Tuomas Jartti

Respiratory Syncytial Virus Genomic Load and Disease Severity Among Children Hospitalized With Bronchiolitis: Multicenter Cohort Studies in the United States and Finland

Abstract Background. We investigated whether children with a higher respiratory syncytial virus (RSV) genomic load are at a higher risk of more-severe bronchiolitis. Methods. Two multicenter prospective cohort studies in the United States and Finland used the same protocol to enroll children aged <2 years hospitalized for bronchiolitis and collect nasopharyngeal aspirates. By using real-time polymerase chain reaction analysis, patients were classified into 3 genomic load status groups: low, intermediate, and high. Outcome measures were a length of hospital stay (LOS) of ≥3 days and intensive care use, defined as admission to the intensive care unit or use of mechanical ventilation. Results. Of 2615 enrolled children, 1764 (67%) had RSV bronchiolitis. Children with a low genomic load had a higher unadjusted risk of having a length of stay of ≥3 days (52%), compared with children with intermediate and those with high genomic loads (42% and 51%, respectively). In a multivariable model, the risk of having a length of stay of ≥3 days remained significantly higher in the groups with intermediate (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.20–1.69) and high (OR, 1.58; 95% CI, 1.29–1.94) genomic loads. Similarly, children with a high genomic load had a higher risk of intensive care use (20%, compared with 15% and 16% in the groups with low and intermediate genomic loads, respectively). In a multivariable model, the risk remained significantly higher in the group with a high genomic load (OR, 1.43; 95% CI, 1.03–1.99). Conclusion. Children with a higher RSV genomic load had a higher risk for more-severe bronchiolitis.

Microbes and asthma: Opportunities for intervention

The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation.

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.

A clustering approach to identify severe bronchiolitis profiles in children

Objective Although bronchiolitis is generally considered a single disease, recent studies suggest heterogeneity. We aimed to identify severe bronchiolitis profiles using a clustering approach. Methods We analysed data from two prospective, multicentre cohorts of children younger than 2 years hospitalised with bronchiolitis, one in the USA (2007–2010 winter seasons, n=2207) and one in Finland (2008–2010 winter seasons, n=408). Severe bronchiolitis profiles were determined by latent class analysis, classifying children based on clinical factors and viral aetiology. Results In the US study, four profiles were identified. Profile A (12%) was characterised by history of wheezing and eczema, wheezing at the emergency department (ED) presentation and rhinovirus infection. Profile B (36%) included children with wheezing at the ED presentation, but, in contrast to profile A, most did not have history of wheezing or eczema; this profile had the largest probability of respiratory syncytial virus infection. Profile C (34%) was the most severely ill group, with longer hospital stay and moderate-to-severe retractions. Profile D (17%) had the least severe illness, including non-wheezing children with shorter length of stay. Two of these profiles (A and D) were replicated in the Finnish cohort; a third group (‘BC’) included Finnish children with characteristics of profiles B and/or C in the US population. Conclusions Several distinct clinical profiles (phenotypes) were identified by a clustering approach in two multicentre studies of children hospitalised for bronchiolitis. The observed heterogeneity has important implications for future research on the aetiology, management and long-term outcomes of bronchiolitis, such as future risk of childhood asthma.

Post-bronchiolitis Use of Asthma Medication: A Prospective 1-year Follow-up Study.

Background: Our aim was to evaluate the association between viral findings during bronchiolitis and the use of asthma controller medication (primary outcome) and systemic corticosteroids (secondary outcome) during the first post-bronchiolitis year. Methods: We enrolled 408 children hospitalized for bronchiolitis at <24 months of age in a prospective, 3-center, 1-year follow-up study in Finland. Viruses were detected with polymerase chain reaction in nasopharyngeal aspirates. The parents underwent a structured interview during hospitalization. Twelve months later, the use of asthma medication was asked in a structured questionnaire. Multivariable logistic regression was used for statistical analysis. Results: In total, 365 (89%) children completed the 1-year follow-up. The use of long-term asthma controller medication was highest in the rhinovirus-positive group (61% vs. 15% in respiratory syncytial virus-positive group; adjusted odd ratios, 7.5; 95% confidence interval: 3.7–15.3), followed by children negative for both respiratory syncytial virus and rhinovirus (36%; adjusted odd ratios, 2.6; 95% confidence interval: 1.3–5.3). Likewise, rhinovirus etiology was associated with more courses of systemic corticosteroids during the follow-up. The main findings were similar in a subset of infants aged <12 months with first wheezing. Conclusions: Children hospitalized for rhinovirus-positive bronchiolitis used long-term asthma controller medication more often than those hospitalized for rhinovirus-negative bronchiolitis during first year after hospitalization.

Rhinovirus species and clinical characteristics in the first wheezing episode in children

The clinical data on the first wheezing episodes induced by different rhinovirus (RV) species are still limited. We aimed to investigate the prevalence of RV genotypes, sensitization status, and clinical characteristics of patients having a respiratory infection caused by either different RV species or other respiratory viruses. The study enrolled 111 patients (aged 3–23 months, 79% hospitalized, 76% with RV infection) with the first wheezing episode. RV‐specific sequences were identified by partial sequencing of VP4/VP2 and 5′ non‐coding regions with 80% success rate. The investigated clinical and laboratory variables included atopic characteristics and illness severity, parental atopic illnesses, and parental smoking. Of the study children, 56% percent had >1 atopic characteristic (atopy, eczema and/or blood eosinophil count >0.4 × 109/L) and 23% were sensitised to allergens. RV‐C was detected in 58% of RV positive samples, followed by RV‐A (20%) and RV‐B (1.2%). Children with RV‐A and RV‐C induced wheezing were older (P = 0.014) and had more atopic characteristics (P = 0.001) than those with non‐RV. RV‐A and RV‐C illnesses had shorter duration of preadmission symptoms and required more bronchodilator use at the ward than non‐RV illnesses (both P < 0.05, respectively). RV‐C is the most common cause of severe early wheezing. Atopic and illness severity features are associated with children having RV‐A or RV‐C induced first wheezing episode rather than with children having a non‐RV induced wheezing. J. Med. Virol. 88:2059–2068, 2016.

Sensitization at the first wheezing episode increases risk for long-term asthma therapy

mended that ASST be carried out in conjunction with the basophil histamine-release assay to demonstrate autoantibody specificity (6). The assay was negative in our patients, which could suggest a different possible cause of autoreactivity, although there were no other signs of chronic inflammatory or autoimmune disease. There have been no previous reports of IA with HI in a pediatric patient. Whether this is pure coincidence or the result of a common underlying pathogenetic mechanism remains to be seen. Histamine is a biogenic amine, affecting human organs and systems in multiple ways. Symptoms of excessive histamine in plasma manifest as acute pseudoallergic illness with skin rash, vomiting, diarrhea, abdominal pain, and/or respiratory distress. HI describes a state where catabolic capacity for endogenously released or exogenously administered histamine is insufficient, leading to histamine-mediated adverse reactions. People with low intestinal histamine inactivation or inhibition of this activity suffer from HI. This diagnosis is based on the careful recording of symptoms and the identification of intestinal or serum activities of DAO and histamine N-methyltransferase (HMT). It may be complemented by an analysis of DAO and HMT gene polymorphisms to identify a possible genetic predisposition. We measured DAO by enzyme immunoassay analysis in serum samples (10). For evaluation, we used the manufacturer’s recommended reference values, and all our patients had highly reduced activity of DAO <40 HDU/ml. The only effective therapy for HI is the avoidance of histamine-containing food, and our patients were advised to follow a histamine-free diet. Controlled trials demonstrating the efficacy of DAO substitution with fresh encapsulated enzymes are still lacking. It has been demonstrated that DAO activity increases in patients on a histamine-free diet, which could be a possible explanation for improvement and remission in case 1 and case 3, respectively. Symptomsandclassifications of IA in thepediatric population are the sameas those inadults, andadult treatment regimenshave been applied to children (2, 3). Two patients were considered to have generalized infrequent IA, and the third had generalized frequent IA (2, 3). Patients were instructed to carry epinephrine and were taught to self-administer it. We suggested prednisone therapy with antihistamine for the third patient, but the parents, fearing the side effects of corticosteroid, accepted only antihistamine daily. The girl has been in remission for 6 months. Idiopathic anaphylaxis has been classified and treated successfully, but the underlying mechanism of this disorder has yet to be revealed. The observation that IA is a steroidresponsive disorder indicates a possible autoimmune etiology. Pediatric IA can show up at any age; therefore, it is important to recognize it so that it may be appropriately treated. This potentially life-threatening syndrome can be successfully managed, and in the majority of patients with IA, the frequency of episodes often declines with age.

Vaccines: could asthma in young children be a preventable disease? .

‬The long battle with asthma is far from over in developed countries. Its incidence, prevalence, and severity have been increasing for decades. By reducing the risk for asthma, significant healthcare costs can be saved. The desire to create a vaccine that might prevent asthma in young children is attractive and widely considered one of the main goals in translational asthma research. Several vaccination strategies have been tested. These include allergen‐specific immunotherapy, vaccination against infectious pathogens, and modification of cell and cytokine responses. The lack of success in the prevention of asthma in young children lies on the complexity of the disease, which involves many genetic, epigenetic, and environmental interactions. This review provides a summary of current literature and aims to address key questions how to develop vaccines to prevent asthma in young children. ‬‬‬‬‬‬‬‬‬‬‬‬‬‬

Review of the clinical significance of respiratory virus infections in newborn infants.

Respiratory viruses have been recognised as causative agents for a wide spectrum of clinical manifestations and severe respiratory compromise in neonates during birth hospitalisation. Early‐life respiratory virus infections have also been shown to be associated with adverse long‐term consequences.

Exercise simultaneously increases nasal patency and bronchial obstruction in asthmatic children.

We found that simultaneous post‐exercise increase in nasal patency and bronchial obstruction occurs only in children with atopic asthma, but not in sensitized children without asthma. In healthy children, the increase in nasal patency is accompanied by bronchial dilatation.