Uncontrolled Asthma is Associated with Comorbid Stress and Somatoform Symptoms

Background: Anxiety and depression are recognized comorbidities that may limit control of asthma. The purpose of this study is to identify the associations between perceived stress, somatization, and perceived asthma control in patients with asthma. Methods: The present study included 100 adult outpatients who were treated at the Tulane Asthma Center for asthmarelated symptoms between March 2018 and November 2018. Patients were asked to complete a 3-item demographics form, an Asthma Control Test (ACT), Patient Health Questionnaire 15 (PHQ-15), and a Perceived Stress Scale (PSS). Results: Using validated scoring for Asthma Control Tests, we classified patients as well controlled (ACT score greater than or equal to 20) and not controlled (ACT score less than or equal to 19). Using SPSS software, chi-squared analysis indicated a significant association between PSS and ACT scores, PHQ-15 and ACT scores, and PSS and PHQ-15 scores. The analysis demonstrated a significant inverse relationship between PHQ-15 and ACT scores, and also between PSS and ACT scores, and a significant direct relationship between PSS and PHQ-15 scores. A statistically significant relative risk was found among moderate-to-high scores on PHQ-15, uncontrolled and moderate-to-high PSS scores, and uncontrolled asthma. A slight increase in relative risk in uncontrolled asthma was found in patients less than or equal to 50 years of age as compared to those older than 50, and the relative risk of uncontrolled asthma was similar in women as compared to men. Conclusion: The results of this study indicate an association between perceived stress, somatization, and uncontrolled asthma. These findings suggest the need to develop effective interventions in patients with asthma and comorbid stress and somatization. Check for updates Citation: Moore M, Duncan CD, Gonis A, et al. (2020) Uncontrolled Asthma is Associated with Comorbid Stress and Somatoform Symptoms. Ann Pulmonol 4(1):45-49 Moore et al. Ann Pulmonol 2020, 4(1):45-49 Open Access | Page 46 | cue medications, and overall perception of asthma control during the previous 4 weeks. Perceived Stress Scale (PSS): Ten questions, each scored on a 5-point Likert-type scale (ranging from 0-4), with a total score ranging from 0 (low stress) to 40 (high stress). The questions measure self-perception of frequency and severity of stressful events within one’s life for the past 4 weeks. Questions include “How often have you been upset because something happened unexpectedly?”, “How often have you felt that you were unable to control important things in your life?”, “ How often have you felt nervous and stressed?”, “How often have you felt confident about your ability to handle your personal problems?”, “How often have you felt that things were going your way?”, “How often have you found that you could not cope with all the things that you had to do?”, “How often have you been able to control irritations in your life?”, “How often have you felt that you were on top of things?”, ”How often have you been angered because of things that were outside of your control?”, and “How often have you felt difficulties were piling up so high that you could not overcome them?” [32]. Patient Health Questionnaire (PHQ-15): Fifteen questions, each scored on a 3-point Likert-type scale (ranging from 0-2), with a total score ranging from 0 (Minimal level of Somatic Symptom Severity) to 30 (High level of Somatic Symptom Severity). The questions measure self-perception of the prevalence and frequency of physical symptoms commonly associated with somatization. Symptoms included: stomach pain, back pain, extremity pain, menstrual cramps, headaches, chest pain, dizziness, fainting spells, heart racing, shortness of breath, pain/problems with sexual intercourse, constipation/loose bowels/diarrhea, nausea/gas/indigestion, low energy, and trouble sleeping [26-28]. The institutional review board at Tulane University approved the use of PSS, PHQ-15, and ACT surveys in clinical practice. Statistical Analysis All raw data from original paper questionnaires was entered into Excel and verified by two research assistants to check for transcribing errors. Overall, summative scores for individual ACT, PSS, and PHQ-15 questionnaires were calculated. Scores were then placed in stratified categories based on accepted validated guidelines. Categorical variables were then analyzed using Chi-Square, Spearman’s Rho Correlation Coefficient, and relative risk using SPSS. Statistical significance was determined based on a p-value < 0.05 or the values of a 95% confidence interval entirely being greater than one. Results Table 1 describes the 100 participants. The majority of the patients were women (76%). The median age of the patients was 55 (range: 18-87). The vast majority of patients (76%) had a diagnosis of asthma greater than 5 years. Table 2 assesses relative risk of uncontrolled asthma based on the clinical data elucidated in this study. Of the 100 patients in the study, 60 had uncontrolled asthma (ACT less than also suggests that clinicians address anxiety and depression in order to achieve symptom control in the majority of their patients [17]. Studies stress the importance of identifying these comorbidities in patients with asthma, as they can negatively affect asthma control if left untreated [18,19]. Chronic stress has been shown to manifest allergic diseases in susceptible individuals as well as complicate control of existing allergic diseases [20]. In one study, patients with anxiety and atopy were shown to have positive skin prick tests (SPTs) for antigens they previously tested negative for [21]. In addition, chronic stress has been shown to alter beta-adrenergic and glucocorticoid receptors gene expression, to change cytokine regulation, and to increase cortisol levels. Many of these same cytokines are often derived from mast cells, which have been shown to be involved in the pathogenesis of asthma [22]. All of these changes may impact development of asthma and allergy flairs, eventually altering therapy response [23,24]. The prevalence of somatization is estimated to be 5-7% of the general population and is an important topic due to its impact on healthcare utilization [25]. One well validated and commonly used tool to measure somatization is the PHQ 15 [26-28]. One study of 2091 primary care clinic patients found comorbid depression, anxiety, and somatization in roughly 50% of patients [29]. According to a study of 1456 patients, those with higher somatization scores had around twice the annual health care costs and around twice the outpatient and inpatient visits compared to those without somatization [30]. Additionally, a survey of 212 asthma patients found that those with anxiety, depressive, and somatoform disorders were at increased risk of asthma related emergency room visits [31]. The purpose of this study was to identify the associations between perceived stress, somatization, and perceived asthma control in patients with asthma. The patient centered and guideline-driven approach used in this study attempts to identify these associations among patients with asthma in an outpatient asthma center. Subjects and Methods Study participants were adult patients with a diagnosis of moderate to severe asthma who were receiving guideline driven outpatient care by a trained allergist and pulmonologist at the Tulane Asthma Center from May 2018 to December 2018. In total, there were 100 participants (76% Female) with a mean age of 53.4 (SD ± 14) and mean time with asthma of 26.1 years (SD ± 2.1). All participants provided verbal informed consent prior to participation. Participants were then instructed to complete the following four self-administered questionnaires: Demographic Data: A brief 3-question questionnaire including sex, age, and time since asthma diagnosis in years. Asthma Control Test (ACT): Five questions, each scored on a 5-point Likert-type scale (ranging from 1-5), with a total score ranging from 5 (poor asthma control) to 25 (well controlled asthma). The questions measure self-perception of asthma’s effect on activities of daily living, frequency of shortness of breath and other asthma symptoms, use of resCitation: Moore M, Duncan CD, Gonis A, et al. (2020) Uncontrolled Asthma is Associated with Comorbid Stress and Somatoform Symptoms. Ann Pulmonol 4(1):45-49 Moore et al. Ann Pulmonol 2020, 4(1):45-49 Open Access | Page 47 | questionnaire findings are statistically significant. Table 3 delves further into the association of individual PHQ-15 symptoms and asthma control. Twelve of the fifteen symptoms in the PHQ-15 questionnaire showed an increased relative risk of uncontrolled asthma. These include stomach pain, back pain, arm/leg/joint pain, headaches, chest pain, dizziness, heart pounding, shortness of breath, constipation, nausea/gas/indigestion, tired/low energy, and trouble sleeping. The symptoms that were not statistically significantly associated were menstrual pain, fainting, and pain with sex. Relative risk of uncontrolled asthma for each of these symptoms can be found in Table 3. Table 4 further elucidates associations between ACT scores, PSS scores, and PHQ-15 scores. A significant association between ACT and PSS was observed (χ2(2) = 6.62, or equal to 19) and 40 had controlled asthma (ACT greater than or equal to 20). The relative risk of uncontrolled asthma was similar in women as compared to men (RR = 1.06; 95% confidence interval 0.70 to 1.60). There was a slight increase in relative risk in uncontrolled asthma in patients less than or equal to 50 years of age as compared to those older than 50; however this was not statistically significant (RR = 1.34; 95% confidence interval 0.98-1.82). Time since diagnosis of asthma had no association on asthma control (RR = 1.09; 95% confidence interval 0.77-1.55). A moderate to high score on the PHQ-15 questionnaire had a higher relative risk of uncontrolled asthma as compared to participants with a minimal to low score (RR = 2.75; 95% CI, 1.62-4.68). A moderate to high score on the PSS questionnaire had higher relative risk of uncontrolled asthma as compared to participants with a low score (RR = 1.78; 95% CI, 1.12-2.83). Both of these validated Table 1: General demographic information for patients in this study. Sex Age Time with Asthma Male Female Prefer Not to Answer Median: 55 Greater Than 5 years LessThan/Equal to 5 Years Unanswered 21 76 3 Range: 18-87 76 22 2 Table 2: Relative risk of uncontrolled asthma based on demographics,stress scores, and somatization. Sex Age (Years) Time with Asthma (Years) PHQ-15 Score Category PSS Score Category Male Female > 50 < or = 50 > 5 < or = 5 Mod to High Low Mod to High Low Uncontrolled 12 46 33 27 44 16 44 16 44 16 Controlled 9 30 29 11 31 9 13 27 20 20 Relative Risk of U/C Asthma If Female: 1.06 (95% Cl: 0.70-1.60) If Age < or = 50: 1.34 (95% Cl: 0.98-1.82) If time w/ asthma > 5:1:09 (95% Cl: 0.771.55) If Mod-High Score: 2.75 (95% Cl: 1.62-4.68) If Mod-High Score: 1.78


Perceived Stress Scale (PSS):
Ten questions, each scored on a 5-point Likert-type scale (ranging from 0-4), with a total score ranging from 0 (low stress) to 40 (high stress). The questions measure self-perception of frequency and severity of stressful events within one's life for the past 4 weeks. Questions include "How often have you been upset because something happened unexpectedly?", "How often have you felt that you were unable to control important things in your life?", " How often have you felt nervous and stressed?", "How often have you felt confident about your ability to handle your personal problems?", "How often have you felt that things were going your way?", "How often have you found that you could not cope with all the things that you had to do?", "How often have you been able to control irritations in your life?", "How often have you felt that you were on top of things?", "How often have you been angered because of things that were outside of your control?", and "How often have you felt difficulties were piling up so high that you could not overcome them?" [32].

Patient Health Questionnaire (PHQ-15):
Fifteen questions, each scored on a 3-point Likert-type scale (ranging from 0-2), with a total score ranging from 0 (Minimal level of Somatic Symptom Severity) to 30 (High level of Somatic Symptom Severity). The questions measure self-perception of the prevalence and frequency of physical symptoms commonly associated with somatization. Symptoms included: stomach pain, back pain, extremity pain, menstrual cramps, headaches, chest pain, dizziness, fainting spells, heart racing, shortness of breath, pain/problems with sexual intercourse, constipation/loose bowels/diarrhea, nausea/gas/indigestion, low energy, and trouble sleeping [26][27][28].
The institutional review board at Tulane University approved the use of PSS, PHQ-15, and ACT surveys in clinical practice.

Statistical Analysis
All raw data from original paper questionnaires was entered into Excel and verified by two research assistants to check for transcribing errors. Overall, summative scores for individual ACT, PSS, and PHQ-15 questionnaires were calculated. Scores were then placed in stratified categories based on accepted validated guidelines. Categorical variables were then analyzed using Chi-Square, Spearman's Rho Correlation Coefficient, and relative risk using SPSS. Statistical significance was determined based on a p-value < 0.05 or the values of a 95% confidence interval entirely being greater than one. Table 1 describes the 100 participants. The majority of the patients were women (76%). The median age of the patients was 55 (range: 18-87). The vast majority of patients (76%) had a diagnosis of asthma greater than 5 years. Table 2 assesses relative risk of uncontrolled asthma based on the clinical data elucidated in this study. Of the 100 patients in the study, 60 had uncontrolled asthma (ACT less than also suggests that clinicians address anxiety and depression in order to achieve symptom control in the majority of their patients [17]. Studies stress the importance of identifying these comorbidities in patients with asthma, as they can negatively affect asthma control if left untreated [18,19].

Results
Chronic stress has been shown to manifest allergic diseases in susceptible individuals as well as complicate control of existing allergic diseases [20]. In one study, patients with anxiety and atopy were shown to have positive skin prick tests (SPTs) for antigens they previously tested negative for [21]. In addition, chronic stress has been shown to alter beta-adrenergic and glucocorticoid receptors gene expression, to change cytokine regulation, and to increase cortisol levels. Many of these same cytokines are often derived from mast cells, which have been shown to be involved in the pathogenesis of asthma [22]. All of these changes may impact development of asthma and allergy flairs, eventually altering therapy response [23,24].
The prevalence of somatization is estimated to be 5-7% of the general population and is an important topic due to its impact on healthcare utilization [25]. One well validated and commonly used tool to measure somatization is the PHQ 15 [26][27][28]. One study of 2091 primary care clinic patients found comorbid depression, anxiety, and somatization in roughly 50% of patients [29]. According to a study of 1456 patients, those with higher somatization scores had around twice the annual health care costs and around twice the outpatient and inpatient visits compared to those without somatization [30]. Additionally, a survey of 212 asthma patients found that those with anxiety, depressive, and somatoform disorders were at increased risk of asthma related emergency room visits [31].
The purpose of this study was to identify the associations between perceived stress, somatization, and perceived asthma control in patients with asthma. The patient centered and guideline-driven approach used in this study attempts to identify these associations among patients with asthma in an outpatient asthma center.

Subjects and Methods
Study participants were adult patients with a diagnosis of moderate to severe asthma who were receiving guideline driven outpatient care by a trained allergist and pulmonologist at the Tulane Asthma Center from May 2018 to December 2018. In total, there were 100 participants (76% Female) with a mean age of 53.4 (SD ± 14) and mean time with asthma of 26.1 years (SD ± 2.1). All participants provided verbal informed consent prior to participation. Participants were then instructed to complete the following four self-administered questionnaires: Demographic Data: A brief 3-question questionnaire including sex, age, and time since asthma diagnosis in years.

Asthma Control Test (ACT):
Five questions, each scored on a 5-point Likert-type scale (ranging from 1-5), with a total score ranging from 5 (poor asthma control) to 25 (well controlled asthma). The questions measure self-perception of asthma's effect on activities of daily living, frequency of shortness of breath and other asthma symptoms, use of res-questionnaire findings are statistically significant. Table 3 delves further into the association of individual PHQ-15 symptoms and asthma control. Twelve of the fifteen symptoms in the PHQ-15 questionnaire showed an increased relative risk of uncontrolled asthma. These include stomach pain, back pain, arm/leg/joint pain, headaches, chest pain, dizziness, heart pounding, shortness of breath, constipation, nausea/gas/indigestion, tired/low energy, and trouble sleeping. The symptoms that were not statistically significantly associated were menstrual pain, fainting, and pain with sex. Relative risk of uncontrolled asthma for each of these symptoms can be found in Table 3. Table 4 further elucidates associations between ACT scores, PSS scores, and PHQ-15 scores. A significant association between ACT and PSS was observed (χ 2 (2) = 6.62, or equal to 19) and 40 had controlled asthma (ACT greater than or equal to 20). The relative risk of uncontrolled asthma was similar in women as compared to men (RR = 1.06; 95% confidence interval 0.70 to 1.60). There was a slight increase in relative risk in uncontrolled asthma in patients less than or equal to 50 years of age as compared to those older than 50; however this was not statistically significant (RR = 1.34; 95% confidence interval 0.98-1.82). Time since diagnosis of asthma had no association on asthma control (RR = 1.09; 95% confidence interval 0.77-1.55). A moderate to high score on the PHQ-15 questionnaire had a higher relative risk of uncontrolled asthma as compared to participants with a minimal to low score (RR = 2.75; 95% CI, 1.62-4.68). A moderate to high score on the PSS questionnaire had higher relative risk of uncontrolled asthma as compared to participants with a low score (RR = 1.78; 95% CI, 1.12-2.83). Both of these validated   improve lung function in patients with asthma [35]. To further clarify the effects of breathing and relaxation interventions, future prospective studies need to focus on lung physiology, inflammation, stress assessment, presence of somatization symptoms, and asthma control.
A number of limitations exist for this six-month study. This study does not include any clinical data, pulmonary physiology data, or inflammation data, as it focused on the assessment of asthma control and validated questionnaires for stress and somatization. Assessment of asthma control, stress, and somatic symptoms are subjective measures. This study included one fall allergy season, and only included pa-tients in the Greater New Orleans area. In addition, this study did not collect information on whether ethnicity and socio-economic class may affect somatic symptom severity [36][37][38].

Conclusion
This study shows a significant association between uncon-trolled asthma, higher levels of perceived stress, and an in-creased incidence of somatic symptoms among patients with asthma. These results reinforce the need for assessment of stress and somatic symptoms in asthma patients, and reveal new research opportunities aimed at analyzing the possible benefits of stress and psychosomatic symptom management treatments in improving asthma control. Future prospective studies would benefit from investigating how these symp-toms change with effective interventions.

Discussion
This study shows that a clinically significant association ex-ists between uncontrolled asthma, perceived stress, and psy-chosomatic symptoms. Significant relationships were found between ACT and PSS scores, ACT and PHQ-15 scores, and PSS and PHQ-15 scores. The increased relative risk of uncon-trolled asthma among participants with a moderate-to-high PSS score seen in this study reveals an association between in-creased anxiety and poorer outcomes for asthma patients. In regard to asthma control and somatization, patients showed an increased relative risk of uncontrolled asthma with both a cumulative moderate-to-high score on the PHQ-15 question-naire and with high scores on a multitude of the individual PHQ-15 questions. The significant association between PSS and PHQ-15 scores is also notable.
Although previous studies have shown a relationship be-tween female gender and more severe asthma symptoms, [29,30] this study was unable to identify a significant associ-ation between gender and asthma. Specifically, female gen-der lacked a statistically significant increase in relative risk of uncontrolled asthma (RR: 1.06 [95% CI: 0.70-1.60]). Further-more, neither age nor time since diagnosis had a statistically significant effect on asthma control in this study.
In light of the findings of both this study and prior re-search, it is clear that patient care teams need to assess for stress and psychosomatic symptoms in patients with asthma in order to properly address these conditions with person-alized care. Some previous studies have approached inter-ventions such as meditation, yoga, and breathing exercises.
These studies did show improvement in overall quality of life without change in lung function [31,33]. A yoga breathing in-tervention study, involving twenty-minute sessions twice a day over three months, showed improvement in both quality of life and FEV1 [34]. Meditations have also been shown to