In this retrospective cohort study based on the NHANES program we explored associations between chronic comorbid conditions and the occurrence of moderate and severe exacerbations in adult subjects with a self-reported diagnosis of asthma drawn from the US general population. We found that obesity and rheumatoid arthritis were statistically significant associated with the odds of severe asthma exacerbations and that rheumatoid arthritis was associated with the odds of moderate asthma exacerbations, as was a history of stroke. Stratification of the study sample in age categories revealed specific associations between certain comorbid conditions and asthma exacerbation occurrence. For example, soft drug use was especially high in younger subjects (i.e., those aged between 18 and 30 years) and associated with a reduced occurrence of severe exacerbations, while depression was associated with an increased occurrence of moderate asthma exacerbations in subjects aged 31–40 years.

A link between obesity and risk of asthma exacerbations has been reported in several previous studies6,7,8,18. Our observed association between rheumatoid arthritis and (moderate as well as severe) asthma exacerbations is consistent with a recent study from Luo et al.15. A possible mechanism could be that patients with rheumatoid arthritis have a dysregulated immune system and often receive treatment with immunosuppressive medication, which may lead to a higher risk of acute respiratory infections (ARI)19, a known trigger for asthma exacerbations2. The observed association in our study of a history of stroke and increased asthma exacerbation occurrence is again in line with previous studies13,14,18. Underlying mechanisms may be that asthma patients with a history of stroke are not only more prone to ARI leading to asthma exacerbation, but also to systemic vascular inflammation with platelet activation, inhibition of fibrinolysis, and elevation of C-reactive protein levels resulting in cardiovascular events20. Besides, increased stroke risk may also be the result of increased atrial fibrillation risk in uncontrolled asthma11, as a result of asthma exacerbation management with β2-agonists, discontinuation of β-blockers and discontinuation of aspirin in patients with aspirin-exacerbated respiratory disease14. In our study, a history of stroke was associated with moderate exacerbations, but not with severe exacerbations. The limited number of subjects in the severe exacerbations category and thus a Type 2 error may explain this.

In the age category of 31–40 years, we found that symptoms of depression were associated with moderate asthma exacerbations. A meta-analysis based on prospective cohort studies strongly suggests that depression significantly increased the risk of asthma exacerbation16. However, we did not observe this association in the total study population nor in the other age categories. Possible explanations for this are that we used a questionnaire-based (PHQ-9) definition for depressive symptoms in the past two weeks instead of a clinical diagnosis of depression, or that previous studies have mainly included asthma patients in this particular age range. Conceivable mechanisms underlying the interaction between depression and asthma exacerbation are that depression may accompany behavior changes in terms of less help-seeking and non-adherence to medication but may also contribute to risk behaviors resulting in smoking, physical inactivity, and obesity16. Furthermore, cerebral changes in depression play a possible role in asthma symptoms21 and long-term stress stimulation may influence airway inflammation and asthma severity17.We also observed a statistically significant association between thyroid problems and severe asthma exacerbations in subjects aged between 51 and 60 years. This observation is difficult to interpret since we cannot determine, based on the data available, what the specific underlying thyroid problems were. Nonetheless, a recent study has reported a close relationship between thyroid hormone levels and severity of asthma in older adults22, providing a possible explanation for the observed association in our study.

In our study current soft drug use in the 18 to 30 years age group showed a statistically significant association with a decreased occurrence of severe asthma exacerbations. This is in contrast with a 2017 review, which found no or insufficient evidence for a statistical association between cannabis smoking and asthma exacerbation23. One possible explanation for our deviating finding could be that younger subjects who have sufficiently controlled asthma may be more likely to smoke cannabis or marijuana than those whose asthma is less well controlled. Another explanation might be that we did not include the most prevalent allergic disease in the younger population (allergic rhinitis and atopic dermatitis) in the study.

A clear strength of our study is that we investigated a large sample of 2387 subjects with doctor-diagnosed asthma in a study population that is presumably representative for the asthma population in the United States. The data we used is from the well-established NHANES program, which routinely collects data every two years using validated measures and questionnaire administration by trained medical personnel24. The data collection in NHANES is rather extensive and robust, which guarantees high-quality data regarding participants’ asthma exacerbations, comorbid conditions, smoking habits, and other risk factors for asthma exacerbations (e.g., PIR and asthma preventer medication use). We also consider the differentiation between moderate and severe exacerbations and the age-stratified analysis of chronic comorbid conditions in relation to asthma exacerbation occurrence strengths of our study, as this provides a more detailed insight compared to pooling all exacerbations and all age groups together.

On the other hand, the main limitation is that this cross-sectional study is depending on self-report of participants, which may have caused self-reporting bias to occur. For instance, 228 participants answered affirmatively on the question about once having received a diagnosis of chronic bronchitis, but that the diagnosis is not active anymore. These participants were not excluded from the study, but incorrect affirmative answers may have led to some subjects who also suffered from COPD (i.e., asthma-COPD overlap) to be included in the study sample. Ideally all NHANES participants would have had an extensive respiratory assessment to establish whether or not asthma (and/or COPD) was present25. Besides, the most reflective definition for moderate and severe asthma exacerbations could not be derived from the data: an episode of progressive increase in asthma symptoms that required a change in treatment2, with ideally health-record derived additional information about the medical management and the in- or outpatient setting during this episode. Thirty-one participants denied having had an episode of asthma worsening in the previous year, but at the time same indicated to have visited an emergency room due to their asthma. We categorized these subjects in the severe asthma exacerbation category, but misclassification may have occurred as the actual validity of the NHANES survey questions on occurrence of exacerbations (i.e., ‘During the past 12 months, have you had an episode of asthma or an asthma attack?’ and ‘During the past 12 months, have you had to visit an emergency room (ER) or urgent care center because of asthma?’) may be limited and phrasing these questions as asthma being ‘worse’ or ‘out of control’ instead may be a better option26.

No information to verify the chronic nature of certain comorbid conditions (e.g., gout and depression) could be extracted from the data, leading to the possible inclusion of single episodes of the conditions instead of truly chronic conditions. The use of a PHQ-9-based definition for depressive symptoms as a surrogate for clinical depression is also a limitation, as a questionnaire-based definition and an actual clinical diagnosis of depression do not necessarily coincide27. Finally, a notable observation was that ICS were used by a relatively small proportion of the study sample (13.6%), which is quite a bit lower than the 30.8% in the CDC’s nationwide BRFSS Asthma Call-back Survey in active asthma28. Although questionnaire-based self-reports of asthma diagnoses are widely used in population surveys29,30, the relatively low rate of ICS use does raise some concern about the validity of participants’ asthma diagnoses in the NHANES survey data. On the other hand inadequate asthma therapy among adults has been demonstrated to be an important issue in the US31 and elsewhere32. The high use of SABA combined with the low use of ICS by subjects in the moderate and severe exacerbations categories fits the observed increased exacerbation occurrence33.

It would have been interesting to determine whether allergic rhinitis, chronic sinusitis, atopic dermatitis and obstructive sleep apnoea are also associated with asthma exacerbations, but data on these conditions is not available in the NHANES database. A final limitation is that there was no measure to determine asthma control available, like—for instance—the Asthma Control Test (ACT)34.

In conclusion, in this study obesity and rheumatoid arthritis were associated with the occurrence of severe asthma exacerbations, whereas rheumatoid arthritis and a history of stroke were associated with the occurrence of moderate asthma exacerbations. Age-stratified analysis showed soft drug use, obesity, depression, thyroid problems, and rheumatoid arthritis to be associated with moderate and/or severe exacerbation occurrence in one or more 10-year age strata. These findings confirm but also complement the current body of knowledge about the role that specific chronic comorbid conditions may have in exacerbation-prone asthma. Health professionals involved in asthma management should be aware of other chronic conditions their asthma patients may have and incorporate this information in their exacerbation risk estimation, chronic disease management, and personalized asthma care.