A Cohort Study of Risk Factors and Prognosis for Frequent Acute Asthma Exacerbations Phenotype

Asthma is an important respiratory disease. Asthma affects 1-18% of the population worldwide.The prevalence of asthma in adults ≥20 years old in China is 4.2% , numbering 45.7 million. An acute asthma exacerbation is defined as a rapid increase in symptoms such as wheezing, shortness of breath, chest tightness, and cough in a short period of time, and deterioration of lung function that requires additional reliever medications to treat. Acute asthma exacerbations are important events in the course of poorly controlled asthma, leading to increased mortality, decreased quality of life and extensive use of health care resources. Reducing the frequency of acute asthma exacerbations is an important principle of asthma treatment. It has been found that some patients with asthma are prone to acute exacerbations and these patients develop a stable phenotype. Compared to patients with infrequent acute exacerbations, asthma patients with frequent exacerbations are characterized by higher doses of inhaled glucocorticoids and/or oral hormones, poorer asthma control, lower quality of life, increased CRP and sputum eosinophils, more rapid decline in lung function, and a greater likelihood of continuing to have frequent acute exacerbations thereafter. A high proportion of patients with frequent acute exacerbations are present in patients with asthma of varying severity. Although treatment adherence and self-management skills are thought to be associated with acute asthma exacerbations, however, a higher proportion of asthma patients with good adherence and self-management skills still seem to be prone to acute exacerbations . Furthermore, reduction in asthma symptoms does not always correspond to the number or severity of acute attacks. Unlike what has been previously observed in severe asthma, there was no significant correlation between frequent acute exacerbations of asthma and asthma duration, age of onset, race, and socioeconomic background. The above studies suggest that frequent asthma exacerbations may represent a distinct asthma phenotype and that the underlying mechanisms of asthma severity and frequent acute exacerbations may be different. We need more research on the pathogenic mechanisms and treatments for frequent acute exacerbations.

Studies on risk factors for frequent acute exacerbations of asthma have yielded inconsistent results. Some studies have shown that asthma severity is an independent risk factor for frequent acute asthma exacerbations. However, other findings show that when patients are compliant with treatment, there are no specific characteristics that distinguish frequent acute exacerbations from infrequent acute exacerbations of the same asthma severity. Poorly controlled asthma also greatly increases the risk of acute exacerbations, but inconsistencies between the current level of control and the risk of acute exacerbations have also been reported. A significant proportion of patients with mild to moderate asthma who have well controlled asthma have frequent exacerbations, suggesting that the underlying mechanisms of baseline disease control and acute exacerbations may be driven by different factors in patients with mild to moderate asthma, and that a reduction in asthma symptoms does not always coincide with the number or severity of acute exacerbations. The pathophysiological mechanisms that cause frequent asthma exacerbations are unclear, and a few studies have explored the inflammatory mechanisms underlying frequent asthma exacerbations, with a multicenter cohort study of severe asthma showing that blood eosinophils were associated with asthma with a predisposition to acute exacerbations. When asthma treatment is aimed at minimizing airway eosinophil counts, the occurrence of frequent exacerbations can be prevented in moderate to severe asthma.High FeNO levels are also a risk factor for frequent acute exacerbations. However, sputum eosinophil percentages below 2% have also been reported in patients with frequent exacerbations. Mechanisms related to viral infection may also play a role in frequent acute attacks. One study evaluated the concentrations of interferon-gamma protein 10 (IP-10) and neopterin, and the results compared to the stable phase suggested that these two biomarkers of inflammation involved in viral infection were increased during acute episodes. However, the study did not confirm a difference in the concentrations of the two biomarkers between frequent and infrequent acute episodes. There is still a need to identify biomarkers, which may help to predict frequent acute episodes.

In summary, frequent acute exacerbations are likely to be a distinct asthma phenotype. Further studies are needed to identify risk factors for frequent acute exacerbations, but previous studies have mostly been cross-sectional studies at a single time point or prospective studies based on smaller sample sizes. Moreover, most of the studies on frequent acute exacerbations have been conducted in severe or refractory asthma, whereas a certain proportion of patients with nonsevere asthma may also have frequent acute exacerbations, and their risk factors still need to be further evaluated; in addition, previous studies have rarely looked at the effect of comorbidities on frequent acute exacerbations; furthermore, there have been no prospective studies to look at the prognosis of patients with frequent acute exacerbations and the response to treatments and prognostic factors associated with such attacks. Finally, the pathophysiologic mechanisms underlying frequent acute exacerbations of asthma require further investigation.

Therefore, the main objectives of this study were to compare the baseline clinical, inflammatory, pathophysiologic, comorbid, and environmental characteristics of patients with frequent acute exacerbations and those with infrequent acute exacerbations, regardless of asthma severity, and to develop a predictive model for frequent acute exacerbations; and to develop a cohort of patients with frequent acute exacerbations of asthma, to observe their prognosis and response to therapy, and to search for prognostic-related factors. The successful implementation of this study will help early identification of patients with frequent acute exacerbations, clarify the factors associated with poor prognosis in this group of patients, and thus provide individualized solutions for the treatment and prevention of patients with this type of asthma; exploring the inflammatory mechanisms of frequent acute exacerbations of asthma will help to elucidate the pathogenesis of this subtype, and to discover new specific therapeutic targets for this subtype.