Screening for Mutations in Isolated Central Hypothyroidism Reveals a Novel Mutation in Insulin Receptor Substrate 4.

Background: Central hypothyroidism (CeH) is a rare condition affecting approximately 1:16 000- 100 000 individuals. Congenital forms can harm normal development if not detected and treated promptly. Clinical and biochemical diagnosis, especially of isolated CeH, can be challenging. Cases are not usually detected in neonatal screening, which, in most countries, is focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth diagnosed with CeH at the age of 5 years. We further evaluated the candidate gene variants in a large genetic database. Methods: Clinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to identify the genetic cause in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen database. Results: A novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in the X-linked IRS4 gene was identified by NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. Diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (p = 1.3e-7) and hypothyroidism (p = 8.3e-7). Conclusions: Here, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen database. Our findings confirm the role of IRS4 in isolated central hypothyroidism.

Antibiotic Treatments During Infancy, Changes in Nasal Microbiota, and Asthma Development: Population-based Cohort Study.

BACKGROUND: Early-life exposures to antibiotics may increase the risk of developing childhood asthma. However, little is known about the mechanisms linking antibiotic exposures to asthma. We hypothesized that changes in the nasal airway microbiota serve as a causal mediator in the antibiotics-asthma link. METHODS: In a population-based birth-cohort study in Finland, we identified longitudinal nasal microbiota profiles during age 2-24 months using 16S rRNA gene sequencing and an unsupervised machine learning approach. We performed a causal mediation analysis to estimate the natural direct effect of systemic antibiotic treatments during age 0-11 months on risks of developing physician-diagnosed asthma by age 7 years and the natural indirect (causal mediation) effect through longitudinal changes in nasal microbiota. RESULTS: In our birth cohort of 697 children, 8.0% later developed asthma. Exposure to ≥2 antibiotic treatments during age 0-11 months was associated with a 4.0% increase in the absolute risk of developing asthma (absolute increase, 95% CI, .9-7.2%; P = .006). The unsupervised clustering approach identified 6 longitudinal nasal microbiota profiles. Infants with a larger number of antibiotic treatments had a higher risk of having a profile with early Moraxella sparsity (per each antibiotic treatment, adjusted RRR, 1.38; 95% CI, 1.15-1.66; P < .001). This effect of antibiotics on asthma was partly mediated by longitudinal changes in the nasal microbiota (natural indirect effect, P = .008), accounting for 16% of the total effect. CONCLUSIONS: Early exposures to antibiotics were associated with increased risk of asthma; the effect was mediated, in part, by longitudinal changes in the nasal airway microbiota.

Longitudinal Changes in Early Nasal Microbiota and the Risk of Childhood Asthma.

OBJECTIVES: Although the airway microbiota is a highly dynamic ecology, the role of longitudinal changes in airway microbiota during early childhood in asthma development is unclear. We aimed to investigate the association of longitudinal changes in early nasal microbiota with the risk of developing asthma. METHODS: In this prospective, population-based birth cohort study, we followed children from birth to age 7 years. The nasal microbiota was tested by using 16S ribosomal RNA gene sequencing at ages 2, 13, and 24 months. We applied an unsupervised machine learning approach to identify longitudinal nasal microbiota profiles during age 2 to 13 months (the primary exposure) and during age 2 to 24 months (the secondary exposure) and examined the association of these profiles with the risk of physician-diagnosed asthma at age 7 years. RESULTS: Of the analytic cohort of 704 children, 57 (8%) later developed asthma. We identified 4 distinct longitudinal nasal microbiota profiles during age 2 to 13 months. In the multivariable analysis, compared with the persistent Moraxella dominance profile during age 2 to 13 months, the persistent Moraxella sparsity profile was associated with a significantly higher risk of asthma (adjusted odds ratio, 2.74; 95% confidence interval, 1.20-6.27). Similar associations were observed between the longitudinal changes in nasal microbiota during age 2 to 24 months and risk of asthma. CONCLUSIONS: Children with an altered longitudinal pattern in the nasal microbiota during early childhood had a high risk of developing asthma. Our data guide the development of primary prevention strategies (eg, early identification of children at high risk and modification of microbiota) for childhood asthma. These observations present a new avenue for risk modification for asthma (eg, microbiota modification).

Respiratory syncytial virus infections in children 0-24 months of age in the community.

OBJECTIVES: Respiratory syncytial virus (RSV) is a major cause of hospitalization in young children, but there are little data on RSV infections in early childhood in the community. We conducted a prospective population-based birth-cohort study to determine the rates and characteristics of RSV infections in young children. METHODS: We followed 923 children for acute respiratory infections (ARIs) from birth to age 24 months with daily diaries and study clinic visits. Nasal swab samples were obtained at the onset of ARIs and analyzed for RSV by RT-PCR and antigen tests. The rates of RSV infections and associated outcomes were estimated. RESULTS: RSV was detected in 289 (6%) of 4728 ARIs with a nasal sample. The mean estimated annual rate of RSV infections was 37 (95% confidence interval [CI], 35-38) per 100 children at age 0-24 months. For RSV-associated outcomes, the estimated annual rates per 100 children were 34 (95% CI, 32-37) physician visits, 16 (95% CI, 15-17) antibiotic treatments, 12 (95% CI, 11-13) acute otitis media, and 6 (95% CI, 4-7) wheezing illnesses. The prevalence of RSV was 0.6% in asymptomatic children. CONCLUSIONS: RSV infections impose a high burden of disease in healthy young children in the community.

Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against all respiratory tract infections in children under two years of age.

BACKGROUND: Pneumococcal conjugate vaccines reduce the incidence of invasive pneumococcal diseases, pneumonia, acute otitis media (AOM), and antimicrobial prescriptions in children. We investigated the effectiveness of at least one dose of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; GSK) against respiratory tract infections (RTIs) in children under two years of age. METHODS: 424 children enrolled in a cluster-randomized, double-blind Finnish Invasive Pneumococcal disease (FinIP) vaccine trial during the years 2009-2010 were actively followed in a prospective cohort study (STEPS study) for RTIs from birth to two years of age. Children received the PHiD-CV10 vaccine, or a control vaccine (hepatitis A or B vaccine) according to an age-specific schedule. Data on RTIs were collected by symptom diaries, clinic visits, an electronic registry on hospitalizations, and by nasal swab samples analyzed for respiratory viruses. We estimated the vaccine effectiveness against all RTI episodes and RTI episodes with or without AOM by comparing the corresponding incidence rates between PHiD-CV10 vaccinated and control children, adjusted for presence of siblings and cluster as a random effect. RESULTS: A total of 3193 RTI episodes were documented after the first vaccination in 368 children with all data available. The majority of the illnesses were upper RTIs caused by rhinovirus. The PHiD-CV10-vaccinated children had lower mean annual rates of all RTI episodes (6.4; 95% confidence interval [CI], 6.0-6.8) and RTI episodes with AOM (1.0; 95% CI, 0.9-1.2) as compared to the control children (7.4; 95% CI, 6.8-8.0 and 1.3; 95% CI, 1.1-1.6, respectively). The vaccine effectiveness was 12% (95% CI, 2-22%) against all RTIs, 23% (95% CI, 0-40%) against RTIs with AOM, and 10% (95% CI, 0-19%) against RTIs without AOM. CONCLUSIONS: Vaccination with PHiD-CV10 resulted in lower rates of RTIs in children under two years of age compared to children vaccinated with control vaccine.

Influenza virus infections from 0 to 2 years of age: A birth cohort study.

BACKGROUND/PURPOSE: Influenza vaccine has been recommended in Finland since 2007 for all children of 6-35 months of age and in 2009 for those ≥6 months against pandemic influenza. We investigated the incidence of influenza and vaccine effectiveness in a birth cohort of children in 2008-2011. METHODS: We followed 923 children from birth to 2 years of age for respiratory tract infections. A nasal swab sample for PCR for influenza A and B viruses was taken at the onset of acute respiratory infections. Samples were collected either at the study clinic or at home by parents. Vaccination data was retrieved from the health registries. RESULTS: Vaccination coverage of children aged 6-23 months was 22-47% against seasonal influenza and 80% against the A(H1N1)pdm09 virus in the pandemic season 2009-2010. During 3 influenza seasons, 1607 nasal swab samples were collected. Influenza was confirmed in 56 (6.1%) of 923 children (16 A(H1N1), 14 A(H3N2), and 26 B viruses). The incidence of influenza was 5.1% in 2008-2009, 2.7% in 2009-2010, and 5.0% in 2010-2011. Effectiveness of the adjuvanted vaccine against the pandemic influenza A(H1N1)pdm09 was 97% (95% confidence interval, 76-100%). Three children with influenza were hospitalized. CONCLUSION: The yearly incidence of seasonal influenza was 5% in this cohort of very young children with variable influenza vaccine coverage. Adjuvanted vaccine against the pandemic influenza was highly effective. Both seasonal and pandemic influenza cases were mostly non-severe.

Daycare attendance and respiratory tract infections: a prospective birth cohort study.

OBJECTIVE: We explored the burden of respiratory tract infections (RTIs) in young children with regard to day-care initiation. DESIGN: Longitudinal prospective birth cohort study. SETTING AND METHODS: We recruited 1827 children for follow-up until the age of 24 months collecting diary data on RTIs and daycare. Children with continuous daycare type and complete data were divided into groups of centre-based daycare (n=299), family day care (FDC) (n=245) and home care (n=350). Using repeated measures variance analyses, we analysed days per month with symptoms of respiratory tract infection, antibiotic treatments and parental absence from work for a period of 6 months prior to and 9 months after the start of daycare. RESULTS: We documented a significant effect of time and type of daycare, as well as a significant interaction between them for all outcome measures. There was a rise in mean days with symptoms from 3.79 (95% CI 3.04 to 4.53) during the month preceding centre-based daycare to 10.57 (95% CI 9.35 to 11.79) at 2 months after the start of centre-based daycare, with a subsequent decrease within the following 9 months. Similar patterns with a rise and decline were observed in the use of antibiotics and parental absences. The start of FDC had weaker effects. Our findings were not changed when taking into account confounding factors. CONCLUSIONS: Our study shows the rapid increase in respiratory infections after start of daycare and a relatively fast decline in the course of time with continued daycare. It is important to support families around the beginning of daycare.

Acquisition and Transmission of Streptococcus pneumoniae Are Facilitated during Rhinovirus Infection in Families with Children.

RATIONALE: Laboratory and clinical evidence suggests synergy between rhinoviruses and Streptococcus pneumoniae in the pathogenesis of respiratory tract infections. However, it is unclear whether rhinoviruses promote pneumococcal acquisition and transmission. OBJECTIVES: To describe the impact of rhinovirus infection on the acquisition and transmission of pneumococci within families with children. METHODS: We investigated 29 families with at least two children. The follow-up started at the onset of respiratory infectious symptoms in any family member and consisted of daily symptom diary and nasal swab samples from each participant twice per week for 3 weeks. Swabs were taken by the parents and sent to a study clinic by mail. Rhinoviruses were detected by reverse transcription-polymerase chain reaction and typed by sequencing. Pneumococci were identified by an antigen test and by standard culture methods, serotyping, and whole-genome sequencing. The effect of rhinovirus infection on the rates of pneumococcal acquisition and within-family transmission was estimated from the observed acquisition events and person-times spent uncolonized, using Poisson regression. MEASUREMENTS AND MAIN RESULTS: Rhinovirus was detected in 38 subjects (30%) at the onset and in 86 subjects (67%) during the follow-up. S. pneumoniae was detected on the first day in 9 (7%) and during follow-up in 38 (30%) subjects. Children with rhinovirus infection had a 4.3-fold rate of pneumococcal acquisition from the community (95% confidence interval, 1.1-15.4) and a 14.8-fold rate of within-family transmission (95% confidence interval, 3.1-69.6) compared with children without rhinovirus infection. CONCLUSIONS: Rhinovirus infection within families facilitates acquisition and within-family transmission of S. pneumoniae.

Rhinovirus Infections in the First 2 Years of Life.

BACKGROUND AND OBJECTIVES: Rhinoviruses frequently cause respiratory infections in young children. We aimed to establish the burden of acute respiratory infections caused by rhinovirus during the first 2 years of life. METHODS: In this prospective birth cohort study, we followed 923 children for acute respiratory infections from birth to 2 years of age. Data on respiratory infections were collected by daily symptom diaries, study clinic visits, and from electronic registries. Respiratory viruses were detected by reverse transcription-polymerase chain reaction and antigen assays during respiratory infections and at the age of 2, 13, and 24 months. The rates of rhinovirus infections and associated morbidities were determined. RESULTS: We documented 8847 episodes of acute respiratory infections, with an annual rate of 5.9 per child (95% confidence interval [CI], 5.7-6.1). Rhinovirus was detected in 59% of acute respiratory infections analyzed for viruses. Rhinovirus was associated with 50% of acute otitis media episodes, 41% of wheezing illnesses, 49% of antibiotic treatments, and 48% of outpatient office visits for acute respiratory infections. The estimated mean annual rate of rhinovirus infections was 3.5 per child (95% CI, 3.3-3.6), 47 per 100 children (95% CI, 42-52) for rhinovirus-associated acute otitis media, and 61 per 100 children (95% CI, 55-68) for rhinovirus-associated antibiotic treatment. The prevalence of rhinovirus at 2, 13, or 24 months of age was 14 to 24%, and 9% of asymptomatic children were positive for rhinovirus. CONCLUSIONS: Rhinovirus infections impose a major burden of acute respiratory illness and antibiotic use on young children.

Burden of Recurrent Respiratory Tract Infections in Children: A Prospective Cohort Study.

BACKGROUND: The burden of recurrent respiratory infections is unclear. We identified young children with recurrent respiratory infections in order to characterize the clinical manifestations, risk factors and short-term consequences. METHODS: In this prospective cohort study, 1089 children were followed from birth to 2 years of age for respiratory infections by a daily symptom diary. Nasal swabs taken during respiratory infections were analyzed for viruses from 714 children. Nasopharyngeal swabs collected at 2 months of age were cultured for bacteria. The 10% of children with the highest number of annual respiratory illness days were defined to have recurrent respiratory tract infections. RESULTS: The 90th percentile in the number of annual respiratory illness days was 98. Children above this limit (n = 109) had a median of 9.6 acute respiratory infections per year. Rhinovirus was detected in 58% of their infections. Of the children with recurrent infections, 60% were diagnosed with at least 3 episodes of acute otitis media, 73% received at least 3 antibiotic treatments and 21% were hospitalized for an acute respiratory infection. Tympanostomy was performed for 35% and adenoidectomy for 13% of the children. Asthma was diagnosed in 12% by 24 months of age. Older siblings increased the risk of recurrent respiratory infections. Early nasopharyngeal colonization with Streptococcus pneumoniae was common in children who later developed recurrent infections. CONCLUSIONS: Children with recurrent respiratory infections frequently use health care services and antibiotics, undergo surgical procedures and are at risk for asthma in early life. Having older siblings increases the risk of recurrent infections.

Association between infant swimming and rhinovirus-induced wheezing.

AIM: Infant swimming has been considered as a risk factor for wheezing, but the role that respiratory viruses play is unclear. We explored the effects of infant swimming on the risk of all wheezing illnesses and wheezing associated with rhinoviruses. METHODS: We followed up a birth cohort of 1827 children until 17 months of age, collecting data on infant swimming, other risk factors and physician-diagnosed bronchiolitis or recurrent wheezing. Viral diagnostics were performed in a subset of children with all respiratory tract infections. RESULTS: Data on infant swimming were obtained for 1038 children, with viral follow-up for 635 children. At least one wheezing illness was documented in 45/469 (9.6%) swimming children versus 39/569 (6.9%) nonswimming children (p = 0.11), and rhinoviruses were associated with wheezing in 11/296 (3.7%) swimming children versus 4/339 (1.2%) nonswimming children (p = 0.04). In adjusted logistic regression analyses, swimming had an odds ratio of 1.71 (p = 0.05) for bronchiolitis and 3.57 (p = 0.06) for rhinovirus-associated wheezing. An association between infant swimming and rhinovirus-associated wheezing was detected for children with atopic eczema (p = 0.006). CONCLUSION: There may be a link between infant swimming and rhinovirus-induced wheezing illnesses in atopic infants.

Effects of Rhinovirus Infection on Nasopharyngeal Bacterial Colonization in Infants With Wild or Variant Types of Mannose-Binding Lectin and Toll-Like Receptors 3 and 4.

BACKGROUND: Development of respiratory tract infections is determined by interactions between viruses, bacteria, and the host innate immune response. We investigated the impact of natural rhinovirus infection on nasopharyngeal bacterial colonization in infants with or without gene polymorphisms of mannose-binding lectin (MBL) and Toll-like receptors (TLRs) 3 and 4. METHODS: Rhinoviruses were detected by reverse transcription-polymerase chain reaction and bacteria by culture of nasopharyngeal specimens from 2- to 3-month-old infants. Gene polymorphisms in MBL at codons 52, 54, and 57, TLR3 Leu412Phe, and TLR4 Asp299Gly were detected by pyrosequencing. RESULTS: Of 337 infants, 61 were positive for rhinovirus and 187 were colonized by Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, or Staphylococcus aureus. Gene polymorphisms of MBL were detected in 32%, TLR3 in 51%, and TLR4 in 18% of subjects. Presence of rhinovirus was associated with increased colonization by S pneumoniae in children with MBL polymorphisms (8 of 20 [40%] with rhinovirus, vs 9 of 87 [10%] without rhinovirus; P = .003), but not in those with wild-type MBL. In logistic regression analyses, S pneumoniae colonization associated with MBL variant (P = .035) and with the interaction between rhinovirus and MBL variant (P = .004), and M catarrhalis colonization associated with the detection of rhinovirus (P = .033). CONCLUSIONS: The association between rhinovirus infection and nasopharyngeal pneumococcal colonization in early infancy is linked to genetic variations of MBL.