The role of CDHR3 in susceptibility to otitis media.

Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.

Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues. RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma. CONCLUSION: SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

Multi-omic studies on missense PLG variants in families with otitis media.

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.

Nasopharyngeal microbiota in infants and changes during viral upper respiratory tract infection and acute otitis media.

BACKGROUND: Interferences between pathogenic bacteria and specific commensals are known. We determined the interactions between nasopharyngeal microbial pathogens and commensals during viral upper respiratory tract infection (URI) and acute otitis media (AOM) in infants. METHODS: We analyzed 971 specimens collected monthly and during URI and AOM episodes from 139 infants. The 16S rRNA V4 gene regions were sequenced on the Illumina MiSeq platform. RESULTS: Among the high abundant genus-level nasopharyngeal microbiota were Moraxella, Haemophilus, and Streptococcus (3 otopathogen genera), Corynebacterium, Dolosigranulum, Staphylococcus, Acinetobacter, Pseudomonas, and Bifidobacterium. Bacterial diversity was lower in culture-positive samples for Streptococcus pneumoniae, and Haemophilus influenzae, compared to cultured-negative samples. URI frequencies were positively associated with increasing trend in otopathogen colonization. AOM frequencies were associated with decreasing trend in Micrococcus colonization. During URI and AOM, there were increases in abundance of otopathogen genera and decreases in Pseudomonas, Myroides, Yersinia, and Sphingomonas. Otopathogen abundance was increased during symptomatic viral infection, but not during asymptomatic infection. The risk for AOM complicating URI was reduced by increased abundance of Staphylococcus and Sphingobium. CONCLUSION: Otopathogen genera played the key roles in URI and AOM occurrences. Staphylococcus counteracts otopathogens thus Staphylococcal colonization may be beneficial, rather than harmful. While Sphingobium may play a role in preventing AOM complicating URI, the commonly used probiotic Bifidobacterium did not play a significant role during URI or AOM. The role of less common commensals in counteracting the deleterious effects of otopathogens requires further studies.

Panel 4: Report of the Microbiology Panel.

Objective To perform a comprehensive review of the literature from July 2011 until June 2015 on the virology and bacteriology of otitis media in children. Data Sources PubMed database of the National Library of Medicine. Review Methods Two subpanels comprising experts in the virology and bacteriology of otitis media were created. Each panel reviewed the relevant literature in the fields of virology and bacteriology and generated draft reviews. These initial reviews were distributed to all panel members prior to meeting together at the Post-symposium Research Conference of the 18th International Symposium on Recent Advances in Otitis Media, National Harbor, Maryland, in June 2015. A final draft was created, circulated, and approved by all panel members. Conclusions Excellent progress has been made in the past 4 years in advancing our understanding of the microbiology of otitis media. Numerous advances were made in basic laboratory studies, in animal models of otitis media, in better understanding the epidemiology of disease, and in clinical practice. Implications for Practice (1) Many viruses cause acute otitis media without bacterial coinfection, and such cases do not require antibiotic treatment. (2) When respiratory syncytial virus, metapneumovirus, and influenza virus peak in the community, practitioners can expect to see an increase in clinical otitis media cases. (3) Biomarkers that predict which children with upper respiratory tract infections will develop otitis media may be available in the future. (4) Compounds that target newly identified bacterial virulence determinants may be available as future treatment options for children with otitis media.

Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene.

BACKGROUND: Previously rare A2ML1 variants were identified to confer otitis media susceptibility in an indigenous Filipino community and in otitis-prone US children. The goal of this study is to describe differences in the middle ear microbiome between carriers and non-carriers of an A2ML1 duplication variant that increases risk for chronic otitis media among indigenous Filipinos with poor health care access. METHODS: Ear swabs were obtained from 16 indigenous Filipino individuals with chronic otitis media, of whom 11 carry the A2ML1 duplication variant. Ear swabs were submitted for 16S rRNA gene sequencing. RESULTS: Genotype-based differences in microbial richness, structure, and composition were identified, but were not statistically significant. Taxonomic analysis revealed that the relative abundance of the phyla Fusobacteria and Bacteroidetes, and genus Fusobacterium were nominally increased in carriers compared to non-carriers, but were non-significant after correction for multiple testing. We also detected rare bacteria including Oligella that was reported only once in the middle ear. CONCLUSIONS: These findings suggest that A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. Knowledge of middle ear microbial profiles according to genetic background can be potentially useful for therapeutic and prophylactic interventions for otitis media and can guide public health interventions towards decreasing otitis media prevalence within the indigenous Filipino community.

Otitis media.

Otitis media (OM) or middle ear inflammation is a spectrum of diseases, including acute otitis media (AOM), otitis media with effusion (OME; 'glue ear') and chronic suppurative otitis media (CSOM). OM is among the most common diseases in young children worldwide. Although OM may resolve spontaneously without complications, it can be associated with hearing loss and life-long sequelae. In developing countries, CSOM is a leading cause of hearing loss. OM can be of bacterial or viral origin; during 'colds', viruses can ascend through the Eustachian tube to the middle ear and pave the way for bacterial otopathogens that reside in the nasopharynx. Diagnosis depends on typical signs and symptoms, such as acute ear pain and bulging of the tympanic membrane (eardrum) for AOM and hearing loss for OME; diagnostic modalities include (pneumatic) otoscopy, tympanometry and audiometry. Symptomatic management of ear pain and fever is the mainstay of AOM treatment, reserving antibiotics for children with severe, persistent or recurrent infections. Management of OME largely consists of watchful waiting, with ventilation (tympanostomy) tubes primarily for children with chronic effusions and hearing loss, developmental delays or learning difficulties. The role of hearing aids to alleviate symptoms of hearing loss in the management of OME needs further study. Insertion of ventilation tubes and adenoidectomy are common operations for recurrent AOM to prevent recurrences, but their effectiveness is still debated. Despite reports of a decline in the incidence of OM over the past decade, attributed to the implementation of clinical guidelines that promote accurate diagnosis and judicious use of antibiotics and to pneumococcal conjugate vaccination, OM continues to be a leading cause for medical consultation, antibiotic prescription and surgery in high-income countries.

Acute Otitis Media and Other Complications of Viral Respiratory Infection.

BACKGROUND: Viral upper and lower respiratory tract infections (URI, LRI) are common in infants. We determined the prevalence of viral URI and its complications, including acute otitis media (AOM) and LRI, and assessed the effect of bacterial-viral interactions, and genetic and environmental risks on AOM development. METHODS: Healthy infants were enrolled from near birth and followed to the first episode of AOM up to 12 months of age. Nasopharyngeal specimens were collected at monthly intervals (months 1-6, 9) and during viral URI episodes for bacterial culture and viral polymerase chain reaction studies. Subjects were followed closely for AOM development. RESULTS: A total of 367 infants were followed for 286 child-years; 887 URI (305 infants) and 180 AOM episodes (143 infants) were documented. Prevalence of URI, LRI, and AOM in the first year was 3.2, 0.25, and 0.67 per child-year, respectively. Cumulative AOM incidence by ages 3, 6, and 12 months was 6%, 23%, and 46%. Infants with and without AOM had 4.7 and 2.3 URI episodes per child-year, respectively (P < .002). Pathogenic bacterial colonization rates by month were significantly higher in infants with AOM (P < .005). Breastfeeding reduced both URI and AOM risks (P < .05). Significant bacterial-viral interactions occurred with Moraxella catarrhalis and a variety of respiratory viruses and altered URI and AOM risks. CONCLUSIONS: Almost half of infants experienced AOM by age 1. Important AOM risk factors included frequent viral URI, pathogenic bacterial colonization, and lack of breastfeeding. Bacterial-viral interactions may play a significant role in AOM pathogenesis and deserve further investigation.

Use of symptoms and risk factors to predict acute otitis media in infants.

OBJECTIVES: Infants and children with upper respiratory tract infection (URI) often have concurrent acute otitis media (AOM). Young infants have fewer specific symptoms than older children. The purpose of this study was to evaluate the usefulness of symptoms and other risk factors in predicting the presence of AOM in infants. METHODS: Healthy infants, age less than four weeks, were enrolled and followed prospectively for up to age one year. Infants were scheduled for a research visit when their parents noted the onset of symptoms. At each URI visit, parents first reported the severity of symptoms. An investigator then diagnosed the presence or absence of concurrent AOM. Risk factors and symptom scores for infants with and without AOM were studied. RESULTS: Infants (N=193, mean age at first URI 3.9±2.5 months) experienced 360 URI episodes and 63 AOM events. Symptoms consisting of fever, earache, poor feeding, restless sleep, and irritability together (ETG-5) were statistically associated with the prediction of AOM (P=0.006). A multiple variable statistical model (J-Score) that included day care attendance, age, severity of cough and earache best predicted AOM (P<0.001), with 95% specificity. Both ETG-5 and J-score yielded relatively low sensitivity for AOM prediction. CONCLUSIONS: In infants with URI in the first year of life, severity of symptoms was significantly associated with concurrent AOM. Daycare attendance, presence and severity of earache and cough added to better correlation. These observations may have clinical application in identification of infants at risk for AOM.

Determining Persistence of Bocavirus DNA in the Respiratory Tract of Children by Pyrosequencing.

BACKGROUND: Although human bocavirus type 1 (HBoV1) is a respiratory pathogen, presence of HBoV-DNA in secretions of asymptomatic children raised the question on the significance of HBoV-positive results. METHODS: Archived specimens from a prospective, longitudinal study were tested for HBoV. A total of 94 children (aged 6-36 months) were HBoV(+) during 172 upper respiratory tract infection (URI) and/or acute otitis media (AOM) episodes. We used pyrosequencing of NP1, VP1 and VP2 genes to type HBoV and subtype HBoV1 in these specimens. RESULTS: Of the specimens tested, HBoV-DNA were successfully sequenced in 128 (74%) samples from 70 children; all were HBoV type 1. Subtypes identified (n = 108) were LWK/TW (63%), LWK/BJ (20%), Bonn/BJ (16%) and LWK/KU3 (1%). Of 46 children for whom shedding pattern could be determined, viral clearance within 30 days (13-29 days) occurred in 28%; another 22% of children had no recurrence after 32-267 days. Prolonged virus presence of >30 days (34-181 days+) occurred in 22%; intermittent detection (61+ to 170+ days) in 20%. Infection with the same HBoV1 subtype after 4-5 negative samples (244 and 265 days interval) occurred in 4%. Infection with 2 different HBoV1 subtypes (29 and 87 days apart) occurred in only 4%. Newly acquired HBoV1-URI resulted in AOM in 53% of cases. CONCLUSIONS: Children with HBoV1 infection commonly shed for a prolonged period leading to repeated viral DNA detection. Recurrence after 8-9 months suggests possible persistence and reactivation. Infections with 2 different HBoV1 subtypes within 1-year period are uncommon. Newly acquired HBoV1-URI is often complicated by AOM.

Rare A2ML1 variants confer susceptibility to otitis media.

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

Factors Affecting Staphylococcus aureus Colonization of the Nasopharynx in the First 6 Months of Life.

BACKGROUND: Staphylococcal aureus (SA) colonization in early infancy is common, but the pattern and factors affecting its acquisition and persistence in the first few months of life are not well studied. The aim is to study the rate of SA nasopharyngeal (NP) colonization at monthly intervals in the first 6 months of life and its association with environmental and host factors and other pathogenic NP bacteria. METHODS: Data from a prospective study were analyzed on bacterial cultures of 1765 NP swabs from 367 infants who were followed from birth to 6 months of age. Demographic, breastfeeding, cigarette smoke exposure and day care attendance data were collected at each monthly visit. RESULTS: The rate of infants colonized with SA was highest at age 1 month (25%) and declined to lowest rate by age 6 months (12%). The proportion of SA strains that was methicillin-resistant SA was also highest at age 1 month and declined rapidly by age 4 months (18% vs. 6%, P = 0.05). Colonization with Streptococcus pneumoniae (SP), nontypeable Haemophilus influenzae (NTHI) and Moraxella catarrhalis (MC) increased at different rates up to age 6 months. Univariate analysis showed that SA colonization rate was significantly lower with increasing age, black race, day care attendance, and colonization with NTHI, MC and SP (P < 0.05). Multivariate analysis showed that this effect was independently associated only with increasing age and MC colonization (P < 0.05). Furthermore, the time to first acquisition of SA from one month of age onwards was significantly associated with day care attendance, and NTHI and MC colonization. None of the infants colonized with SA developed SA infections through age 6 months. CONCLUSIONS: SA colonization of NP begins very early in life and declines quickly. Methicillin-resistant SA has lower ability to maintain prolonged colonization status than methicillin-susceptible strains in the first 6 months of life. As the NP is colonized with other respiratory bacterial pathogens, the colonization with SA declines; however, this effect is stronger with Gram-negative bacteria, such as NTHI and MC.

The Multidisciplinary Translational Team (MTT) Model for Training and Development of Translational Research Investigators.

Multiinstitutional research collaborations now form the most rapid and productive project execution structures in the health sciences. Effective adoption of a multidisciplinary team research approach is widely accepted as one mechanism enabling rapid translation of new discoveries into interventions in human health. Although the impact of successful team-based approaches facilitating innovation has been well-documented, its utility for training a new generation of scientists has not been thoroughly investigated. We describe the characteristics of how multidisciplinary translational teams (MTTs) promote career development of translational research scholars through competency building, interprofessional integration, and team-based mentoring approaches. Exploratory longitudinal and outcome assessments from our experience show that MTT membership had a positive effect on the development of translational research competencies, as determined by a self-report survey of 32 scholars. We also observed that all trainees produced a large number of collaborative publications that appeared to be associated with their CTSA association and participation with MTTs. We conclude that the MTT model provides a unique training environment for translational and team-based learning activities, for investigators at early stages of career development.

Importance of viruses in acute otitis media.

PURPOSE OF REVIEW: Acute otitis media occurs as a complication of viral upper respiratory tract infection. Bacterial otopathogens and respiratory viruses interact and play important roles in acute otitis media development. A better understanding of viral and bacterial interactions may lead to innovative ways to lessen the burden of this common childhood disease. RECENT FINDINGS: There has been increasing evidence that acute otitis media occurs during upper respiratory infection, even in the absence of nasopharyngeal bacterial colonization. Among the types of viruses associated with acute otitis media, respiratory syncytial virus continues to be the most commonly detected. It is still unclear whether viral load plays an important role in acute otitis media development, but symptomatic upper respiratory tract infection (as opposed to asymptomatic viral infection) is crucial. Widespread use of bacterial and viral vaccines in young children, including pneumococcal conjugate and influenza vaccines, has led to the reduction in otitis media-related healthcare use between 2001 and 2011. There has been no new vaccine against respiratory viruses other than influenza. SUMMARY: Progress has been made toward the reduction of the burden of acute otitis media in the last decade. Success in reducing acute otitis media incidence will rely mainly on prevention of nasopharyngeal otopathogen colonization, as well as reduction in the incidence of viral upper respiratory tract infection.

Symptomatic and asymptomatic respiratory viral infections in the first year of life: association with acute otitis media development.

BACKGROUND: Sensitive diagnostic assays have increased the detection of viruses in asymptomatic individuals. The clinical significance of asymptomatic respiratory viral infection in infants is unknown. METHODS: High-throughput, quantitative polymerase chain reaction assays were used to detect 13 common respiratory viruses from nasopharyngeal specimens collected during 2028 visits from 362 infants followed from near birth up to 12 months of age. Specimens were collected at monthly interval (months 1-6 and month 9) and during upper respiratory tract infection (URTI) episodes. Subjects were followed closely for acute otitis media (AOM) development. RESULTS: Viruses were detected in 76% of 394 URTI specimens and 27% of asymptomatic monthly specimens. Rhinovirus was detected most often; multiple viruses were detected in 29% of the specimens. Generalized mixed-model analyses associated symptoms with increasing age and female sex; detection of respiratory syncytial virus (RSV), influenza, rhinovirus, metapneumovirus, and adenovirus was highly associated with symptoms. Increasing age was also associated with multiple virus detection. Overall, 403 asymptomatic viral infections in 237 infants were identified. Viral load was significantly higher in URTI specimens than asymptomatic specimens but did not differentiate cases of URTI with and without AOM complication. The rate of AOM complicating URTI was 27%; no AOM occurred following asymptomatic viral infections. AOM development was associated with increasing age and infection with RSV, rhinovirus, enterovirus, adenovirus, and bocavirus. CONCLUSIONS: Compared to symptomatic infection, asymptomatic viral infection in infants is associated with young age, male sex, low viral load, specific viruses, and single virus detection. Asymptomatic viral infection did not result in AOM.

Duration of rhinovirus shedding in the upper respiratory tract in the first year of life.

BACKGROUND: Current molecular diagnostic methods have detected rhinovirus RNA in a high proportion of asymptomatic infants and children, raising the question of the clinical significance of these findings. This study investigates the prevalence of prolonged rhinovirus RNA presence in the upper respiratory tract of infants during the first year of life. METHODS: In a longitudinal study, infants were followed from birth up to 12 months. Nasopharyngeal specimens were collected monthly (months 1-6 and month 9) and during an upper respiratory infection. Rhinoviruses were detected by quantitative reverse-transcription polymerase chain reaction. Presence of repeated rhinovirus RNA was evaluated by nucleotide sequence analysis. RESULTS: A total of 2153 specimens from 362 infants were studied; 341 distinct rhinovirus infections in 216 infants were identified. Follow-up specimens were available within 30 days for 179 infections, creating the sample set to assess prolonged rhinovirus presence. Of the 179 infections, 46 involved the detection of the same rhinovirus strain in repeated specimens, including 8 events of prolonged presence of the same strain (detected in specimens collected >30 days apart), representing 4.5% of the evaluable rhinovirus infections. There were 26 events in which a rhinovirus strain was replaced by a different strain within a 30-day interval, representing 14.5% of the 179 infections. CONCLUSIONS: Although rhinovirus infections are common in healthy infants, prolonged presence of rhinovirus RNA in the respiratory tract after an upper respiratory infection was uncommon (<5%). Detection of rhinovirus RNA in an infant most likely represents an infection within a 30-day period.

Polymorphisms of immunity genes and susceptibility to otitis media in children.

BACKGROUND: Acute otitis media (OM) is a common disease which often develops through complex interactions between the host, the pathogen and environmental factors. We studied single nucleotide polymorphisms (SNPs) of genes involved in innate and adaptive immunity, and other host and environmental factors for their role in OM. METHODS: Using Sequenom Massarray platform, 21 SNPs were studied in 653 children from prospective (n = 202) and retrospective (n = 451) cohorts. Data were analyzed for the relationship between SNPs and upper respiratory infection (URI) frequency, risk of acute OM during URI episodes, and proneness to recurrent OM. RESULTS: Increased risk for OM proneness was associated with CX3CR1 (Thr280Met) SNP and with a jointly interactive group of IL-10 (-1082) SNP, IL-1ß (-511) wild type genotype and white race. Family history of OM proneness independently increased the risk for frequent URIs, OM occurrence during URI, and OM proneness. Additionally, IL-1ß (-31) SNP was associated with increased risk for frequent URIs, but IL-10 (-592), IL-1ß (-511), IL-5 (-746) and IL-8 (-251) SNPs were associated with decreased risk of URI. CONCLUSION: IL-1ß (-31), CX3CR1 (Thr280Met), IL-10 (-1082) and IL-1ß (-511) SNPs were associated with increased risk for frequent URIs or OM proneness.

Acute bacterial sinusitis complicating viral upper respiratory tract infection in young children.

BACKGROUND: Acute bacterial sinusitis (ABS) is a common complication of viral upper respiratory tract infections (URI). Clinical characteristics of URIs complicated by ABS in young children have not been well studied. METHODS: We identified ABS episodes in a prospective, longitudinal cohort study of 294 children (6-35 months of age at enrollment), who were followed up for 1 year to capture all URI episodes and complications. At the initial URI visit seen by the study personnel (median day = 4 from symptoms onset), nasopharyngeal samples were obtained for bacterial cultures and viral studies. RESULTS: Of 1295 documented URI episodes, 103 (8%) episodes (in 73 children) were complicated by ABS, 32 of which were concurrent with acute otitis media. The majority (72%) of ABS episodes were diagnosed based on persistent symptoms or a biphasic course. Average age at ABS diagnosis was 18.8 ± 7.2 months; White children were more likely to have ABS episodes than Blacks (P = 0.01). Hispanic/Latino ethnicity (P < 0.0001) was negatively associated, and adequate 7-valent pneumococcal conjugate vaccine immunization status (P = 0.001) appeared to increase the risk of ABS. Girls had more ABS episodes than boys (0.5 ± 0.8 vs. 0.3 ± 0.6 episodes/yr, respectively, P = 0.03). Viruses were detected in 63% during the initial URI visit; rhinovirus detection was positively correlated with ABS risk (P = 0.01). Bacterial cultures were positive in 82/83 (99%) available samples obtained at the initial URI visit; polymicrobial (56%), Moraxella catarrhalis (20%) and Streptococcus pneumoniae (10%) were the most common cultures. Presence of pathogenic bacteria overall and presence of M. catarrhalis during URI were positively correlated with the risk for ABS (P = 0.04 for both). CONCLUSIONS: ABS complicates 8% of URI in young children. Girls have more frequent ABS episodes than boys. Presence of rhinovirus and M. catarrhalis during URI are positively correlated with the risk for ABS complication.

Role of Human Bocavirus in Upper Respiratory Tract Infections and Acute Otitis Media.

BACKGROUND: Human bocavirus (HBoV) is a newly described parvovirus. HBoV1 has been associated with respiratory infections, including acute otitis media (AOM), but the knowledge on the significance of HBoV1 in upper respiratory tract infections (URI) and AOM in relation to other respiratory viruses is limited. The objective of this study was to compare the rate of detection of HBoV1 to that of other respiratory viruses in specimens from children with URI, with and without AOM complication. METHODS: Nasopharyngeal secretions (NPS) were collected during URI from healthy children (6-35 months) followed prospectively for 1 year; specimens have been previously analyzed for broad spectrum of respiratory viruses. Archived NPS were analyzed for HBoV1 using a high-throughput, quantitative polymerase chain reaction method. RESULTS: Seven hundred and seven NPS samples collected during URI episodes from 201 children were studied for HBoV1. A total of 94 (47%) children tested positive for HBoV1 DNA during 172 (24%) URI episodes; HBoV1 was present as the only virus in 44 (6%) URI episodes. Overall, 37% of URI episodes were complicated by AOM. Of URI associated with single virus (n = 303), the rate of AOM complicating URI associated with HBoV1 only was 52% (23 of 44); this was a higher AOM rate, compared to that of other respiratory viruses. CONCLUSIONS: Among URI associated with single respiratory virus, HBoV1-URI was commonly associated with AOM complication. The important role of HBoV1 on AOM pathogenesis needs to be studied further.