Frederick W. Henderson

Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children.

To better understand acquired immunity to respiratory-syncytial-virus infections, we analyzed data from a 10-year study of respiratory illness in normal children who were followed longitudinally from early infancy. Immunity was measured in terms of failure to become infected or reduction in severity of clinical illness upon reinfection. Outbreaks of infections occurred seven times over the 10-year-period. During epidemics the attack rate for first infection was 98 per cent. The rate for second infections (75 per cent) was modestly reduced (P less than 0.001); that for third infections was 65 per cent. Age and history of infection both influenced illness. Immunity induced by a single infection had no demonstrable effect on illness associated with reinfection one year later; however, a considerable reduction in severity occurred with the third infection. These observations suggest that amelioration of illness--rather than prevention of infection--may be a realistic goal for immunoprophylaxis.

A Longitudinal Study of Respiratory Viruses and Bacteria in the Etiology of Acute Otitis Media with Effusion

We analyzed data from a 14-year longitudinal study of respiratory infections in young children to determine the relative importance of viral respiratory infection and nasopharyngeal colonization with Streptococcus pneumoniae and Haemophilus influenzae as factors influencing the occurrence of acute otitis media with effusion. The incidence of this disorder was increased in children with viral respiratory infections (average relative risk, 3.2; P less than 0.0001). Infection with respiratory syncytial virus, influenza virus (type A or B), and adenovirus conferred a greater risk of otitis media than did infection with parainfluenza virus, enterovirus, or rhinovirus. Colonization of the nasopharynx with Str. pneumoniae or H. influenzae had a lesser effect on the incidence of the disease (average relative risk; 1.5; P less than 0.01). Infections with the viruses more closely associated with acute otitis media (respiratory syncytial virus, adenovirus, and influenza A or B) were correlated with an increased risk of recurrent disease. Prevention of selected otitis-associated viral infections should reduce the incidence of this disease.

The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice.

To develop a broad understanding of the causes and patterns of occurrence of wheezing associated respiratory infections, we analyzed data from an 11-year study of acute lower respiratory illness in a pediatric practice. Although half of the WARI occurred in children less than 2 years of age, wheezing continued to be observed in 19% of children greater than 9 years of age who had lower respiratory illness. Males experienced LRI 1.25 times more often than did females; the relative risk of males for WARI was 1.35. A nonbacterial pathogen was recovered from 21% of patients with WARI; respiratory syncytial virus, parainfluenza virus types 1 and 3, adenoviruses, and Mycoplasma pneumoniae accounted for 81% of the isolates. Patient age influenced the pattern of recovery of these agents. The most common cause of WARI in children under 5 years of age was RSV whereas Mycoplasma pneumoniae was the most frequent isolate from school age children with wheezing illness. The data expand our understanding of the causes of WARI and are useful to diagnosticians and to researchers interested in the control of lower respiratory disease.

Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial.

Background. Influenza infection rates are higher in children than in other age groups. This study evaluated the efficacy, safety and tolerability of a 5-day course of twice daily inhaled zanamivir, 10 mg, compared with placebo in the treatment of symptomatic influenza A and B viral infections among children 5 to 12 years of age. Methods. This double blind, randomized, placebo-controlled, parallel group, multicenter study conducted in the Northern Hemisphere during the 1998 and 1999 influenza season enrolled 471 patients with influenza-like symptoms for ≤36 h. Patients were randomly assigned to zanamivir (n = 224) or placebo (n = 247). Symptoms were recorded on diary cards twice daily during treatment, for 9 days after treatment and for 14 additional days (if still reporting moderate/severe cough and/or taking relief medication). Findings. A total of 346 (73%) patients were influenza-positive by culture, serology or polymerase chain reaction (65% influenza A, 35% influenza B). Zanamivir reduced the median time to symptom alleviation by 1.25 days compared with placebo among patients with confirmed influenza infection (P < 0.001). Zanamivir-treated patients returned to normal activities significantly faster and took significantly fewer relief medications than placebo-treated patients. Zanamivir was well-tolerated, demonstrating adverse event profiles similar to those of placebo and no clinically significant changes in laboratory findings. Viral susceptibility testing revealed no zanamivir-resistant strains of influenza A or B. Conclusions. Zanamivir was effective in shortening the duration and severity of influenza symptoms and was well-tolerated among children 5 to 12 years of age.

Multiple Markers of Inflammation and Weight Status: Cross-sectional Analyses Throughout Childhood

OBJECTIVE: Inflammatory markers such as C-reactive protein (CRP) are related to obesity in adults, but the association is less clear in children. Our objective was to examine relationships between multiple markers of inflammation and childrens weight status; we hypothesized that the prevalence of inflammatory markers would increase as weight status increased. METHODS: We conducted a cross-sectional analysis of children in the United States aged 1 to 17 years in the National Health and Nutrition Examination Survey, 1999–2006. Children were categorized using weight-for-length when age <2 years and BMI for ≥2 years, as very obese (≥99th percentile), obese (<99th and ≥95th percentile), overweight (<95th and ≥85th percentile), and healthy weight (>5th to ≤85th percentile) according to expert consensus. Our main outcome measures were high-sensitivity CRP and absolute neutrophil count, in addition to a novel third measure: ferritin controlled for iron status using a ferritin/transferrin ratio. We used Cox proportional hazards models to examine risk of abnormal values of inflammatory markers according to weight. RESULTS: Increased risk of a CRP level of >1.0 mg/L was evident among very obese children from ages 3 to 5 years (hazard ratio [HR]: 2.29; P < .01) through 15 to 17 years (HR: 4.73; P < .01). Increased risk of abnormal neutrophil count among very obese children began at 6 to 8 years (HR: 2.00; P = .049), and increased prevalence of abnormal ferritin/transferrin ratio began at 9 to 11 years (HR: 7.06; P < .001). CONCLUSIONS: Multiple inflammatory markers are strongly and positively associated with increasing weight status in children, and this relationship starts as young as age 3. Elevated inflammatory markers in very young obese children are particularly concerning, because inflammation may cause long-term, cumulative vascular damage. This deserves additional research via longitudinal design.

Otitis media, hearing sensitivity, and maternal responsiveness in relation to language during infancy

The relation of otitis media with effusion (OME) and associated hearing loss to language and cognitive skills at 1 year of age was studied to determine whether OME-related hearing loss had a direct association with language and cognitive outcomes at 1 year of age or an indirect association with these outcomes, as mediated by the child-rearing environment. Subjects were 61 black infants attending community-based child care programs. The presence of OME was assessed biweekly from 6 to 12 months of age by otoscopy and tympanometry. Hearing was assessed with visual reinforcement audiometry when children were well and when ill with OME. Language and cognitive skills and the child-rearing environment at home and in child care were examined. The results indicated a modest correlation between hearing loss associated with OME and receptive language. However, the direct association between OME-related hearing loss and all the language and cognitive measures was negligible. Hearing loss had an indirect association with receptive and expressive language, cognitive development, and overall communication as mediated by child-rearing factors. That is, children with more frequent hearing loss tended to have less responsive mothers and home environments, and this association was linked to lower performance on the infant assessments.

Characterization of Genetic and Phenotypic Diversity of Invasive Nontypeable Haemophilus influenzae

ABSTRACT The ability of unencapsulated (nontypeable) Haemophilus influenzae (NTHi) to cause systemic disease in healthy children has been recognized only in the past decade. To determine the extent of similarity among invasive nontypeable isolates, we compared strain R2866 with 16 additional NTHi isolates from blood and spinal fluid, 17 nasopharyngeal or throat isolates from healthy children, and 19 isolates from middle ear aspirates. The strains were evaluated for the presence of several genetic loci that affect bacterial surface structures and for biochemical reactions that are known to differ among H. influenzae strains. Eight strains, including four blood isolates, shared several properties with R2866: they were biotype V (indole and ornithine decarboxylase positive, urease negative), contained sequence from the adhesin gene hia, and lacked a genetic island flanked by the infA and ksgA genes. Multilocus sequence typing showed that most biotype V isolates belonged to the same phylogenetic cluster as strain R2866. When present, the infA-ksgA island contains lipopolysaccharide biosynthetic genes, either lic2B and lic2C or homologs of the losA and losB genes described for Haemophilus ducreyi. The island was found in most nasopharyngeal and otitis isolates but was absent from 40% of invasive isolates. Overall, the 33 hmw-negative isolates were much more likely than hmw-containing isolates to have tryptophanase, ornithine decarboxylase, or lysine decarboxylase activity or to contain the hif genes. We conclude (i) that invasive isolates are genetically and phenotypically diverse and (ii) that certain genetic loci of NTHi are frequently found in association among NTHi strains.

Otitis Media, the Caregiving Environment, and Language and Cognitive Outcomes at 2 Years

Objective. To examine the relationship between otitis media with effusion (OME) and associated hearing loss between 6 and 24 months of age and childrens language and cognitive development at 2 years of age. Study Design. A prospective cohort design in which 86 African-American infants who attended group child-care centers were recruited between 6 and 12 months of age. Between 6 and 24 months, assessments included serial ear examinations using otoscopy and tympanometry, serial hearing tests, two ratings of the childrearing environment at home and in child care, and language and cognitive outcomes at 2 years. Results. Children experienced either unilateral or bilateral OME an average of 63% and reduced hearing sensitivity an average of 44% of the time between 6 and 24 months of age. Although proportion of time with OME or with hearing loss was modestly correlated with measures of language and cognitive skills, these relationships were no longer significant when the ratings of the home and child-care environments were also considered. Children with more OME or hearing loss tended to live in less responsive caregiving environments, and these environments were linked to lower performance in expressive language and vocabulary acquisition at 2 years. Conclusions. Both OME and hearing loss were more strongly related to the quality of home and child-care environments than to childrens language and cognitive development. Study results might be explained either by suggesting that children in less responsive caregiving environments experience conditions that make them more likely to experience OME and/or by suggesting that it may be more difficult for caregivers to be responsive and stimulating with children with more OME.

Neutrophil influx measured in nasal lavages of humans exposed to ozone

Neutrophils (PMNs) obtained by nasal lavage were counted to determine if ozone, an oxidant air pollutant, induces an acute inflammatory response in the upper respiratory tract (URT) of humans. Background data were obtained by the nasal lavages from 200 nonexperimentally exposed subjects. Then, using a known inflammatory agent for the URT, rhinovirus-type 39, the induction, peak, and resolution of an acute inflammatory response was shown to be documented by the nasal lavage PMN counts. To determined if ozone induces this response, 41 subjects were exposed to either filtered air or 0.5 ppm ozone for 4 hr, on 2 consecutive days. Nasal lavages were taken pre-, immediately post each exposure, and 22 hr following the last exposure. Lavage PMN counts increased significantly (p = .005) in the ozone-exposed group, with 3.5-, 6.5-, and 3.9-fold increases over the air-exposed group at the post 1, pre 2, and post 2 time points, respectively. Ozone induces an inflammatory response in the URT of humans, and nasal lavage PMN counts are useful to assay the inflammatory properties of air pollutants.

Effect of upper respiratory tract infection on eustachian tube ventilatory function in the preschool child.

A prospective tympanometric and microbiologic study of 28 pre-schoolchildren was undertaken to better define the effect of acute URI on induction of eustachian tube dysfunction. Significant negative middle ear pressure was present in 12.7% of tympanograms from well children. However, abnormal tympanograms were detected during 74.7% of acute URIs. The abnormality was present on day 1 or 2 of illness in the majority of cases; 10.1% of illnesses were complicated by OME. Respiratory viruses or Sp were etiologically implicated in 40.5% of illnesses; isolation rates of Pn and HF from well and ill children were similar. Although colonization of the nasopharynx of well children with Pn or HF was associated with a higher incidence of abnormal middle ear pressure, colonization with Pn or HF during URI did not influence the frequency of tympanogram abnormality.