Question: Epidemiological studies suggest respiratory viral infections are major triggers of asthma exacerbations, and clinical studies have suggested the involvement of an increased interleukin-6 (IL-6) release. What is the pathophysiological role of IL-6 in asthma exacerbation, and which mechanisms lead to enhanced IL-6 release? Material & Methods: Exacerbations of ovalbumin-induced experimental allergic asthma were elicited in wildtype and IL-6 deficient mice by intra-nasal (i.n.) application of poly(I:C). Airway inflammation, cytokine expression and release, mucus production, and airway hyperresponsiveness were measured. IL-6 was neutralised by i.n. anti-IL-6 antibody application. Human bronchial epithelial cells were exposed to poly(I:C) or infected with human rhinovirus-16, with IL6 expression and DNA methylation quantified. Genome-wide DNA methylation was assessed in airway epithelial cells from adults with asthma (cohort I, n=54) and in nasal epithelial cells from children and adults in the All-Age-Asthma cohort (ALLIANCE, n=53 and n=108 respectively). Results: Poly (I:C)-induced experimental exacerbations in mice were preceded and paralleled by exaggerated IL-6 release in the airway epithelium, with IL-6 neutralisation completely preventing experimental exacerbations. Repetitive infection/stimulation with RV16 or poly(I:C) resulted in training of the IL-6 release in human respiratory epithelial cells. In patients, hypomethylation at the IL6 gene methylation was associated with high IL6 expression and future exacerbations. Answer: An exaggerated IL-6 release is required for exacerbation of experimental asthma, potentially the result of viral PAMP-induced immune training of airway epithelial cells. Additionally, patients with asthma carrying the epigenetic signature of a trained IL-6 response exacerbate more frequently. These findings open new avenues to identify and treat exacerbation-prone patients.

Long-term changes in health-related quality of life (HrQoL) after SARS-CoV-2 infection are common, but the causes and consequences of these changes are not well understood. HrQoL was assessed using the European Quality-of-Life-5-Dimensions-5-Level-Version (EQ-5D-5L) in 2,618 participants (56% female; aged 18–88 years) approximately 9 months (baseline) and 26 months (follow-up) after their first infection. The results were compared to 40 different demographic and clinical variables. A clinically important improvement in HrQoL was noted during the observation period. At baseline, the number of remaining symptoms from the infection (RS), fatigue (FACIT-Fatigue Scale), depressive symptoms (PHQ-8), muscle pain, age, and anxiety (GAD-7) explained 43% of the variance in HrQoL. At follow-up, fatigue, RS, depressive symptoms, anxiety, and muscle pain explained 50% of the variance. Although changes in fatigue, depressive symptoms, anxiety, and RS were associated with a change in HrQoL, the predictive value of the variables was virtually zero. The study suggests that HrQoL improves statistically significantly during the observation period. However, the extent of recovery is difficult to predict from concurrent changes in demographic and clinical variables. Besides a high RS number, fatigue is the main predictor of poor HrQoL after infection, followed by the presence of depressive and anxiety symptoms.