 53% by PCV13 and 60% by PPSV23. All pneumococcal isolates were susceptible to penicillin., Conclusions: Because S. pneumoniae was the primary cause of invasive infections, pneumococcal vaccines may be considered as a preventive intervention in children with nephrotic syndrome. Additionally, penicillin can be used to prevent and treat pneumococcal infections in children with nephrotic syndrome in Bangladesh.

Background: Community-wide impact of pneumococcal conjugate vaccines (PCV) is conferred by reductions in vaccine-type nasopharyngeal carriage. We evaluated the impact of PCV13 on carriage of PCV13-specific types (1, 3, 5, 6A, 7F and 19A) and 6C among American Indians., Methods: A nasopharyngeal specimen was collected from community members of all ages between January 2010 and April 2012 (3 months before and 24 months after PCV13 introduction). Pneumococci were isolated by culture and serotyped using antisera. Monthly carriage prevalence and PCV13 coverage were calculated to identify the timing of vaccine impact relative to PCV13 introduction. Prevalence ratios (PRs) were used to compare PCV13-specific carriage before and in years 1 and 2 of PCV13 use. Coverage was calculated according to age and number of doses received., Results: 6645 participants (2859 <5 years and 3786 ≥5 years of age) provided 6628 specimens. A decline in PCV13-specific and type 6C carriage among children <5 years of age was observed 9 and 15 months after PCV13 introduction, respectively. Among underimmunized children, a decline in PCV13-specific carriage was observed 11 months after PCV13 introduction, when coverage in the community reached 58%. In year 2 of PCV13 use, PCV13-specific and 6C carriage were reduced by 60% and 70%, respectively (PCV13 specific: PR = 0.4, P < 0.001; 6C: PR = 0.3, P < 0.001) among children <5 years of age. The reduction in PCV13-specific carriage among those 5 to <8 years and 18+ years of age in year 2 of PCV13 use was not statistically significant., Conclusions: PCV13 reduced PCV13-specific and 6C carriage among children <5 years of age. Low pre-PCV13 carriage prevalence of PCV13-specific types limited confirming this reduction for adults.

Background: Because Bangladesh intended to introduce pneumococcal conjugate vaccine (PCV)-10 in 2015, we examined the baseline burden of invasive pneumococcal disease (IPD) to measure impact of PCV., Methods: During 2007-2013, we performed blood and cerebrospinal fluid cultures in children <5 years old with suspected IPD identified through active surveillance at 4 hospitals. Isolates were serotyped by quellung and tested for antibiotic susceptibility by disc diffusion and E-test. Serotyping of culture-negative cases, detected by Binax or polymerase chain reaction, was done by sequential multiplex polymerase chain reaction. Trends in IPD case numbers were analyzed by serotype and clinical syndrome., Results: The study identified 752 IPD cases; 78% occurred in children <12 months old. Serotype information was available for 78% (442/568), including 197 of 323 culture-negative cases available for serotyping. We identified 50 serotypes; the most common serotypes were 2 (16%), 1 (10 %), 6B (7%), 14 (7%) and 5 (7%). PCV-10 and PCV-13 serotypes accounted for 46% (range 29%-57% by year) and 50% (range 37%-64% by year) of cases, respectively. Potential serotype coverage for meningitis and nonmeningitis cases was 45% and 49% for PCV-10, and 48% and 57% for PCV-13, respectively. Eighty-two percent of strains were susceptible to all antibiotics except cotrimoxazole., Conclusion: The distribution of serotypes causing IPD in Bangladeshi children is diverse, limiting the proportion of IPD cases PCV can prevent. However, PCV introduction is expected to have major benefits as the country has a high burden of IPD-related mortality, morbidity and disability.

Background: The etiology of >90% of cases of suspected neonatal infection remains unknown. We conducted community-based surveillance in conjunction with hospital-based surveillance in a rural region in Bangladesh from June 2006 to September 2007 to assess the incidence and etiology of community-acquired viral infections among neonates., Methods: Community health workers (CHWs) assessed neonates at home on days 0, 2, 5 and 8 after birth and referred cases of suspected illness to the hospital (CHW surveillance). Among neonates with clinically suspected upper respiratory tract infection (URTI), pneumonia, sepsis and/or meningitis, virus identification studies were conducted on nasal wash, cerebrospinal fluid and/or blood specimens. In the hospital-based surveillance, similar screening was conducted among all neonates (referred by CHWs and self-referred) who were admitted to the hospital., Results: CHW surveillance found an incidence rate of 15.6 neonatal viral infections per 1000 live births with 30% of infections identified on the day of birth. Among neonates with suspected sepsis, a viral etiology was identified in 36% of cases, with enterovirus accounting for two-thirds of those infections. Respiratory syncytial virus was the most common etiologic agent among those with viral pneumonia (91%) and URTI (68%). There was a low incidence (1.2%) of influenza in this rural population., Conclusion: Viral infections are commonly associated with acute newborn illness, even in the early neonatal period. The estimated incidence was 5-fold greater than reported previously for bacterial infections. Low-cost preventive measures for neonatal viral infections are urgently needed.

Background: Pneumococcal conjugate vaccine (PCV) induces protective anticapsular IgG, which mediates disease immunity. IgG persistence may influence long-term protection., Methods: An observational, prospective, longitudinal study of nasopharyngeal carriage among American Indian households from 2006 to 2008 evaluated long-term immunogenicity of 7-valent PCV (PCV7). Children unimmunized with PCV were age-matched to those PCV7 immunized at least 4 years prior (ratio 1:3 or 1:4). Blood collected at the final study visit was analyzed for PCV7 serotype IgG (enzyme-linked immunosorbent assay) and for functional activity (multiplex-opsonophagocytic assay) for serotypes 4, 6B, 14 and 23F. Geometric mean concentrations (GMCs), titers (GMTs) and the odds of serotype-specific IgG ≥0.35 μg/mL were compared according to immunization status using a matched regression approach., Results: Eight unimmunized and 28 immunized children age-matched at the time of serum collection (mean age: 7.9 years) were included. Serotype-specific GMCs, GMTs and proportions above the correlate of protection did not differ between the groups except for serotypes 14 and 23F. Serotype 14 GMCs (immunized 0.7 vs. unimmunized 0.2; P = 0.02) and serotype 23F GMTs (immunized 388.3 vs. unimmunized 47.8; P = 0.03) were significantly higher among immunized children. IgG concentrations and functional titers among immunized children were strongly correlated for serotypes 4 (r = 0.78; P ≤ 0.001) and 14 (r = 0.52; P ≤ 0.01)., Conclusions: PCV serotype-specific IgG concentrations 4 years following PCV vaccination do not persist above natural levels for most serotypes. Exposure to pneumococcus may be critical in maintaining persistent serotype-specific IgG; the elimination of circulating vaccine type pneumococci by PCV may have effects on long-term immunity.

Background: Native American children have higher rates of morbidity associated with acute respiratory infection than children in the general US population, yet detailed information is lacking regarding their principal clinical presentations and infectious etiologies., Methods: We pursued a comprehensive molecular survey of bacteria and viruses in nasal wash specimens from children with acute respiratory disease collected prospectively over 1 year (January 1 through December 31, 2009) from 915 Navajo and White Mountain Apache children in their second or third year of life who had been enrolled in an efficacy study of a respiratory syncytial virus monoclonal antibody in the first year of life., Results: During the surveillance period, 1476 episodes of disease were detected in 669 children. Rates of outpatient and inpatient lower respiratory tract illness were 391 and 79 per 1000 child-years, respectively, and were most commonly diagnosed as pneumonia. Potential pathogens were detected in 88% of specimens. Viruses most commonly detected were respiratory syncytial virus and human rhinovirus; the 2009 pandemic influenza A (H1N1) illnesses primarily occurred in the fall. Streptococcus pneumoniae was detected in 60% of subjects; only human rhinovirus was significantly associated with S. pneumoniae carriage. The presence of influenza virus, human rhinovirus or S. pneumoniae was not associated with increased risk for lower respiratory tract involvement or hospitalization., Conclusions: Acute lower respiratory illnesses occur at disproportionately high rates among young American Indian children and are associated with a range of common pathogens. This study provides critical evidence to support reducing the disproportionate burden of acute respiratory disease among young Native Americans.

Background: Pneumococcal conjugate vaccines (PCV) are emerging as one of the most promising means to prevent pediatric disease. The 7-valent PCV (PCV-7) has been extensively evaluated in clinical trials, and recent evidence from the introduction of PCV-7 through national immunization programs has demonstrated impact on pneumococcal disease., Methods: Clinical trials have shown PCV-7 to be effective against the more severe forms of pneumococcal infections: pneumonia and invasive pneumococcal disease (IPD), as well as overall child mortality. A review shows the tremendous impact PCV-7 has had to date, and the potential further benefits of the emerging multi-valent vaccines., Results: Since its introduction, the PCV-7 has substantially reduced the incidence of IPD, hospital admissions due to pneumonia and acute otitis media in numerous, mostly high income, low-disease burden countries. The reductions in IPD and pneumonia have also been observed among unvaccinated age groups in countries with routine use of PCV-7, demonstrating that PCV-7 provides herd immunity. Some settings observed an increase in rate of nonvaccine serotype IPD, yet rates of overall and vaccine-serotype IPD show marked reductions post-PCV-7 introduction. Limited data are available on the impact of PCV-7 in lower income countries. The available data from efficacy trials from The Gambia and South Africa suggest that PCV-7 will have substantial impact on reducing pneumococcal disease., Conclusion: PCV-7 has shown dramatic reduction in disease and mortality rates in the countries in which it has been introduced. The newly introduced 10-valent and 13-valent pneumococcal vaccines are expected to have substantial disease impact, but monitoring is essential to determine their true impact and sustain further introduction of pneumococcal conjugate vaccines.

Background: Before the widespread use of rotavirus vaccines, rotavirus was a leading cause of gastroenteritis among children. Navajo and White Mountain Apache children suffer a disproportionate burden of severe rotavirus disease compared with the general U.S. population., Methods: We enrolled Navajo and White Mountain Apache infants in a multicenter, double-blind, placebo-controlled trial of pentavalent human-bovine reassortant rotavirus vaccine (PRV). Subjects received 3 doses of vaccine or placebo at 4 to 10 week intervals, with the first dose given between 6 and 12 weeks of age. Gastroenteritis episodes were identified by active surveillance. Disease severity was determined by a standardized scoring system., Results: There were 509 and 494 randomized children who received vaccine and placebo, respectively. Among placebo recipients, the incidence of rotavirus gastroenteritis was 34.2 episodes/100 child-years (95% confidence interval [95% CI]: 25.8-38.9) versus 8.1 episodes/100 child-years (95% CI: 5.4-12.5) in the vaccine group. The percentage of rotavirus episodes caused by serotypes G1, G2, and G3 was 72.3%, 23.4%, and 2.1%, respectively. There were no severe rotavirus episodes among vaccinees and 4 among placebo recipients. PRV was 77.1% (95% CI: 59.7-87.6), 89.5% (95% CI: 65.9-97.9), and 82.9% (95% CI: 61.1-93.6) effective against G1-G4 rotavirus disease, severe and moderate rotavirus disease combined, and outpatient visits for rotavirus disease, respectively. The risk of adverse events was similar for the vaccine and placebo groups., Conclusions: PRV was highly effective in preventing rotavirus disease and related health care utilization in these American Indian infants. Vaccine efficacy and immunogenicity were similar to the overall study population enrolled in the multicenter trial.

Background: Numerous sequelae have been noted in survivors of bacterial meningitis; however, few studies document sequelae for several years following a childhood episode of bacterial meningitis. In addition, studies generally focus on the more commonly found sequelae. To review the known information and highlight this gap, this article presents a comprehensive literature review of the long-term (≥ 5 years of follow-up) sequelae of childhood bacterial meningitis., Methods: A systematic literature search was conducted between December 2009 and February 2010. English-language articles published between January 1970 and January 2010 were selected for screening. Articles were included if the subjects were between the ages of 1 month and <18 years at the time of diagnoses of meningitis., Results: A total of 1433 children who were survivors of childhood bacterial meningitis were evaluated for sequelae after the time of discharge. Of these children, 705 (49.2%) were reported to have 1 or more long-term sequelae. A majority of reported sequelae were behavioral and/or intellectual disorders (n 455, 45.0%). Hearing changes accounted for 6.7% (n 68) of sequelae and gross neurologic deficits accounted for 14.3% (n 145)., Discussion: A majority of childhood bacterial meningitis survivors with long-term sequelae that are documented in the literature have academic and behavioral limitations. While neurologic deficits may resolve over time, subtle behavioral deficits may not be appreciated initially and may continue to affect survivors for many years. Further studies are needed to quantify the true societal and economic burden of long-term sequelae as well as fully understand the breadth of types of sequelae that survivors experience.

Background: Infants and children are frequently colonized with pneumococcus. Recent nasopharyngeal acquisition of pneumococcus is thought to precede disease episodes. The increased risk of pneumococcal disease among Navajo and White Mountain Apache populations has been documented. Little is known about the dynamics of pneumococcal carriage in these populations., Methods: A group randomized, controlled trial of 7-valent conjugate pneumococcal vaccine (PnCRM7, Wyeth) was conducted on the Navajo and Apache reservations. A nasopharyngeal (NP) carriage study was nested in the trial to evaluate the impact of PnCRM7 on carriage. Children <6 years of age had NP swabs collected at enrollment and at 6 and 12 months following enrollment. We analyzed carriage data from children in control vaccine randomized communities to describe the epidemiology of pneumococcal carriage., Results: Of the 410 participants enrolled, 92% were colonized with pneumococcus at least once during the course of the study. Sixty-three percent of NP specimens were positive for pneumococcus. The most common serotypes were 6A, 6B, nontypable, 23F, 14, 19F, 19A, and 9V. Thirty-eight percent of isolates were vaccine serotypes. Age <2 years, male sex, daycare attendance, and having a sibling colonized with pneumococcus were associated with an increased risk of carriage., Conclusions: The high carriage prevalence among Navajo and Apache children reflects an intense exposure to pneumococcus. The lack of modifiable risk factors for carriage highlights the importance of preventive strategies for disease control.

Background: : Infections account for about half of neonatal deaths in low-resource settings. Limited evidence supports home-based treatment of newborn infections by community health workers (CHW)., Methods: : In one study arm of a cluster randomized controlled trial, CHWs assessed neonates at home, using a 20-sign clinical algorithm and classified sick neonates as having very severe disease or possible very severe disease. Over a 2-year period, 10,585 live births were recorded in the study area. CHWs assessed 8474 (80%) of the neonates within the first week of life and referred neonates with signs of severe disease. If referral failed but parents consented to home treatment, CHWs treated neonates with very severe disease or possible very severe disease with multiple signs, using injectable antibiotics., Results: : For very severe disease, referral compliance was 34% (162/478 cases), and home treatment acceptance was 43% (204/478 cases). The case fatality rate was 4.4% (9/204) for CHW treatment, 14.2% (23/162) for treatment by qualified medical providers, and 28.5% (32/112) for those who received no treatment or who were treated by other unqualified providers. After controlling for differences in background characteristics and illness signs among treatment groups, newborns treated by CHWs had a hazard ratio of 0.22 (95% confidence interval [CI] = 0.07-0.71) for death during the neonatal period and those treated by qualified providers had a hazard ratio of 0.61 (95% CI = 0.37-0.99), compared with newborns who received no treatment or were treated by untrained providers. Significantly increased hazards ratios of death were observed for neonates with convulsions (hazard ratio [HR] = 6.54; 95% CI = 3.98-10.76), chest in-drawing (HR = 2.38, 95% CI = 1.29-4.39), temperature <35.3 degrees C (HR = 3.47, 95% CI = 1.30-9.24), and unconsciousness (HR = 7.92, 95% CI = 3.13-20.04)., Conclusions: : Home treatment of very severe disease in neonates by CHWs was effective and acceptable in a low-resource setting in Bangladesh.

Background: Navajo and White Mountain Apache infants have respiratory syncytial virus (RSV) hospitalization rates 2-5 times that of the general U.S. infant population. To evaluate whether these high rates can be attributable to low concentrations of maternally derived RSV neutralizing antibodies, we conducted a case-control study., Methods: Study subjects enrolled in a prospective, hospital-based surveillance study of RSV disease and a group randomized clinical trial of a 7-valent pneumococcal conjugate vaccine. Cord blood specimens were assayed for neutralizing RSV antibody titers. Infants hospitalized with a respiratory illness had a nasal aspirate obtained to determine whether RSV was present. Infants with an RSV respiratory hospitalization were matched by date of birth and geographic location to infants who did not have an RSV hospitalization before 6 months of age., Results: For every 1 log2 increase in titer of cord blood RSV neutralizing antibodies there was a 30% reduced risk of hospitalization with RSV (OR = 0.69, P = 0.003). However, among infants hospitalized with RSV, there was no association between cord blood RSV neutralizing antibody and the severity of the RSV illness., Conclusions: These findings indicate that American Indian infants with high concentrations of maternally derived RSV neutralizing antibodies are protected from RSV hospitalization before 6 months of age. However, these antibodies do not modify the severity of illness once disease has occurred. The basis for elevated rates of RSV disease among American Indian infants cannot be attributed to a failure of maternal RSV neutralizing antibodies to confer protection.

We report the phase III trial efficacy of 7-valent pneumococcal conjugate vaccine against clinical and culture proven otitis media (OM) among Navajo and White Mountain Apache infants. Efficacy was -0.4% (95% CI: -19.4 to 15.6) for clinically-diagnosed OM, 5.1% (95% CI: -51.5 to 40.6) for severe OM, and 64% (95% CI: -34% to 90%) for vaccine serotype pneumococcal OM suggesting that this vaccine is efficacious for pneumococcal OM in this high risk population.

Background: Multidrug resistance (MDR), specifically to ampicillin and chloramphenicol, has complicated the treatment of Haemophilus influenzae type b (Hib) meningitis. This is worsened by use of prior antibiotics, which limits identification of the causative agent by culture and increases reliance on antigen detection., Objective: We aimed to develop a PCR assay for detecting the family of Haemophilus integrating and conjugative elements (ICEs) represented by ICEHin1056 among antibiotic resistant Hib, and then apply this directly to CSF to diagnose Hib meningitis and predict organism susceptibility, irrespective of culture results., Study Design: Primers specific for orf 51 of ICEHin1056 were designed and multiplexed with Bex primers, specific for H. influenzae, and tested on culture positive and negative cases., Results: Of 73 Hib isolates, orf 51 PCR amplicons, predicting the presence of ICEs, were found in all 33 MDR isolates while only in 1 of 33 sensitive strains. The remaining 7 ampicillin susceptible, chloramphenicol and tetracycline resistant strains did not produce a PCR product to orf 51. PCR amplification from CSF specimens of these culture positive cases produced identical results with 100% and 97% positive and negative predictive values, respectively. Multiplex PCR to detect Bex and orf 51 identified another 16 MDR Hib cases among 81 culture-negative CSF samples., Conclusions: Direct PCR for orf 51 in CSF identified resistance pattern of 51% more Hib strains than culture alone (110 versus 73). The ability to detect MDR, in culture negative Hib meningitis cases has significant implications for better directing antibiotic treatment of meningitis cases and thus for preventing disability and death.

Background: Few Asian countries have introduced Haemophilus influenzae type b (Hib) conjugate vaccine because of its cost and uncertainty regarding disease burden., Methods: To estimate the effectiveness of Hib conjugate vaccine in preventing pneumonia and meningitis in children age <2 years, an incident case-control study was conducted in a birth cohort of about 68,000 infants in Dhaka city, Bangladesh. DPT vaccine was systematically replaced by a combined Hib-DPT vaccine in selected immunization centers of the study area. Four matched community- and 2 hospital-controls were randomly selected for each confirmed case of pneumonia and meningitis from the study area., Results: About 35% of the infants received each of the 3 doses of Hib-DPT vaccine. There were 2679 children who had a chest roentgenogram. For 475 children, a radiologist and a pediatrician independently identified substantial alveolar consolidation. Following at least 2 doses of Hib vaccine, the preventable fractions [95% confidence intervals (CI)] using community and hospital controls were 17% (-10% to 38%) and 35% (13% to 52%) respectively. Of these 475 cases, 2 radiologists with the World Health Organization concurred with the findings for 343 patients, yielding preventable fractions of 34% (6% to 53%) and 44% (20% to 61%). Fifteen confirmed Hib meningitis cases were identified; the preventable fractions (95% CI) using community and hospital controls, respectively, were 89% (28% to 100%) and 93% (53% to 100%)., Conclusions: The study documented that significant fractions of pneumonia and meningitis in Bangladeshi children age <2 years can be prevented by the Hib conjugate vaccine.

Background: Because the therapeutic options for managing infections in neonates in developing countries are often limited, innovative approaches to preventing infections are needed. Topical therapy with skin barrier-enhancing products may be an effective strategy for improving neonatal outcomes, particularly among preterm, low birth weight infants whose skin barrier is temporarily but critically compromised as a result of immaturity., Methods: We tested the impact of topical application of sunflower seed oil 3 times daily to preterm infants <34 weeks gestational age at the Kasr El-Aini neonatal intensive care unit at Cairo University on skin condition, rates of nosocomial infections and mortality., Results: Treatment with sunflower seed oil (n = 51) resulted in a significant improvement in skin condition (P = 0.037) and a highly significant reduction in the incidence of nosocomial infections (adjusted incidence ratio, 0.46; 95% confidence interval, 0.26-0.81; P = 0.007) compared with infants not receiving topical prophylaxis (n = 52). There were no reported adverse events as a result of topical therapy., Conclusions: Given the low cost (approximately .20 dollars for a course of therapy) and technologic simplicity of the intervention and the effect size observed in this study, a clinical trial with increased numbers of subjects is indicated to evaluate the potential of topical therapy to reduce infections and save newborn lives in developing countries.

Background: Immunization of healthy women before pregnancy is a potential approach to providing increased levels of maternal antibody to newborns to protect them from infections occurring during the perinatal period and first months of life., Methods: Healthy nonpregnant Pima Indian women of childbearing age were randomized to receive one of two Haemophilus influenzae type b (Hib) conjugate vaccines [HbOC or Hib-meningococcal outer membrane protein complex (OMP)] or a 23-valent pneumococcal polysaccharide vaccine (PnPs). Infants received Hib-OMP vaccine at 2, 4 and 12 months of age. Vaccine safety and immunogenicity was evaluated in the women and their infants., Results: Anti-polyribose ribitol phosphate antibody titers were significantly higher in women in both Hib conjugate vaccine groups than in the pneumococcal vaccine group throughout the 37-month observation period. Antibody responses to HbOC vaccine were significantly higher than those to Hib-OMP. A subsequent booster dose of each Hib conjugate vaccine induced reactions and antibody responses similar to those of the first dose. Infants born to mothers immunized with Hib vaccines compared with PnPs had significantly higher polyribose ribitol phosphate-specific IgG antibody titers at birth and 2 months of age but lower antibody responses to Hib-OMP at 6 months and similar titers before and after boosting with Hib-OMP at 1 year of age. By contrast women immunized with PnPs did not have significantly elevated concentrations of pneumococcal-specific antibody at delivery, and their infants had pneumococcal antibody titers similar to those of infants born to mothers who did not receive pneumococcal vaccine before pregnancy., Conclusion: Hib conjugate vaccine given to women before pregnancy significantly increased the proportion of infants who had protective Hib antibody levels at birth and 2 months of age.

Objective: To describe the age-specific distribution of typhoid fever including the degree of Salmonella typhi bacteremia among patients evaluated at a large private diagnostic center in Bangladesh, a highly endemic area., Methods: We conducted a prospective-, passive- and laboratory-based study to identify patients with S. typhi bacteremia. Subjects (n = 4,650) from whom blood cultures were obtained during 16-month period were enrolled from private clinics and hospitals throughout Dhaka. Isolation and quantification of S. typhi from blood cultures were performed by the lysis direct plating/ centrifugation method., Results: Bacterial pathogens were recovered from blood of 538 of 4,650 patients (11.6%) evaluated. S. typhi was the single most common pathogen recovered, comprising nearly three-fourths of isolates (72.7%; 391 of 538). Isolation rate of S. typhi was highest in monsoon and summer seasons and lowest in winter months. The majority (54.5%; 213 of 391) of S. typhi isolates were from children who were younger than 5 years, and 27% (105 of 391) were from children in the first 2 years of life. The isolation rate was highest (17.4%, 68 of 486) in the second year of life. The number of bacteria in blood on the basis of colony-forming units per ml of blood by age group was inversely related to age., Conclusions: Detection of S. typhi bacteremia in young children in Dhaka, Bangladesh, was considerably higher than previously appreciated, with a peak detection rate in children < or =2 years of age, indicating the need to reassess the age-specific burden of typhoid fever in the community on a regional basis. Contrary to current recommendations this study suggests that development of new vaccines should target infants and young children.

Background: Streptococcus pneumoniae is the most frequent bacterial cause of morbidity and mortality in young children. Bacteria carried in the nasopharynx of healthy children reflect the prevalent strains circulating in the community., Methods: We recruited 464 newborns from a rural area in South India with endemic vitamin A deficiency. Nasopharyngeal specimens were collected from each infant at ages 2, 4 and 6 months., Results: Fifty-four percent of study infants were colonized by age 2 months, with 64.1 and 70.2% carriage prevalence at ages 4 and 6 months, respectively. The odds of carriage at 2 months were significantly increased in female infants, infants living in a household in which 20 or more cigarettes were smoked each day, infants whose mothers had less than 1 year of schooling and infants fed colostrum. At age 4 months infants having 2 or more siblings <5 years of age were at significantly increased risk of carriage. At age 6 months none of the potential risk factors examined achieved statistical significance, but maternal night blindness increased the risk of colonization 3-fold. The odds of carrying a PncCRM197 vaccine serotype were increased among infants born to mothers who experienced night blindness during pregnancy. The most prevalent serogroups/types during the first 6 months of life were 6, 9, 10, 11, 14, 15, 19, 23 and 33, accounting for 76.7% of all serotyped isolates., Conclusions: South Indian infants experience high rates of pneumococcal carriage during the first 6 months of life, which may partially explain their increased risk for pneumonia.

Background: Acute lower respiratory illnesses (ALRI) have been associated with exposure to domestic smoke. To examine further this association, a case-control study was conducted among Navajo children seen at the Public Health Service Indian Hospital at Fort Defiance, AZ., Methods: Cases, children hospitalized with an ALRI (n = 45), were ascertained from the inpatient logs during October, 1992, through March, 1993. Controls, children who had a health record at the same hospital and had never been hospitalized for ALRI, were matched 1:1 to cases on date of birth and gender. Home interviews of parents of subjects during March and April, 1993, elicited information on heating and cooking fuels and other household characteristics. Indoor air samples were collected for determination of time-weighted average concentrations of respirable particles (i.e. < 10 microns in diameter)., Results: Age of cases at the time of admission ranged from 1 to 24 months (median, 7 months); 60% of the cases were male. Matched pair analysis revealed an increased risk of ALRI for children living in households that cooked with any wood (odds ratio (OR), 5.0; 95% confidence interval (CI), 0.6 to 42.8), had indoor air concentrations of respirable particles > or = 65 micrograms/m3 (i.e. 90th percentile) (OR 7.0, 95% CI 0.9 to 56.9), and where the primary caretaker was other than the mother (OR 9, 95% CI 1.1 to 71.4). Individual adjustment for potential confounders resulted in minor change (i.e. < 20%) in these results. Indoor air concentration of respirable particles was positively correlated with cooking and heating with wood (P < 0.02) but not with other sources of combustion emissions., Conclusions: Cooking with wood-burning stoves was associated with higher indoor air concentrations of respirable particles and with an increased risk of ALRI in Navajo children.

Objective: The purpose of this study was to measure the effect of concurrent diarrheal illness on seroconversion to trivalent oral polio vaccine (OPV)., Methods: Six- to 16-week-old infants with acute diarrhea and age-matched controls received single doses of OPV at enrollment, 4 weeks after enrollment and 8 weeks after enrollment. Serum specimens were obtained at enrollment, before the second OPV dose and 4 weeks after the third OPV dose for measurement of antibody titers to polio virus by the microneutralization assay., Results: Four weeks after the first OPV dose, the serologic responses to poliovirus types 2 and 3 in the case cohort were lower by 26 and 34%, respectively, than in the control cohort (P < 0.002 for both comparisons). Poliovirus type 2 and 3 geometric mean antibody titers in the diarrhea cohort were approximately 50% of the geometric mean antibody titers in the control cohort (235 (95% confidence interval (CI) 154 to 359) vs. 446 (95% CI 350 to 569) and 64 (95% CI 45 to 90) vs. 112 (95% CI 88 to 143), respectively, P < 0.01 for both comparisons). After the third OPV dose the seroconvertion rates to poliovirus types 2 and 3 each remained about 10% lower in the case cohort than in the control cohort, but the differences were not statistically significant., Conclusion: Concurrent acute diarrhea adversely affects seroconvertion rates of type 2 and 3 polioviruses among infants in Bangladesh receiving the first dose of trivalent OPV.

The Navajo are known to be at high risk for hepatitis A virus (HAV) infection. This study investigated the safety and immunogenicity of an investigational, alum-adjuvanted, formalin-inactivated HAV vaccine (VAQTA) developed by Merck Research Laboratories in Navajo children. One hundred two of 212 children, ages 4 to 12 years, were HAV-seronegative (< 10 mIU/ml by an enhanced sensitivity modification of the HAVAB; Abbott). Ninety of these children received the HAV vaccine. Study participants were given vaccines containing various viral protein concentrations: Group A (n = 18), 6 units; Group B (n = 36), 13 units; and Group C (n = 36), 25 units HAV protein (1 unit approximately 1 ng viral protein antigen). Three-dose (0, 8, 24 weeks) and two-dose (0, 24 weeks) regimens were compared in subgroups within B and C. The vaccine was well-tolerated and there were no serious adverse reactions; no vaccinee developed hepatitis A. After 1 dose 82 to 100% of children seroconverted (> or = 10 mIU/ml, modified HAVAB; Abbott) and 100% seroconverted after 2 doses. After 1 dose the geometric mean titer for antibody was: Group A, 22 mIU/ml; Group B, 18 mIU/ml; and Group C, 38 mIU/ml. After 3 doses geometric mean titers increased to 10,106 mIU/ml in Group A, 7258 mIU/ml in Group B and 11,856 mIU/ml in Group C. Further field studies are indicated to evaluate its use in high risk populations, such as the Navajo.

We compared in 12- to 15-month-old American Indian infants the safety and immunogenicity of two licensed Haemophilus influenzae type b (Hib) conjugate vaccines, PRP-OMP (PedvaxHib) and HbOC (HibTITER), administered as booster vaccinations. All infants previously received PRP-OMP for their primary Hib vaccinations at 2 and 4 months of age. The geometric mean Hib antibody concentrations (microgram/ml) measured by radioactive antigen-binding assay for those receiving PRP-OMP (n = 17) or HbOC (n = 18) were 0.593 and 0.449, respectively, before boosting (P not significant) and 7.46 and 29.5 micrograms/ml, respectively, after boosting (P < 0.05). PRP-OMP recipients also had lower geometric mean IgG anti-Hib antibody concentrations than HbOC recipients (7.21 vs 28 micrograms/ml, P = 0.003) and lower bactericidal titers (3.18 vs. 15.4, not significant). We conclude that HbOC vaccine produced a significantly greater booster response than PRP-OMP vaccine when given at 12 to 15 months of age to children primed with two doses of PRP-OMP vaccine at 2 and 4 months of age.

Eighty-five American Indian children less than 16 years of age with Haemophilus influenzae bacteremia were retrospectively determined to have been treated as outpatients after their initial evaluation. We hoped to determine the proportion that developed new foci, the time interval to this development and whether age or temperature at presentation predicted outcome. Fifty-one (60%) presented with nonfocal findings. Seventy-two (85%) were treated with antibiotics at the initial visit. Although 49 (58%) of the patients were never hospitalized, a new focus was identified in 25 (29%), including 13 (15%) with a final diagnosis of meningitis. The new foci were identified within 6 days of presentation (median, 2 days). An additional 15 (18%) patients had no new focus but were febrile and/or ill at follow-up. All patients with meningitis or a second positive culture were hospitalized at the first follow-up visit. Age and temperature at presentation did not help predict outcome. All patients with H. influenzae bacteremia require prompt reevaluation and close follow-up by an experienced physician.

Testing for urinary excretion of capsular polysaccharide antigen was carried out in 40 four-month-old Navajo infants who had received injections of a Haemophilus influenzae type b Neisseria meningitidis outer membrane protein conjugate vaccine (PedvaxHIB; Merck, Sharp and Dohme Research Laboratories) as part of an ongoing efficacy trial of the vaccine. Urine from 12 placebo recipients was also analyzed. Urine samples were collected on the day of injection (the first voided urine following the injection) and 3, 7, 10, 14, 21 and 30 days later. All vaccine recipients had at least 1 positive specimen. Vaccine recipients excreted antigen for a median period of 14 days after injection. On the first day 54% of vaccinees excreted antigen. Antigen was excreted by 89% of vaccinees on Day 3, 79% on Day 7, 82% on Day 10, 64% on Day 14, 56% on Day 21 and 41% on Day 30. Urine from placebo recipients tested positive in 12% on Day 1, 18% on Day 3, none on Day 7, 14% on Day 10, 11% on Day 14, 10% on Day 21 and none on Day 30. The rate of positive test results was significantly higher among vaccine recipients than among controls. Physicians should not rely on urinary antigen detection tests for predicting the presence of invasive disease caused by H. influenzae type b in infants for at least 30 days after injections with this conjugate vaccine, and possibly longer.

The safety and immunogenicity of a Haemophilus influenzae type b polysaccharide conjugate vaccine linked to the outer membrane protein complex of Neisseria meningitidis (Hib-OMP) were evaluated among Apache and Navajo infants and children. One dose of the Hib-OMP was given to 42 children who were from 12 and 60 months of age. Ninety-two infants 6 to 8 weeks old were given one dose of Hib-OMP at the time of enrollment. A subsequent dose of the vaccine was given 2 months later and a third dose was offered between 12 and 15 months of age. All of the 12- to 60-month-old children achieved a protective antibody concentration (greater than 1 microgram/ml) 1 month postvaccination. Among the 6- to 8-week-old infants only 11% of the Apaches and 8% of Navajos had a protective anti-PRP antibody concentration prevaccination. One month post vaccination 68% of the Apaches and 69% of the Navajos had protective anti-PRP antibody concentrations. One month after the second immunization 67% of the Apaches and 75% of Navajos had protective anti-PRP concentrations. Among the infants that received the third (booster) immunization (N = 28) 74% had protective anti-PRP antibody titers just before the booster immunization. One month after the booster immunization all of the infants had protective concentrations of anti-PRP antibody. We conclude that the Hib-OMP is safe and highly immunogenic among Apache and Navajo infants and children.

In a high risk Navajo population we compared the immunogenicity of a new Haemophilus influenzae type b mutant-diphtheria toxic conjugate vaccine (HbOC) with simultaneous active (HbOC) and passive immunization with bacterial polysaccharide immunoglobulin prepared from adults immunized with H. influenzae b, pneumococcal and meningococcal vaccines. Only 7 of 26 (27%) 2-month-olds had an increase in H. influenzae b capsular polysaccharide antibody after a single dose of HbOC, a proportion similar to that of saline controls (9 of 25, 36%). After a second HbOC dose at 4 months 88% had antibody concentrations of 0.15 microgram or more, and after a third dose at 6 months all had antibody levels greater than or equal to 0.15 microgram/ml. The group receiving both HbOC and bacterial polysaccharide immunoglobulin at 2 months uniformly had H. influenzae b CP antibody concentrations of greater than or equal to 0.15 microgram/ml at 4 months (P less than 0.001 relative to "HbOC alone" group) and subsequently responded similarly to second and third doses of HbOC vaccine as did also the "HbOC alone" group. We conclude that combined passive/active immunization with bacterial polysaccharide immunoglobulin and HbOC at 2 months maintains antibody at concentrations thought to be protective (greater than or equal to 0.15 microgram/ml) without interfering with the active antibody response to second and third doses of HbOC at 4 and 6 months of age.