Updated Evaluation of Dupilumab in the Treatment of Asthma: Patient Selection and Reported Outcomes.

Uncontrolled asthma continues to be a problem for many patients with moderate-to-severe allergic asthma. Dupilumab, which blocks the receptors for interleukin-4 and interleukin-13, has been effective in reducing asthma exacerbations, improving forced expiratory volume in one second (FEV1), and reducing oral corticosteroid use. When selecting patients for dupilumab, it is important to consider entry criteria for the original studies, subgroups that have responded best, and the presence of comorbid diseases that may also respond to dupilumab. Factors that were considered when selecting patients likely to respond to dupilumab in asthma studies include: failure of moderate or high dose inhaled steroids in combination with an additional controller medication, baseline FEV1 reversibility of 12% or greater, and Asthma Control Questionnaire > 1.5. The baseline characteristics that predicted a better response to dupilumab included blood eosinophils > 150 cells/mm3 and fractional exhaled nitric oxide > 25 parts per billion. Comorbidities that may also respond to treatment with dupilumab include atopic dermatitis, chronic rhinosinusitis, and allergic rhinitis. A combination of these factors should be considered when selecting the patients most likely to benefit from dupilumab.

Temperature-related changes in airborne allergenic pollen abundance and seasonality across the northern hemisphere: a retrospective data analysis.

BACKGROUND: Ongoing climate change might, through rising temperatures, alter allergenic pollen biology across the northern hemisphere. We aimed to analyse trends in pollen seasonality and pollen load and to establish whether there are specific climate-related links to any observed changes. METHODS: For this retrospective data analysis, we did an extensive search for global datasets with 20 years or more of airborne pollen data that consistently recorded pollen season indices (eg, duration and intensity). 17 locations across three continents with long-term (approximately 26 years on average) quantitative records of seasonal concentrations of multiple pollen (aeroallergen) taxa met the selection criteria. These datasets were analysed in the context of recent annual changes in maximum temperature (Tmax) and minimum temperature (Tmin) associated with anthropogenic climate change. Seasonal regressions (slopes) of variation in pollen load and pollen season duration over time were compared to Tmax, cumulative degree day Tmax, Tmin, cumulative degree day Tmin, and frost-free days among all 17 locations to ascertain significant correlations. FINDINGS: 12 (71%) of the 17 locations showed significant increases in seasonal cumulative pollen or annual pollen load. Similarly, 11 (65%) of the 17 locations showed a significant increase in pollen season duration over time, increasing, on average, 0·9 days per year. Across the northern hemisphere locations analysed, annual cumulative increases in Tmax over time were significantly associated with percentage increases in seasonal pollen load (r=0·52, p=0·034) as were annual cumulative increases in Tmin (r=0·61, p=0·010). Similar results were observed for pollen season duration, but only for cumulative degree days (higher than the freezing point [0°C or 32°F]) for Tmax (r=0·53, p=0·030) and Tmin (r=0·48, p=0·05). Additionally, temporal increases in frost-free days per year were significantly correlated with increases in both pollen load (r=0·62, p=0·008) and pollen season duration (r=0·68, p=0·003) when averaged for all 17 locations. INTERPRETATION: Our findings reveal that the ongoing increase in temperature extremes (Tmin and Tmax) might already be contributing to extended seasonal duration and increased pollen load for multiple aeroallergenic pollen taxa in diverse locations across the northern hemisphere. This study, done across multiple continents, highlights an important link between ongoing global warming and public health-one that could be exacerbated as temperatures continue to increase. FUNDING: None.

Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life.

BACKGROUND: Viral infections are the major cause of acute wheezing illnesses in childhood. Variations in immunologic responses at birth may be determinants of the risk of acquiring these illnesses. OBJECTIVES: To determine the immunologic risk factors for virus-induced wheezing in high-risk infants. METHODS: The study involves 285 children with a parental history of asthma and/or respiratory allergies. Mononuclear cells obtained at birth (umbilical cord blood) and at 1 year of age were incubated with phytohemagglutinin, respiratory syncytial virus, or rhinovirus, and supernatants were analyzed for IL-5, IL-10, IL-13, and IFN-gamma. Nasal secretions obtained at well child visits and during respiratory illnesses were analyzed for common respiratory viruses. RESULTS: Respiratory syncytial virus-induced wheezing was associated with reduced phytohemagglutinin-induced IL-13 responses (medians, 213 vs 304 pg/mL; P = .026) from cord blood cells, and similar trends were found for wheezing in general. Furthermore, median IL-13 responses diminished by 28% in non-wheezing children by age 1 year, versus only 3% in wheezing children (P = .013). Children with > or =2 episodes of wheezing had lower phytohemagglutinin-induced IFN-gamma responses and were less likely to have rhinovirus-induced IFN-gamma responses at birth (P < .05). Finally, children with measurable cord blood IFN responses to respiratory syncytial virus were less likely to wheeze in their first year (odds ratio, 0.43 [0.23, 0.79]). CONCLUSION: In children with a family history of allergies and/or asthma, mononuclear cell phytohemagglutinin-induced IL-13 and virus-induced IFN-gamma responses at birth are indicative of the risk for wheezing in the first year of life.

Rhinovirus-induced interferon-gamma and airway responsiveness in asthma.

The majority of asthma exacerbations are caused by respiratory infections, with rhinovirus (RV) being the most common virus. Recent evidence has suggested that decreased generation of IFN-gamma is associated with more severe colds and delayed elimination of virus. Whether the generation of IFN-gamma also has any relationship to general features of asthma severity has yet to be determined. To evaluate this hypothesis, peripheral blood mononuclear cells from 19 subjects with atopy and asthma were incubated with RV16 for 6 days to determine IFN-gamma and interleukin (IL)-5 production; these responses were then compared with measurements of airflow obstruction and airway responsiveness. RV16-induced IFN-gamma production correlated significantly with the methacholine PD (r = 0.50, p = 0.03), and the ratio of RV16-induced IFN-gamma:IL-5 correlated with % predicted FEV1 (r = 0.53, p = 0.02). In contrast, there were no significant associations between measures of asthma severity and RV-induced IL-5. These findings suggest that a cytokine imbalance with a deficient Th1 response to RV, but not a Th2 response, is associated with measures of asthma severity and support the concept that impaired antiviral responses may be associated with asthma severity.

Infections and asthma.

Infections have a variety of influences in the asthmatic patient. Respiratory syncytial virus (RSV) is the most common cause of wheezing illnesses in children under the age of 2 years and may be a risk factor for the inception of asthma in the first decade of life. Once asthma has become recognized clinically, rhinovirus is the leading cause of acute asthma exacerbations in adults and older children. Certain respiratory infections may induce chronic lower airway inflammation that may contribute to disease progression or severity in asthma. Paradoxically, some infections may even protect against the development of asthma. This article reviews the evidence for these associations and the mechanisms proposed to explain these various outcomes.