Association between cytokine gene polymorphisms and risk for upper respiratory tract infection and acute otitis media.

BACKGROUND: We previously reported an association between tumor necrosis factor alpha (TNFalpha)(-308)and interleukin (IL)-6(-174) polymorphisms and otitis susceptibility by history. Acute otitis media occurs most commonly as a complication of upper respiratory tract infection (URI); it is not clear why some children develop acute otitis media after URI and others do not. Our objective was to prospectively evaluate the association of TNFalpha(-308)and IL-6(-174) polymorphisms with URI and with acute otitis media development after URI. METHODS: Children aged 6-35 months were prospectively followed for occurrences of URI and acute otitis media. Blood or buccal mucosa samples were collected for DNA extraction to determine cytokine genotypes. Active and passive surveillance was used to capture all URI episodes during the 1-year follow-up period in order to study the rate of acute otitis media following URI. Data were analyzed using SAS software (SAS Institute) and general estimating equations modeling. RESULTS: Two hundred forty-two children were followed over 2689 patient-months and had DNA genotyped; 1235 URI episodes occurred, and 392 (32%) were complicated by acute otitis media. Children who had IL-6(-174) polymorphism had a higher susceptibility to URI during the study period (incidence density ratio, 1.24) and were more likely to meet established otitis susceptibility criteria (P < .01). Presence of TNFalpha(-308) polymorphism was associated with increased risk for acute otitis media after an episode of URI (odds ratio, 1.43). CONCLUSIONS: TNFalpha(-308) and IL-6(-174) genotypes are associated with increased risk for symptomatic URI and acute otitis media following URI. Future studies may be designed to carefully look at the interaction of these genetic polymorphisms with modifiable environmental risk factors.

Systemic cytokine response profiles associated with respiratory virus-induced acute otitis media.

BACKGROUND: Acute otitis media (AOM) results from a complex interplay between the infectious agents and host immune responses. Cytokines play a major role in the pathogenesis of AOM, but there are few studies on the systemic cytokine response during AOM. METHODS: Sera were collected from 145 children (median age = 13.5 months) at the time of diagnosis of AOM. Concentrations of 17 cytokines (IL-1beta, -2, -4, -5, -6, -7, -8, -10, -12, -13, -17, granulocyte-colony stimulating factor (G-CSF), granulocyte-monocyte-colony stimulating factor, interferon-gamma, MCP-1, MIP-1beta, TNF-alpha) were determined and correlated with viral etiology and clinical outcome. The statistical analysis was conducted using bioinformatics software. RESULTS: Cluster patterns of concentrations of cytokines were examined by unsupervised hierarchical clustering algorithms. Four major cluster groups were identified, one of the groups was significantly enriched for cases of respiratory syncytial virus (RSV)-induced AOM as compared with other viruses. Specifically, RSV-induced AOM had significantly higher concentrations of G-CSF, MCP-1, IL-10, IL-6, interferon-gamma, and IL-8 (P < 0.05). Using a decision tree classifier, higher G-CSF concentrations produced 87.6% accuracy to predict RSV-induced AOM. Overall, higher IL-13 concentrations produced 84.2% accuracy to predict early clinical failure of antibiotic treatment. CONCLUSIONS: Children with AOM have a unique pattern of systemic cytokine response that relates to virus etiology and clinical outcome. Based on G-CSF and IL-13 measurements, it is possible to accurately classify RSV-induced AOM and early treatment failure, respectively; these observations will need to be validated in an independent population.

Association of nasopharyngeal bacterial colonization during upper respiratory tract infection and the development of acute otitis media.

Acute otitis media occurs mostly after upper respiratory tract infection; the causative bacteria are those colonized in the nasopharynx. We studied 709 episodes of upper respiratory tract infection and found that children with no bacteria in the nasopharynx were at low risk for acute otitis media, whereas children with 3 pathogenic bacteria were at the greatest risk.

Viral upper respiratory tract infection and otitis media complication in young children.

BACKGROUND: The common cold or upper respiratory infection (URI) is highly prevalent among young children and often results in otitis media (OM). The incidence and characteristics of OM complicating URI due to specific viruses have not been well studied. METHODS: We performed a prospective, longitudinal cohort study of 294 healthy children (age range, 6 months to 3 years). Each child was observed for 1 year to assess the occurrence of URI, acute OM (AOM), and OM with effusion (OME) complicating URI due to specific viruses. RESULTS: We documented 1295 URI episodes (5.06 episodes per child-year) and 440 AOM episodes (1.72 episodes per child-year). Virus studies were performed for 864 URI episodes; 63% were virus positive. Rhinovirus and adenovirus were most frequently detected during URI. The overall incidence of OM that complicated URI was 61%, including a 37% incidence of AOM and a 24% incidence of OME. Young age was the most important predictor of AOM that complicated URI. AOM occurred in approximately one-half of children with URI due to adenovirus, respiratory syncytial virus, or coronavirus and in approximately one-third of those with URI due to influenza virus, parainfluenza virus, enterovirus, or rhinovirus. CONCLUSIONS: More than 60% of episodes of symptomatic URI among young children were complicated by AOM and/or OME. Young age and specific virus types were predictors of URI complicated by AOM. For young children, the strategy to prevent OM should involve prevention of viral URI. The strategy may be more effective if the priority is given to development of means to prevent URI associated with adenovirus and respiratory syncytial virus.

Microbial interactions during upper respiratory tract infections.

Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus often colonize the nasopharynx. Children are susceptible to bacterial infections during or soon after upper respiratory tract infection (URI). We describe colonization with these 4 bacteria species alone or in combination during URI. Data were from a prospective cohort of healthy children 6 to 36 months of age followed up for 1 year. Analyses of 968 swabs from 212 children indicated that S. pneumoniae colonization is negatively associated with colonization by H. influenzae. Competitive interactions shifted when H. influenzae and M. catarrhalis colonized together. In this situation, the likelihood of colonization with all 3 species is higher. Negative associations were identified between S. pneumoniae and S. aureus and between H. influenzae and S. aureus. Polymicrobial interactions differed by number and species of bacteria present. Antimicrobial therapy and vaccination strategies targeting specific bacterial species may alter the flora in unforeseen ways.

Tympanometric findings in young children during upper respiratory tract infections with and without acute otitis media.

BACKGROUND: Upper respiratory tract infections (URI) likely lead to acute otitis media (AOM) by causing Eustachian tube dysfunction which creates negative middle ear pressure. Children younger than 2 years of age are at highest risk for AOM compared with older children and adults. There has been no published study comparing the middle ear status during URI in infants and young children by age group. METHODS: We analyzed data from a prospective, longitudinal study of virus-induced AOM. Healthy children 6-35 months of age were enrolled in a study designed to capture all AOM after URI during a 1-year follow-up period. Tympanometry was used to address the middle ear status; tympanometric findings during the first week of URI were compared among different age groups. Tympanograms were classified into type A (normal), type B (middle ear effusion), and type C (negative middle ear pressure). RESULTS: Children 6-11 months of age with URI experienced abnormal tympanograms more frequently than older children (P < 0.001). The peak day for an abnormal tympanogram was day 2 of the URI. Abnormal tympanogram tended to be type B in children age 6-23 months and type C in children age 24-47 months (P < 0.001). One-third of children older than 24 months of age had type C tympanogram during the first week of URI. CONCLUSIONS: Eustachian tube dysfunction and middle ear abnormality during URI are more severe in children younger than 2 years of age, compared with older children. These findings could help explain the higher incidence of AOM after URI in younger children.

Acute otitis media severity: association with cytokine gene polymorphisms and other risk factors.

BACKGROUND: We have previously shown an association between polymorphisms of proinflammatory cytokine genes and susceptibility to upper respiratory tract infection and acute otitis media. It has not been known whether polymorphisms or risk factors are associated with the severity of acute otitis media. OBJECTIVE: To evaluate the influences of proinflammatory cytokine gene polymorphisms and other risk factors on severity of acute otitis media following upper respiratory tract infection. METHODS: In a prospective, longitudinal study, children aged 6-35 months were followed for one year for occurrences of upper respiratory tract infection and acute otitis media. Children were studied for TNFα(-308), interleukin (IL)-6(-174) and IL-1ß(+3953) polymorphisms, taking into account age, gender, race, family history of otitis, tobacco smoke exposure, breast feeding, day of upper respiratory tract infection at the time of diagnosis and pneumococcal vaccine status. Symptoms and signs of acute otitis media were graded according to a validated scale. The association between acute otitis media clinical severity, polymorphic genotypes, and risk factors were analyzed using statistical models that account for multiple episodes of acute otitis media per child. RESULTS: A total of 295 episodes of acute otitis media in 128 subjects was included. More severe acute otitis media symptoms were associated with young age (P=0.01), family history of acute otitis media (P=0.002), tobacco smoke exposure (P=0.008), and early diagnosis of otitis after onset of upper respiratory tract infection (P=0.02). Among children with a bulging or perforated tympanic membrane (206 episodes, 104 subjects), those who had the IL-1 ß(+3953) polymorphism, experienced higher symptom scores (P<0.02). CONCLUSION: This is the first report of the association between risk factors and acute otitis media severity. Risk factors such as tobacco smoke exposure and a positive family history appear to be more significantly associated with acute otitis media severity than proinflammatory gene polymorphisms. Clinical severity may be an important factor contributing to the incidence and costs of acute otitis media, because children with more severe symptoms might be more likely to be brought for a medical visit, receive a diagnosis of acute otitis media, and be prescribed an antibiotic.

Clinical spectrum of acute otitis media complicating upper respiratory tract viral infection.

BACKGROUND: acute otitis media (AOM) often occurs as a complication of upper respiratory tract infection (URI). OBJECTIVE: to describe otoscopic findings during URI, the full clinical spectrum of AOM, and outcome of cases managed with watchful waiting. METHODS: : In a prospective study of 294 healthy children (6 months-3 years), characteristics of AOM complicating URI were studied. Otoscopic findings were categorized by tympanic membrane (TM) position, color, translucency, and mobility. Otoscopic score was assigned based on McCormick otoscopy scale (OS)-8 scale. RESULTS: during days 1 to 7 of URI, otoscopic findings at 1114 visits were consistent with AOM in 22%; myringitis (inflamed TM, no fluid) was diagnosed in 7%. In AOM episodes diagnosed within 28 days of URI onset, TM position was described as: nonbulging (19%), mild bulging (45%), bulging (29%), and TM perforation occurred in (6%). OS-8 scale showed mild TM inflammation (OS, 2-3) in 6%, moderate (OS, 4-5) in 59%, and severe (OS, 6-8) in 35%. In 54% of 126 bilateral AOM episodes, inflammation of both TMs was at different stages. Of 28 cases of nonsevere AOM managed with watchful waiting, 4 progressed and 3 later required an antibiotic. CONCLUSIONS: AOM is a spectrum of infection that may present at various stages, even in the same child with bilateral disease. During URI, otoscopic changes are observed from the first day of onset. Understanding the wide clinical spectrum of AOM is needed to help with future clinical trial design and development of a scoring system to establish treatment criteria that will minimize antibiotic use.

Persistence of adenovirus nucleic acids in nasopharyngeal secretions: a diagnostic conundrum.

BACKGROUND: Polymerase chain reaction (PCR) assays increase the rate of viral detection in clinical specimens, compared with conventional virologic methods. Studies suggest that PCR may detect virus nucleic acid (NA) that persists in the respiratory tract. METHODS: We analyzed virologic data from children having frequent upper respiratory infections (URI), who were followed up in a longitudinal study. Nasopharyngeal secretions were collected at URI onset and when acute otitis media was diagnosed; virus studies were performed using conventional diagnostics and PCR. Repeated presence of adenovirus by PCR was further studied by sequencing and phylogenetic analysis. RESULTS: Of 581 URI episodes in 76 children, 510 viruses were detected. Of the viruses detected by PCR, 15% were those detected previously; repeated positives occurred most frequently with adenovirus. Sequencing results were available in 13 children with repeated adenovirus detection; the following 4 patterns of infection were identified (16 instances): (1) adenovirus of the same serotype and strain detected continuously (n = 8 instances), (2) adenovirus of different serotypes detected during sequential URI episodes (n = 3), (3) adenovirus of the same serotype but different strains detected during sequential URI episodes (n = 3), and (4) adenovirus of the same serotype and strain detected intermittently (n = 2). CONCLUSIONS: Among children with frequent URIs, repeated positive PCR results for adenovirus NA may represent a new serotype/strain, or persistence of viral NA. Results must be interpreted with caution; clinical correlation and presence of other viruses are important. Further longitudinal studies of children during and after infection are required for better understanding of the clinical significance of positive PCR tests for adenovirus NA in the respiratory tract.

Hospital distribution of formula discharge bags: opinions of Texas pediatricians.

OBJECTIVE: Exclusive breastfeeding is the gold standard for infant nutrition in the first 6 months of life. Despite this, significant obstacles prevent breastfeeding mothers from achieving this goal. The distribution of formula company-sponsored gift bags has been identified as one factor that negatively impacts breastfeeding exclusivity and duration. METHODS: The Texas Pediatric Society surveyed its members regarding their opinions about the distribution of formula company-sponsored gift bags. RESULTS: Of the survey respondents, 55% favored the elimination of gift bags for breastfeeding mothers, but only 24% were in favor of legislation prohibiting the distribution of gift bags. CONCLUSIONS: Grassroots advocacy has been very successful in persuading hospitals to eliminate formula company-sponsored gift bags. Physicians who would like to end the practice of distributing these bags should work with their local hospitals to develop alternatives that take into account the best interests of patients and hospitals. These efforts may be more successful than working to legislate the elimination of formula company-sponsored gift bags.

Nasopharyngeal acute phase cytokines in viral upper respiratory infection: impact on acute otitis media in children.

BACKGROUND: The role of acute phase cytokines generated in the nasopharynx during viral upper respiratory infection (URI) in subsequent development of acute otitis media (AOM) has not been examined. METHODS: We studied 326 virus-positive URI episodes in 151 children aged 6-36 months. Nasopharyngeal secretions collected within 1 to 7 days of URI onset were studied for viruses by conventional and molecular techniques, and for concentrations of IL-1beta, IL-6, and TNFalpha by multiplex enzyme-linked immunosorbent assay. Children were followed up for 28 days to document AOM complication. RESULTS: IL-1beta, IL-6, and TNFalpha concentrations correlated positively with each other (P<0.001). IL-6 and TNFalpha concentrations were higher in males than in females (P=0.01 and 0.02). IL-6 and TNFalpha concentrations were inversely correlated with age (P=0.02 and 0.05). IL-6 concentrations correlated positively with duration of fever (P=0.006) and correlated negatively with the number of days of URI symptoms (P=0.026). Furthermore, IL-6 concentrations were significantly higher during adenovirus and influenza virus URIs as compared with enterovirus and rhinovirus URIs (P<0.01). IL-1beta concentrations were higher during URI episodes with AOM than those without AOM (P<0.001). CONCLUSIONS: We found IL-6 nasopharyngeal secretions concentrations to be higher with adenovirus and influenza infection, and in children with systemic febrile response during URI. However, IL-1beta was found to play a more important role in the development of AOM after URI. Additional studies are needed to further define the role of acute phase cytokines in virus-induced AOM.

Role of respiratory syncytial virus in acute otitis media: implications for vaccine development.

We summarize herein the results of various virologic studies of acute otitis media (AOM) conducted at our site over a 10-year period. Among 566 children with AOM, respiratory syncytial virus (RSV) was the most common virus identified in either middle ear fluid or nasal wash; it was found in 16% of all children and 38% of virus-positive children. Seventy-one percent of the children with RSV were 1 year of age or older, which was significantly older than all other viruses combined (P=0.045). RSV infection was associated with the common bacterial pathogens causing AOM. Past efforts to develop vaccines for RSV have emphasized prevention of lower respiratory tract infection in infants, which is a more serious problem but less common than AOM. Our results suggest that RSV vaccines that work only against infection in older children may have value in preventing AOM, the most common pediatric disease.

Incidence of acute otitis media and sinusitis complicating upper respiratory tract infection: the effect of age.

Infants and young children are prone to developing upper respiratory tract infections, which often result in bacterial complications such as acute otitis media and sinusitis. We evaluated 623 upper respiratory tract infection episodes in 112 children (6-35 months of age) to determine the proportion of upper respiratory tract infection episodes that result in acute otitis media or sinusitis. Of all upper respiratory tract infections, 30% were complicated by acute otitis media and 8% were complicated by sinusitis. The rate of acute otitis media after upper respiratory tract infection declined with increasing age, whereas the rate of sinusitis after upper respiratory tract infection peaked in the second year of life. Risk for acute otitis media may be reduced substantially by avoiding frequent exposure to respiratory viruses (eg, avoidance of day care attendance) in the first year of life.

Effect of pneumococcal conjugate vaccine on nasopharyngeal bacterial colonization during acute otitis media.

The heptavalent pneumococcal conjugate vaccine (PCV7) has been shown to reduce the incidence of acute otitis media (AOM) caused by Streptococcus pneumoniae by 34% and reduces the overall incidence of AOM by 6% to 8%. More recent studies have shown increases in the proportion of Haemophilus influenzae and Moraxella catarrhalis in the middle-ear fluid of PCV7-immunized children. There has been no report on the effect of PCV7 on all 3 bacterial pathogens combined, either in the middle-ear fluid or nasopharynx of individual children with AOM. We investigated the impact of PCV7 on nasopharyngeal colonization with bacterial pathogens during AOM in the pre-PCV7 and post-PCV7 vaccination eras. Four hundred seventeen children (6 months to 4 years of age) were enrolled onto AOM studies between September 1995 and December 2004. Of these, 200 were enrolled before the vaccine use (historical controls), and 217 were enrolled after the initiation of PCV7 vaccination (101 were underimmunized, and 116 were immunized). Although the nasopharyngeal colonization rate for S pneumoniae was not different between the 3 groups, a significantly higher proportion of PCV7-immunized children with AOM were colonized with M catarrhalis. Overall, the mean number of pathogenic bacteria types isolated from immunized children (1.7) was significantly higher than in controls (1.4). The increase in bacterial colonization of the nasopharynx during AOM could be associated with an increase in AOM pathogens and theoretically can predispose PCV7-immunized children with AOM to a higher rate of antibiotic treatment failure or recurrent AOM.

Association of proinflammatory cytokine gene polymorphisms with susceptibility to otitis media.

OBJECTIVE: Susceptibility to otitis media results from complex interactions among genetic factors of the host, exposure to pathogens, and environmental influences. The objective of this study was to study the role of single-nucleotide polymorphisms of regulatory elements of proinflammatory cytokine genes tumor necrosis factor-alpha(-308), interleukin-1beta(+3953), and interleukin-6(-174), in susceptibility to recurrent otitis media in childhood. METHODS: A total of 505 children (296 otitis media susceptible, 209 nonsusceptible as control) were enrolled at 2 sites (Texas and Kentucky). DNA of the children was studied for specific single-nucleotide polymorphisms by restriction fragment length polymorphism assay and confirmed by gene sequencing. RESULTS: In the overall study group, tumor necrosis factor-alpha(-308) and interleukin-6(-174) heterozygous or homozygous polymorphisms (high cytokine-producing genotypes) were significantly associated with otitis media susceptibility. The same association was found in a match-paired subgroup of 384 subjects. In the overall study group, there was a significant step-wise increase in otitis media susceptibility with increasing number of concomitant polymorphic genotypes. Simultaneous combination of tumor necrosis factor-alpha(-308) and interleukin-6(-174) polymorphisms further increased the risk for otitis media susceptibility. These 2 polymorphic genotypes also were associated with the increased risk for tympanostomy tube placement. Children who had tumor necrosis factor-alpha(-308) polymorphism and were breastfed for <1 month or exposed to cigarette smoke were more likely to be otitis media susceptible. CONCLUSIONS: Our data suggest that tumor necrosis factor-alpha(-308) and interleukin-6(-174) polymorphisms are associated with increased risk for otitis media susceptibility and placement of tympanostomy tubes. Environmental factors such as breastfeeding may modify the risk for otitis media susceptibility in polymorphic individuals.