Viral wheeze and risk factors for childhood asthma : an evaluation of clinical, immunological and genetic factors

It’s not fully understood why some children wheeze with viral infections, and why some develop severe asthma. In this study we compared two study groups; children presenting with acute wheeze (AW) before the age of four and age-matched healthy controls (HC), and we investigated factors that might contribute to increased vulnerability for airway infections and risk of later asthma development.

In Study I we identified several hereditary and environmental risk factors in the AW group, including significantly lower vitamin D levels and recurrent episodes of viral wheeze compared with the HC group. Rhinovirus (RV) was the most common virus detected. Bacterial co-infections were also common at the acute visit in the AW group. In Study II we investigated which subtypes of RV were detected during the acute phase, and the change in RV-specific IgG1 between the acute visit and a follow-up three months later. It is currently debated whether or not RV-C is more pathogenic than RV-A and RV-B. RV-C was the most frequently detected subtype, but we found no correlation between RV subtypes and clinical symptoms, or RV-specific IgG1 increase at follow-up. Children with an increase in specific IgG1 against both RV-A and RV-C, reported the longest duration of respiratory symptoms, indicating a possible synergistic effect of two RV subtypes and possibly an increased risk of asthma.

Recently, CDHR3 has been identified as an asthma susceptibility gene, and it encodes the RV-C receptor, cadherin-related family member 3. In Study III we investigated CDHR3 rs6967330 G>A genotype in the AW and HC groups, and AG/AA was found to be overrepresented in the AW group. Furthermore, reduced mRNA levels for CDHR3 were shown in children with acute wheeze. The chitinase like protein YKL-40 has been associated with airway remodeling, and severe asthma in school-children. In Study IV we investigated blood YKL-40 at the acute, 3-month and 1-year follow-up visits. We studied the distribution of the genetic variant rs4950928 (-131C>G) in the gene encoding YKL-40, CHI3L1. The distribution was similar in the AW and HC groups, although rs4950928 variants were found to strongly affect circulating YKL-40 levels. The levels of YKL-40 were higher in the AW children during acute wheeze and at the 3-month follow-up, but did not differ between the groups at the one-year follow-up visit.

In conclusion, preschool children in the AW group had several environmental and hereditary risk factors for later asthma development, as well as lower levels of vitamin D. RV-C was detected in the majority of children in the AW group and co-infection with bacteria was common. The asthma susceptibility gene variant rs6967330 in CDHR3 was associated with wheeze, and reduced mRNA levels of CDHR3 were shown in children with acute wheeze. However, the proposed biomarker YKL-40 did not facilitate the identification of children with persistent airway inflammation. Several of our findings indicate that children with wheeze may constitute a group of children with an increased vulnerability, both immunologically and genetically, placing them at greater risk of developing asthma compared to the healthy, age-matched HC group.

List of scientific papers

I. K. Stenberg Hammar, G. Hedlin, J.R. Konradsen, B. Nordlund, I. Kull, C.G. Giske, C. Pedroletti, C. Söderhäll, E. Melén. Subnormal levels of vitamin D are associated with acute wheeze in young children. Acta Paediatrica. 2014 Aug; 103(8):856-61.
https://doi.org/10.1111/apa.12666

II. K. Stenberg Hammar, K. Niespodziana, C. Söderhäll, A. James, C. Cabauatan, J.R. Konradsen, E. Melén, M. van Hage, R. Valenta, G. Hedlin. Rhinovirus-specific antibody responses in preschool children with acute wheeze reflect severity of respiratory symptoms. Allergy. 2016 Jul 22.
https://doi.org/10.1111/all.12991

III. K. Stenberg Hammar, K. Niespodziana, M. van Hage, J. Kere, R. Valenta, G. Hedlin, C. Söderhäll. CDHR3 in preschool children with acute wheeze. [Manuscript]

IV. A. James, K. Stenberg Hammar, L. Reinius, J.R. Konradsen, S-E. Dahlén, C. Söderhäll, G. Hedlin. A longitudinal assessment of YKL-40 levels in preschool children with wheeze. Pediatr Allergy Immunol. 2016 Oct 12.
https://doi.org/10.1111/pai.12669