The Effects of Cognitive Stress on Asthma Exacerbations among University Students

Introduction: Many asthmatics complain of worsening respiratory symptoms during periods of stress. This study evaluated the relationship among asthma symptoms, lung physiology, inflammatory parameters and perceived cognitive stress and quality of life in healthy adult students. This relationship was assessed at two time points: a time of normal activity and at a time of cognitive stress during academic examinations.

wheezing, sputum production, and cough. It is associated with variable airflow limitation and varying degrees of airway hyper-responsiveness to endogenous and exogenous stimuli (Becker et al., 2005;Global Initiative for Asthma, 2016).
Asthma is the most common chronic disease of childhood and affects over 8% of Canadians over the age of twelve (Global Initiative for Asthma, 2016;Statistics Canada, 2017).
Many factors affect disease activity and severity of symptoms, including exposure to allergens, upper and lower airway infections, air pollution, and psychological/ cognitive stress (Christensen et al., 2008).
The association of asthma symptoms with stress has been recognized as early as the 12 th century (Rosner, 1981); Sir William Osler similarly referred to asthma as "a neurotic affliction" (Osler, 1892).
Stress was first described by Hans Selye as the common denominator of all the adaptive reactions in the body (Selye, 1970). Stress can be viewed as a process that accentuates the airway inflammatory response to environmental triggers and, in doing so, increases the frequency, duration, and severity of asthma patients' symptoms . It is the maladaptive response to stress, which Selye named "distress", that is considered to be detrimental for human homeostasis and for diseases such as asthma (Selye, 1970).
Psychological morbidity has been linked to asthma mortality (Strunk et al., 1985;Sears et al., 1986) and underlying psychological distress (depression and anxiety) (Wright et al., 1998). Depression and asthma have a bidirectional relationship, with depression increasing the chance of asthma exacerbations and asthma increasing the chance of depressive symptomatology (Lu et al., 2014;Trueba et al., 2016). Between 20-35% of asthmatics experience asthma exacerbations during periods of stress (Isenberg et al., 1992).
The National Institutes of Health commissioned a workshop to promote a better understanding of this relationship (Busse et al., 1995); however, little has been done to evaluate the mechanism of these interactions (Smyth et al., 1999;Davis et al., 2002).
Some asthmatics experience a reduction in lung function with stress; however, these results are not consistent (Lehrer et al., 1993). A survey of over 3,000 adults in the United States showed increased prevalence of panic attacks in those with obstructive lung disease (Goodwin, & Pine, 2002). Similarly, depression and anxiety are over-represented in children (Vila et al., 1999;Sundbom et al., 2016) and adults (Sundbom et al., 2016;Krommydas et al., 2004;Harrison, 1998)   The PSS is a validated tool, sensitive to examination stress and was used to quantify stress levels in participating individuals (Cohen et al., 1988;Chiu et al., 2003;Garg et al., 2001).
The MASQ is a series of 77 questions divided into three subsections (general distress, symptoms specific to depression and symptoms specific to anxiety) (Watson et al., 1995a). The MASQ, which discriminates between depressive anhedonia, an inability to feel pleasure, and somatic anxiety (Watson et al., 1995a;Watson et al., 1995b), was used to rate symptoms in the week prior to each test. The AQLQ is a disease-specific quality of life measure for asthma that has been validated (Juniper et al., 1999). The AQLQ is a series of 32

Statistical Analysis
Data are shown as mean values ± standard error of the mean (SEM). For methacholine challenge results the geometric mean is shown. Paired t-test was used for data analysis.

Screening
Thirty-eight people were interviewed and twentytwo were brought in for a screening visit. The majority of subjects interviewed by telephone and who did not come for a screening visit declined to participate because of the time commitment or the lack of financial compensation.
Of the twenty-two subjects that attended the screening visit (Table 2), eight (36.4%) failed the MINI screen for reasons of generalized or social anxiety disorder, depressive or manic episodes, and alcohol abuse (four subjects failed for more than one of these reasons). Eighty percent of participants who completed the study were taking inhaled steroids at the time of the study.
Two subjects did not have current asthma. One subject was no longer a student so could not meet the criteria of exam stress. Five subjects dropped out before completing the study due to the time commitment. Five subjects completed the study.

Study Subjects
The demographics of the five subjects who completed the study are shown in Table 3 and the asthma and stress data from these subjects is summarized in. Of these five subjects, three were females and two were males, four were atopic and one was non-atopic, as measured by allergen skin testing (

Physiological Measures
Two of the five subjects had a history of stressrelated worsening of their asthma. The geometric mean PC 20 (at screening visit) for the group that completed the study was 0.5913 mg/mL.

Psychosocial Measures
Subjects who completed the study showed no significant change in the PSS between the LSV and HSV (p=0.5078). Similarly, no change was noted in total scores for the MASQ (p=0.3057). There was a trend towards increase in the General Distress subsection of this questionnaire (p=0.0795), although this also did not reach statistical significance (Table 4).

Quality of Life Measures
No significant change was noted in the general quality of life questionnaire (EQ-5D) evaluations or disease specific AQLQ (AQLQ Overall: p=0.6460, Symptoms: p=0.9331) between the LSV and HSV (Table 4).

Airway Physiology
No significant change was noted in lung function (FEV 1 %) between LSV and HSV (p=0.5275) ( Table   4). The results of the methacholine challenge (PC 20 ) also showed no significant difference (p=0.9813) in airway hyper-responsiveness between low and high stress visits (Figure 1).  (Table 4).
Underlying psychiatric diagnoses (as per the DSM-IV, the current edition of the DSM at the time of recruitment) were prevalent in this "healthy asthma" population recruited for our study. The recruitment resulted in the exclusion of a large number of subjects (36%) -similar to numbers quoted in other studies (Harrison, 1998;Krommydas et al., 2004;Strunk et al., 2016 (Black, 2002;.  (Rod et al., 2012).
The low sample size reflects study interruption, which could increase the likelihood of type 2 error, noting no significant difference when a difference exists (Kadam et al., 2016). The low study completion (n=5) related to the large number of inclusion and exclusion criteria and inflexibility in scheduling the HSV (within 24 hours of their exam).
For future studies, incentivizing completion of follow-up appointments, sending reminder emails about upcoming appointments and making follow-up appointments less complex to reduce the time commitment may increase the subject pool (Ngune et al., 2012;Kadam et al., 2016).
We do believe this information is still important to share given the implications for future study designs in asthma clinical trials. From this data and review of the literature, it is important to use an interdisciplinary approach to management of asthma including family physicians, allied health, psychiatry and pulmonary medicine. Identification of risk factors, medication management and adjustments by stress and regular followup will promote improved functioning and quality of life among individuals with asthma.
Studies on asthma should incorporate measures of psychiatric comorbidity to better elucidate factors related to loss of asthma control.