Pneumonia, wheezing and asthma were more common in children after thymectomy due to open-heart surgery.

AIM: This nationwide study evaluated the clinical impact that an early thymectomy, during congenital heart defect (CHD) surgery, had on the health of children and adolescents. METHODS: The subjects were patients aged 1-15 years who had undergone CHD surgery at the University Children's Hospital, Helsinki, where all CHD surgery in Finland is carried out, from 2006 to 2018. The parents or the cases and population-based controls, matched for sex, age and hospital district, completed electronic questionnaires. We excluded those with low birth weights or a known immunodeficiency. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated for prespecified outcomes. RESULTS: We received responses relating to 260/450 (58%) cases and 1403/4500 (31%) controls and excluded 73 cases with persistent cardiac or respiratory complaints after surgery. The CHD group reported more recurrent hospitalisations due to infections (aOR 6.3, 95% CI 3.0-13) than the controls and more pneumonia episodes (aOR 3.5, 95% CI 2.1-5.6), asthma (aOR 2.5, 95% CI 1.5-4.1) and wheezing (aOR 2.1, 95% CI 1.5-2.9). CONCLUSION: Hospitalisation due to infections, pneumonia, wheezing and asthma was more common in children after a thymectomy due to open-heart surgery than population-based controls, underlining the importance of immunological follow-ups.

Characterization of low-density granulocytes in COVID-19.

Severe COVID-19 is characterized by extensive pulmonary complications, to which host immune responses are believed to play a role. As the major arm of innate immunity, neutrophils are one of the first cells recruited to the site of infection where their excessive activation can contribute to lung pathology. Low-density granulocytes (LDGs) are circulating neutrophils, whose numbers increase in some autoimmune diseases and cancer, but are poorly characterized in acute viral infections. Using flow cytometry, we detected a significant increase of LDGs in the blood of acute COVID-19 patients, compared to healthy controls. Based on their surface marker expression, COVID-19-related LDGs exhibit four different populations, which display distinctive stages of granulocytic development and most likely reflect emergency myelopoiesis. Moreover, COVID-19 LDGs show a link with an elevated recruitment and activation of neutrophils. Functional assays demonstrated the immunosuppressive capacities of these cells, which might contribute to impaired lymphocyte responses during acute disease. Taken together, our data confirms a significant granulocyte activation during COVID-19 and suggests that granulocytes of lower density play a role in disease progression.

A comprehensive assessment of four whole blood stabilizers for flow-cytometric analysis of leukocyte populations.

Though cryopreservation of cell fractions is widely used in flow cytometry studies, whole blood cryopreservation is more challenging due to the presence of erythrocytes and effects of fixatives commonly used for preservation. Here, we evaluated and compared head-to-head the performance of four commercial whole blood cryopreservation kits; (1) Cytodelics, (2) Stable-Lyse V2 and Stable-Store V2 (SLSS-V2), (3) Proteomic stabilizer (PROT-1), and (4) Transfix. We found that PROT-1, Transfix, and Cytodelics maintained the distribution of major leukocyte subsets-granulocytes, T cells, natural killer cells, and B cells, on a comparable level to unpreserved samples, despite the attenuation of fluorescence intensities in flow cytometric assays. Moreover, these three stabilizers also maintained the activated phenotypes of neutrophils upon stimulation with N-formylmethionyl-leucyl-phenylalanine and lipopolysaccharides. The upregulation of adhesion molecules (CD11b), Fc receptors (CD16), and granule proteins (CD66b), as well as the shedding of surface L-selectin (CD62L), was conserved most efficiently in PROT-1 and Cytodelics when compared to samples only treated with erythrocyte lysing. However, none of the stabilizers provided a reliable detection of CCR7 for accurate quantification of T cell maturation stages. We also evaluated the performance of Cytodelics in longitudinal clinical samples obtained from acute COVID-19 patients, where it allowed reliable detection of lymphopenia and granulocyte expansion. These results support the feasibility of whole blood cryopreservation for immunophenotyping by flow cytometry, particularly in longitudinal studies. In conclusion, the performance of different stabilizers is variable and therefore the choice of stabilizers should depend on cell type of interest, as well as antibody clones and experimental design of each study.

Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood.

BACKGROUND: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. METHODS: In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. RESULTS: In the STEPS Study (n = 1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.97], respectively. In the FinnBrain cohort (n = 971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus-positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other IFN-related genes. CONCLUSIONS: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.

Rhinovirus Detection in Symptomatic and Asymptomatic Children: Value of Host Transcriptome Analysis.

RATIONALE: Rhinoviruses (RVs) are a major cause of symptomatic respiratory tract infection in all age groups. However, RVs can frequently be detected in asymptomatic individuals. OBJECTIVES: To evaluate the ability of host transcriptional profiling to differentiate between symptomatic RV infection and incidental detection in children. METHODS: Previously healthy children younger than 2 years old (n = 151) were enrolled at four study sites and classified into four clinical groups: RV- healthy control subjects (n = 37), RV+ asymptomatic subjects (n = 14), RV+ outpatients (n = 30), and RV+ inpatients (n = 70). Host responses were analyzed using whole-blood RNA transcriptional profiles. MEASUREMENTS AND MAIN RESULTS: RV infection induced a robust transcriptional signature, which was validated in three independent cohorts and by quantitative real-time polymerase chain reaction with high prediction accuracy. The immune profile of symptomatic RV infection was characterized by overexpression of innate immunity and underexpression of adaptive immunity genes, whereas negligible changes were observed in asymptomatic RV+ subjects. Unsupervised hierarchical clustering identified two main clusters of subjects. The first included 93% of healthy control subjects and 100% of asymptomatic RV+ subjects, and the second comprised 98% of RV+ inpatients and 88% of RV+ outpatients. Genomic scores of healthy control subjects and asymptomatic RV+ children were similar and significantly lower than those of RV+ inpatients and outpatients (P < 0.0001). CONCLUSIONS: Symptomatic RV infection induced a robust and reproducible transcriptional signature, whereas identification of RV in asymptomatic children was not associated with significant systemic transcriptional immune responses. Transcriptional profiling represents a useful tool to discriminate between active infection and incidental virus detection.

Nasopharyngeal Microbiota, Host Transcriptome, and Disease Severity in Children with Respiratory Syncytial Virus Infection.

RATIONALE: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and hospitalizations in infants worldwide. Known risk factors, however, incompletely explain the variability of RSV disease severity, especially among healthy children. We postulate that the severity of RSV infection is influenced by modulation of the host immune response by the local bacterial ecosystem. OBJECTIVES: To assess whether specific nasopharyngeal microbiota (clusters) are associated with distinct host transcriptome profiles and disease severity in children less than 2 years of age with RSV infection. METHODS: We characterized the nasopharyngeal microbiota profiles of young children with mild and severe RSV disease and healthy children by 16S-rRNA sequencing. In parallel, using multivariable models, we analyzed whole-blood transcriptome profiles to study the relationship between microbial community composition, the RSV-induced host transcriptional response, and clinical disease severity. MEASUREMENTS AND MAIN RESULTS: We identified five nasopharyngeal microbiota clusters characterized by enrichment of either Haemophilus influenzae, Streptococcus, Corynebacterium, Moraxella, or Staphylococcus aureus. RSV infection and RSV hospitalization were positively associated with H. influenzae and Streptococcus and negatively associated with S. aureus abundance, independent of age. Children with RSV showed overexpression of IFN-related genes, independent of the microbiota cluster. In addition, transcriptome profiles of children with RSV infection and H. influenzae- and Streptococcus-dominated microbiota were characterized by greater overexpression of genes linked to Toll-like receptor and by neutrophil and macrophage activation and signaling. CONCLUSIONS: Our data suggest that interactions between RSV and nasopharyngeal microbiota might modulate the host immune response, potentially affecting clinical disease severity.

Effects of antibiotics, hospitalisation and surgical complications on self-reported immunological vulnerability following paediatric open-heart surgery and thymectomy: a single-centre retrospective cohort study.

BACKGROUND: Partial or complete thymectomy is routinely performed in paediatric open-heart surgeries when treating congenital heart defects. Whether or not thymectomised children require systematic immunological monitoring later in life is unknown. The objective of this study was to investigate the effects of preoperatively and postoperatively used antibiotics, hospitalisation and surgical complications on self-reported immunological vulnerability in paediatric patients with early thymectomy to better recognise the patients who could benefit from immunological follow-up in the future. METHODS: We conducted a retrospective cohort study, including 98 children and adolescents aged 1-15 years, who had undergone an open-heart surgery and thymectomy in infancy and who had previously answered a survey regarding different immune-mediated symptoms and diagnoses. We performed a comprehensive chart review of preoperative and postoperative factors from 1 year preceding and 1 year following the open-heart surgery and compared the participants who had self-reported symptoms of immunological vulnerability to those who had not. RESULTS: The median age at primary open-heart surgery and thymectomy was 19.5 days in the overall study population (60% men, n=56) and thymectomies mainly partial (80%, n=78). Broad-spectrum antibiotics were more frequently used preoperatively in participants with self-reported immunological vulnerability (OR=3.05; 95% CI 1.01 to 9.23). This group also had greater overall use of antibiotics postoperatively (OR=3.21; 95% CI 1.33 to 7.76). These findings were more pronounced in the subgroup of neonatally operated children. There was no statistically significant difference in the duration of intensive care unit stay, hospitalisation time, prevalence of severe infections, surgical complications or glucocorticoid use between the main study groups. CONCLUSION: Antimicrobial agents were more frequently used both preoperatively and postoperatively in thymectomised children with self-reported immunological vulnerability after thymectomy. Substantial use of antimicrobial agents early in life should be considered a potential risk factor for increased immunological vulnerability when evaluating the significance of immune-mediated symptom occurrence in thymectomised paediatric patients.

Mucosal-Associated Invariant T Cells are not susceptible in vitro to SARS-CoV-2 infection but accumulate into the lungs of COVID-19 patients.

Prolonged T cell lymphopenia is common in COVID-19, caused by SARS-CoV-2. While the mechanisms of lymphopenia during COVID-19 remain elusive, it is especially pronounced in a specialized innate-like T cell population called Mucosal Associated Invariant T cells (MAITs). MAITs has been suggested to express Angiotensin-Converting Enzyme 2 (ACE2), which is the well-known cellular receptor for SARS-CoV-2. However, it is still unclear if SARS-CoV-2 can infect or affect MAIT cells directly. In this study, we performed multicolor flow cytometry on peripheral blood mononuclear cells obtained from COVID-19 patients to assess the frequencies of CD8+Vα7.2+CD161+ MAIT subsets at acute and convalescent disease phases. The susceptibility of MAITs and T cells to direct exposure by SARS-CoV-2 was analysed using cells isolated from healthy donor buffy coats by viability assays, virus-specific RT-PCR, and flow cytometry. In situ lung immunofluorescence was used to evaluate retention of T cells, especially MAIT cells, in lung tissues during acute COVID-19. Our study confirms previous reports indicating that circulating MAITs are activated, and their frequency is declined in patients with acute SARS-CoV-2 infection, whereas an accumulation of MAITs and T cells was seen in the lung tissue of individuals with fatal COVID-19. However, despite a fraction of MAITs found to express ACE2, no evidence for the susceptibility of MAITs for direct infection or activation by SARS-CoV-2 particles was observed. Thus, their activation and decline in the circulation is most likely explained by indirect mechanisms involving other immune cells and cytokine-induced pro-inflammatory environment but not by direct exposure to viral particles at the infection site.

Young infants display heterogeneous serological responses and extensive but reversible transcriptional changes following initial immunizations.

Infants necessitate vaccinations to prevent life-threatening infections. Our understanding of the infant immune responses to routine vaccines remains limited. We analyzed two cohorts of 2-month-old infants before vaccination, one week, and one-month post-vaccination. We report remarkable heterogeneity but limited antibody responses to the different antigens. Whole-blood transcriptome analysis in an initial cohort showed marked overexpression of interferon-stimulated genes (ISGs) and to a lesser extent of inflammation-genes at day 7, which normalized one month post-vaccination. Single-cell RNA sequencing in peripheral blood mononuclear cells from a second cohort identified at baseline a predominantly naive immune landscape including ISGhi cells. On day 7, increased expression of interferon-, inflammation-, and cytotoxicity-related genes were observed in most immune cells, that reverted one month post-vaccination, when a CD8+ ISGhi and cytotoxic cluster and B cells expanded. Antibody responses were associated with baseline frequencies of plasma cells, B-cells, and monocytes, and induction of ISGs at day 7.

Risk factors for severe respiratory syncytial virus infection during the first year of life: development and validation of a clinical prediction model.

BACKGROUND: Novel immunisation methods against respiratory syncytial virus (RSV) are emerging, but knowledge of risk factors for severe RSV disease is insufficient for optimal targeting of interventions against them. Our aims were to identify predictors for RSV hospital admission from registry-based data and to develop and validate a clinical prediction model to guide RSV immunoprophylaxis for infants younger than 1 year. METHODS: In this model development and validation study, we studied all infants born in Finland between June 1, 1997, and May 31, 2020, and in Sweden between June 1, 2006, and May 31, 2020, along with the data for their parents and siblings. Infants were excluded if they died or were admitted to hospital for RSV within the first 7 days of life. The outcome was hospital admission due to RSV bronchiolitis during the first year of life. The Finnish study population was divided into a development dataset (born between June 1, 1997, and May 31, 2017) and a temporal hold-out validation dataset (born between June 1, 2017, and May 31, 2020). The development dataset was used for predictor discovery and selection in which we screened 1511 candidate predictors from the infants', parents', and siblings' data, and developed a logistic regression model with the 16 most important predictors. This model was then validated using the Finnish hold-out validation dataset and the Swedish dataset. FINDINGS: In total, there were 1 124 561 infants in the Finnish development dataset, 130 352 infants in the Finnish hold-out validation dataset, and 1 459 472 infants in the Swedish dataset. In addition to known predictors such as severe congenital heart defects (adjusted odds ratio 2·89, 95% CI 2·28-3·65), we confirmed some less established predictors for RSV hospital admission, most notably oesophageal malformations (3·11, 1·86-5·19) and lower complexity congenital heart defects (1·43, 1·25-1·63). The prediction model's C-statistic was 0·766 (95% CI 0·742-0·789) in Finnish data and 0·737 (0·710-0·762) in Swedish validation data. The infants in the highest decile of predicted RSV hospital admission probability had 4·5 times higher observed risk compared with others. Calibration varied according to epidemic intensity. The model's performance was similar to a machine learning (XGboost) model using all 1511 candidate predictors (C-statistic in Finland 0·771, 95% CI 0·754-0·788). The prediction model showed clinical utility in decision curve analysis and in hypothetical number needed to treat calculations for immunisation, and its C-statistic was similar across different strata of parental income. INTERPRETATION: The identified predictors and the prediction model can be used in guiding RSV immunoprophylaxis in infants, or as a basis for further immunoprophylaxis targeting tools. FUNDING: Sigrid Jusélius Foundation, European Research Council, Pediatric Research Foundation, and Academy of Finland.

Stable Levels of Antibodies Against Unrelated Toxoid Vaccines After COVID-19: COVID-19 Infection Does Not Affect Toxoid Vaccine Antibody Levels.

Background: Lymphopenia is common in COVID-19. This has raised concerns that COVID-19 could affect the immune system akin to measles infection, which causes immune amnesia and a reduction in protective antibodies. Methods: We recruited COVID-19 patients (n = 59) in Helsinki, Finland, and collected plasma samples on 2 to 3 occasions during and after infection. We measured IgG antibodies to diphtheria toxin, tetanus toxoid, and pertussis toxin, along with total IgG, SARS-CoV-2 spike protein IgG, and neutralizing antibodies. We also surveyed the participants for up to 17 months for long-term impaired olfaction as a proxy for prolonged post-acute COVID-19 symptoms. Results: No significant differences were found in the unrelated vaccine responses while the serological response against COVID-19 was appropriate. During the acute phase of the disease, the SARSCoV-2 IgG levels were lower in outpatients when compared to inpatients. SARS-CoV-2 serology kinetics matched expectations. In the acute phase, anti-tetanus and anti-diphtheria IgG levels were lower in patients with prolonged impaired olfaction during follow up than in those without. Conclusions: We could not detect significant decline in overall humoral immunity during or after COVID-19 infection. In severe COVID-19, there appears to be a temporary decline in total IgG levels.

Nasal expression of SARS-CoV-2 entry receptors in newborns.

BACKGROUND: SARS-CoV-2 infection is typically mild in children. Lower expression of SARS-CoV-2 entry receptors in the nasal epithelia have been described in children compared with adults. However, data from newborns are lacking. We compared nasal expression of four SARS-CoV-2 entry receptors between term and preterm newborns and adults. METHODS: Nasal scrape samples were obtained from 28 newborns (17 term and 11 preterm) and 10 adults. Reverse-transcription quantitative PCR was used to measure mRNA expression of ACE2, transmembrane serine protease 2 (TMPRSS2), neuropilin 1 (NRP1) and neuropilin 2 (NRP2) and insulin-like growth factor 1 receptor (IGF1R). RESULTS: Expression levels of ACE2, TMPRSS2, NRP1 and NRP2 were lower in term and preterm newborns and IGF1R lower in term newborns compared with adults (p<0.05). CONCLUSIONS: Both term and preterm newborns, compared with adults, have lower expression of SARS-CoV-2 entry receptors in nasal epithelium.

New-onset type 1 diabetes in Finnish children during the COVID-19 pandemic.

BACKGROUND: Viral infections may trigger type 1 diabetes (T1D), and recent reports suggest an increased incidence of paediatric T1D and/or diabetic ketoacidosis (DKA) during the COVID-19 pandemic. OBJECTIVE: To study whether the number of children admitted to the paediatric intensive care unit (PICU) for DKA due to new-onset T1D increased during the COVID-19 pandemic, and whether SARS-CoV-2 infection plays a role. METHODS: This retrospective cohort study comprises two datasets: (1) children admitted to PICU due to new-onset T1D and (2) children diagnosed with new-onset T1D and registered to the Finnish Pediatric Diabetes Registry in the Helsinki University Hospital from 1 April to 31 October in 2016-2020. We compared the incidence, number and characteristics of children with newly diagnosed T1D between the prepandemic and pandemic periods. RESULTS: The number of children admitted to PICU due to new-onset T1D increased from an average of 6.25 admissions in 2016-2019 to 20 admissions in 2020 (incidence rate ratio [IRR] 3.24 [95% CI 1.80 to 5.83]; p=0.0001). On average, 57.75 children were registered to the FPDR in 2016-2019, as compared with 84 in 2020 (IRR 1.45; 95% CI 1.13 to 1.86; p=0.004). 33 of the children diagnosed in 2020 were analysed for SARS-CoV-2 antibodies, and all were negative. CONCLUSIONS: More children with T1D had severe DKA at diagnosis during the pandemic. This was not a consequence of SARS-CoV-2 infection. Instead, it probably stems from delays in diagnosis following changes in parental behaviour and healthcare accessibility.

Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial.

BACKGROUND: Oseltamivir provides modest clinical benefits to children with influenza when started within 48 hours of symptom onset. The effectiveness of oseltamivir could be substantially greater if the treatment were started earlier during the course of the illness. METHODS: We carried out a randomized, double-blind, placebo-controlled trial of the efficacy of oseltamivir started within 24 hours of symptom onset in children 1-3 years of age with laboratory-confirmed influenza during the seasons of 2007-2008 and 2008-2009. Eligible children received either orally administered oseltamivir suspension or a matching placebo twice daily for 5 days. The children received clinical examinations, and the parents filled out detailed symptom diaries for 21 days. RESULTS: Of 408 randomized children who received the study drug (oseltamivir, 203, and placebo, 205), 98 had laboratory-confirmed influenza (influenza A, 79, and influenza B, 19). When started within 12 hours of the onset of symptoms, oseltamivir decreased the incidence of acute otitis media by 85% (95% confidence interval, 25%-97%), but no significant reduction was observed with treatment started within 24 hours. Among children with influenza A, oseltamivir treatment started within 24 hours shortened the median time to resolution of illness by 3.5 days (3.0 vs 6.5 days; P = .006) in all children and by 4.0 days (3.4 vs 7.3; P = .006) in unvaccinated children and reduced parental work absenteeism by 3.0 days. No efficacy was demonstrated against influenza B infections. CONCLUSIONS: Oseltamivir treatment started within 24 hours of symptom onset provides substantial benefits to children with influenza A infection. Clinical trials registration. ClinicalTrials.gov identifier: NCT00593502.

Immune profiles provide insights into respiratory syncytial virus disease severity in young children.

Respiratory syncytial virus (RSV) is associated with major morbidity in infants, although most cases result in mild disease. The pathogenesis of the disease is incompletely understood, especially the determining factors of disease severity. A better characterization of these factors may help with development of RSV vaccines and antivirals. Hence, identification of a "safe and protective" immunoprofile induced by natural RSV infection could be used as a as a surrogate of ideal vaccine-elicited responses in future clinical trials. In this study, we integrated blood transcriptional and cell immune profiling, RSV loads, and clinical data to identify factors associated with a mild disease phenotype in a cohort of 190 children <2 years of age. Children with mild disease (outpatients) showed higher RSV loads, greater induction of interferon (IFN) and plasma cell genes, and decreased expression of inflammation and neutrophil genes versus children with severe disease (inpatients). Additionally, only infants with severe disease had increased numbers of HLA-DRlow monocytes, not present in outpatients. Multivariable analyses confirmed that IFN overexpression was associated with decreased odds of hospitalization, whereas increased numbers of HLA-DRlow monocytes were associated with increased risk of hospitalization. These findings suggest that robust innate immune responses are associated with mild RSV infection in infants.

Systems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19.

Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.

Transient Tachypnea of the Newborn Is Associated With an Increased Risk of Hospitalization Due to Respiratory Syncytial Virus Bronchiolitis.

BACKGROUND: Transient tachypnea of the newborn (TTN) is a self-limiting respiratory disorder, resulting from a failure to clear the lungs of perinatal fluid. As similar pathophysiologic features are present in children with respiratory syncytial virus (RSV) bronchiolitis, we hypothesized that these two conditions may be connected. METHODS: This was a population-based cohort study that included all children born in term (≥37 weeks of gestation) without congenital malformations in Finland between 1996 and 2015. Children diagnosed with TTN (International Statistical Classification of Diseases and Related Health Problems, 10th Revision [ICD-10] code P22.1) after birth and children hospitalized because of RSV bronchiolitis (ICD-10 code J21.0) during first year of life were identified from the Medical Birth Register and National Hospital Discharge Register, respectively, and the data were linked. Logistic regression was used to analyze the association between these two conditions. RESULTS: Of the 1,042,045 children included in the study cohort, 16,327 (1.57%) were diagnosed with TTN at birth and 12,345 (1.18%) were hospitalized because of RSV bronchiolitis during the first year of life. The rate of RSV hospitalization was higher in children with a history of TTN compared with children without TTN diagnosis [260/16,327 (1.59%) vs. 12,085/1,025,718 (1.18%), respectively; P value <0.0001]. After adjusting for gestational age at birth, mode of delivery, gender, birth weight, multiple births, older siblings and maternal smoking, TTN was associated with increased risk for RSV hospitalization (odds ratio: 1.31, 95% confidence interval: 1.16-1.48). CONCLUSIONS: TTN diagnosis after birth was associated with increased risk for RSV hospitalization during the first year of life.

Infant Immune Response to Respiratory Viral Infections.

Of all respiratory viruses that affect infants, respiratory syncytial virus (RSV) and rhinovirus (RV) represent the leading pathogens causing acute disease (bronchiolitis) and are associated with the development of recurrent wheezing and asthma. The immune system in infants is still developing, and several factors contribute to their increased susceptibility to viral infections. These factors include differences in pathogen detection, weaker interferon responses, lack of immunologic memory toward the invading pathogen, and T-cell responses that are balanced to promote tolerance and restrain inflammation. These aspects are reviewed here with a focus on RSV and RV infections.