Viral: Bacterial interactions in childhood asthma

We have learned a lot about the roles of viruses and bacteria in childhood asthma from longitudinal birth cohorts. These include the Childhood Asthma Study (CAS), Perth, Australia; the Childhood Origins of Asthma and Allergies (COAST), Wisconsin, USA; Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Copenhagen, Denmark; and Observational Research in Childhood Infectious Diseases (ORCHiD), Brisbane, Australia. These studies have all addressed the impact of early life viral infections on development of asthma. They have questioned whether viral infections cause asthma or whether asthma predisposition causes viral infections. The nasal epithelium is the point of first contact between respiratory viruses and the respiratory system. Many viruses can be detected from nasal secretions in the absence of clinical symptoms. Under these circumstances, the term “viral detection” is commonly used. Indeed multiple studies show the human rhinoviruses (HRV) can be detected in the nose of approximately 20% of asymptomatic children. Other viruses, for example, respiratory syncytial virus (RSV) are almost always associated with respiratory symptoms and detections as generally referred to as “viral infections.” The ontogeny of respiratory viral acquisition was studied in ORCHiD, where parents took weekly nasal swabs for viral (and bacterial) identification. This community-based cohort with approximately 30% of first-born children showed that the most common viruses acquired in the first month of life where HRV, most of which were asymptomatic. The presence of viruses in the nose induces an immune response designed to stop the virus spreading to the lower airways. Balanced immune responses, directed by mucosal-homing regulatory T-cells, limit the spread of viruses, especially in healthy children. The normal antiviral response from the respiratory epithelium is the secretion of type 3 (interferon lambda) and type 1 (interferon beta) interferons to prevent epithelial cell apoptosis and limit viral spread, followed by proinflammatory cytokines (tumor necrosis factor alpha and ilter-leukin 8) to recruit inflammatory cells to kills and clear the virus. Asthmatics do respond differently to respiratory viral infections, with decreased ability to secrete interferons and increased airway responsiveness post infection. A number of common genetic susceptibilities for asthma and viral respiratory infections have been uncovered, including ORMDL3 & GSDMB genes on 17q21 locus, associated with asthma and wheezing with HRV but not RSV; CDHR3, a know susceptibility for early onset childhood asthma, is the surface receptor for HRV type C; and rs6967330-A, a gain of function allele in CDHR3 has been associated with wheezing with HRVc, but not other viruses (COAST). Epidemiological studies have long suggested a role for early life lower respiratory viral infections increasing the risk of childhood asthma. Both CAS and COAST clearly demonstrated that the risk was magnified, and perhaps only existed when allergic sensitization developed by the age of 2 or 3 years. The risk was also magnified in these infections were accompanied by fever, indicating probable activation of inflammasome pathways. One of the first observations that bacteria in the upper airway may play a role in asthma risk came from the original COPSAC study of infants born to mothers with asthma. They showed that the presence of one or more of Streptococcus pneumonia, Haemophilus influenzae, or Moraxella catarrhalis, but not Staphylococcus aureus was associated with an increased risk of persistent wheeze (Odds ratio 2.01 [95% CI 1.13−3.57]) and hospitalization (3.57 [1.55−8.23]) over the first 5 years of life. This concept was extended in the CAS study where the upper airway microbiome in the first year of life was characterized and showed that healthy asymptomatic children had a simple microbiome consisting of the bacteria genera (by 16 s sequencing) staphylococcus, corynebacterium, and alloiococcus. The upper airway microbiome changed during viral infections, becoming dominated by Moraxella, streptococcus, and haemophilus. In addition, the early asymptomatic carriage of streptococcus was associated with a shorter time of severe viral lower respiratory illnesses (i.e., those associated with wheeze and/or fever). Asthma risk appeared to be maximal in those who could not revert their upper airway microbiome to a healthy profile. However, the interactions between bacteria and viruses in the upper airway are clearly complex, as exemplified by the finding in the CAS study that the abundance of Moraxella increased in the weeks before a symptomatic viral lower respiratory infection. This was not seen before an asymptomatic viral infection. We clearly have more to learn about interaction between bacteria and viruses in the upper airway and how these influence asthma risk in children. Peter D. Sly is soley responsible for this presentation. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. The author declares no conflict of interest. Research data are not shared.