Correlation of gastro-esophageal reflux disease with asthma control and quality of life: a cross-sectional study from a low-middle income country

Abstract

Background:

Gastro-esophageal reflux disease (GERD) is a chronic disease that coexists with asthma and is often responsible for repeated exacerbations, as well as has a negative impact on the quality of life (QoL). However, from our continent, there is limited data available on the exact prevalence of GERD in asthma and its association with asthma control and QoL.

Objective:

To determine the prevalence of GERD in asthma and see its association with asthma control and QoL.

Design:

A prospective, cross-sectional study was conducted over 8 months from September 2020 to April 2021.

Methods:

Patients with a confirmed diagnosis of asthma aged 18 years and above were recruited from the outpatient department of pulmonology. Patients’ GERD score was calculated using the FSSG SCALE (Frequency Scale for Symptoms of GERD) questionnaire and the Asthma Control Test (ACT) was used to determine asthma control. To assess the QoL, the short form of health survey (SF-36) questionnaire was used. Patients were recruited through a convenience sampling technique.

Results:

A total of 190 patients were enrolled, the mean age was 33.7 ± 13.3 years and 55.8% were female. Prevalence of GERD was (136) 71.6%. According to the ACT score, 81 (42.6%) patients had very poorly controlled asthma (mean GERD score of 13.73 ± 7.66), compared to 59 (31.1%) asthmatic patients who had well-controlled asthma (mean GERD score of 11.97 ± 7.39, p = 0.43). SF-36 questionnaire was used to measure QoL showed GERD patients had statistically lower scores in the following domains of QoL: “Role Limitations due to Physical Functioning” (37.78 vs 57.44, p = 0.003), “Energy/Fatigue” (47.47 vs 55.07, p = 0.02), and “Bodily Pain” (63.40 vs 72.84, p = 0.01).

Conclusion:

This study showed a high prevalence of GERD among asthmatic patients with a negative impact on QoL but did not demonstrate a statistically significant relationship between GERD and asthma control.

Plain language summary

Relationship of gastro-esophageal reflux disease (GERD) with asthma control and quality of life

1. Gastro-esophageal reflux disease (GERD) is a common condition which leads to heart burn. It can affect asthma and is often responsible for the repeated attacks of asthma.

2. The relationship between asthma and GERD is inconclusive. It was found in previous studies that GERD had a negative impact on the quality of life (QoL) both in general and asthmatic population.

3. Data from Pakistan regarding the prevalence of GERD in asthmatic patients and its effect on asthma control and the QoL is limited.

4. In this study, we found that GERD is quite common (71.6%) in our asthmatic population, but it does not relate to asthma control assessed through the Asthma Control Test.

5. We also found that GERD in asthma is associated with negative impact on QoL in certain domain of health, like role limitations due to physical functioning, energy level, and bodily pain compared to asthmatic patients without GERD.

6. We suggest further larger studies to clarify our findings and whether adding treatment of GERD improved QoL in asthmatic patients.

Background

Gastro-esophageal reflux disease (GERD) is a common clinical problem usually demonstrated by heartburn and acid regurgitation. The symptoms occur daily in up to 10%–15% of healthy individuals. ¹ Several research studies have indicated 15%–82% GERD prevalence in asthma.^2–4 Although the exact mechanism of the relationship between GERD and asthma is unclear, many theories proposed that increasing thoracic pressure escalates acid release, which triggers vagal stimulation, resulting in bronchoconstriction. Moreover, medications for the treatment of asthma, such as methylxanthines and β-agonist, relax the lower esophageal sphincter, which also results in acid reflux. ⁵ Furthermore, laryngopharyngeal reflux (LPR) is frequently found in asthmatic patients, and treatment of LPR has also been found to improve asthma symptoms. ⁶

Chronic cough is common in adults and is mostly seen in the older population. GERD, asthma, and allergic or chronic rhinitis are frequently seen in patients with chronic cough. ⁷ A study showed GERD, along with smoking, asthma, and chronic obstructive pulmonary disease (COPD), are independent risk factors for chronic cough. ⁸ Sykes et al. demonstrated that 66% of patients had esophageal dysmotility in refractory respiratory symptoms and contributed to respiratory diseases such as asthma, chronic cough and interstitial lung disease. ⁹ GERD is reported to contribute to the severity of several respiratory tract diseases including sinusitis, chronic cough, laryngeal disorders, asthma, bronchiectasis, COPD, idiopathic pulmonary fibrosis, cystic fibrosis, and bronchiolitis obliterans postlung transplant. ¹⁰ Moreover, recurrent use of oral corticosteroids (OCS) in asthma can lead to multiple side effects, including GERD. The use of OCS should be minimized as a last resort for severe asthma.^11,12 A recent study showed patients who are treated with biologics for severe asthma, control was achieved in 25.3% of patients only. In this study, GERD and obstructive sleep apnea syndrome were identified as independent factors associated with persistent insufficient control. ¹³

Medical and surgical treatment options for GERD are available, but data are limited. ¹⁰ Proton pump inhibitors (PPIs) are superior to histamine-2 receptor antagonists in gastric acid suppression and control of GERD symptoms, but some patients are PPIs refractory. ¹⁴ In a meta-analysis, PPI therapy did not show a statistically significant improvement in morning peak expiratory flow in asthma patients having GERD and does not support PPI therapy as an empirical treatment in GERD patients. ¹⁵ A Cochrane Database systemic review showed GERD treatment uncertainty on asthma exacerbation and hospitalization. It also showed a slight improvement in lung function and the use of rescue medications with GERD treatment in asthma. ¹⁶ However, overprescribing PPIs is common, and long-term use is associated with nutrient malabsorption, enteric infections, and cardiovascular events. Cost–benefit, symptom control, and quality-of-life outcomes favor laparoscopic fundoplication rather than chronic PPI treatment and are endorsed by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), the National Institute of Health Care and Excellence (NICE), the American College of Gastroenterology (ACG), and PPI-refractory GERD by the American Gastroenterological Association (AGA) and SAGES guidelines. ¹⁷ It is also found a BMI decrease of ⩾3.5 kg/m² is associated with a 40% decrease in GERD symptoms in women. ¹⁴

The relationship between asthma and GERD is inconclusive and still debatable. Despite the high prevalence of GERD in asthma, the relationship between the two is lacking. ¹⁸ Some studies have reported positive associations, ¹⁹ while others reported a negative association of GERD and asthma.^19–21 Lee et al. found that GERD had a greater impact on daily activities. ²² A systematic review showed GERD was associated with a high burden of disease and had impaired health-related quality of life (QoL). ²³ Xu et al. showed in patients with chronic rhinosinusitis, those with GERD experienced significantly worse preoperative QoL, but higher QoL improvements were seen following functional-endoscopic-sinus-surgery. ²⁴

To the best of our knowledge so far, no studies have been conducted in Pakistan regarding the prevalence of GERD in asthmatic patients and its effect on asthma control and QoL. Therefore, our research aims to explore the association of GERD with asthma control and its impact on QoL in our population.

Methods

Study design and settings

A prospective, cross-sectional study was conducted in the outpatient pulmonology department, which included teaching hospitals, that is, Jinnah Medical and Dental College Hospital, Jinnah Post Graduate Medical College, and Civil Hospital Karachi, over 8 months from September 2020 to April 2021 after receiving ERC approval. Patients were recruited through a convenience sampling technique.

Sample size calculation

The prevalence of GERD in bronchial asthma patients is 40% which was observed by using the FSSG questionnaire. The sample size was calculated to estimate the prevalence of GERD in bronchial asthma patients using the FSSG scale and assuming 40% prevalence with a 95% confidence level and a bound-on error of ±7%, the estimated sample size was 189.

Study participant

Patients with a confirmed diagnosis of asthma based on Global initiative of Asthma (GINA) guidelines ²⁵ (either follow-up or first-visit patients) were recruited from a pulmonology clinic, and their GERD score was calculated using the FSSG SCALE (Frequency Scale for Symptoms of GERD) questionnaire,^2,26 and the Asthma Control Test (ACT) ²⁷ was used to determine patients’ asthma control. Data were collected on predesigned Proforma, which included the age of the patient, sex, comorbidities, smoking history, drug history, occupational history, and pet history. The inclusion criteria were a confirmed diagnosis of asthma based on GINA guidelines, ²⁵ age 18 years and above, a diagnosis made by a pulmonologist, willingness to participate, and being able to answer the questionnaire sufficiently. While patients were aged less than 18 years, did not give consent, had insufficient answers to the questionnaire, had upper gastrointestinal (GI) surgery, had known gastric diseases such as gastric ulcers, acute asthma exacerbation, active malignancy, chronic obstructive pulmonary disease, interstitial lung disease, allergic bronchopulmonary aspergillosis, and bronchiectasis were excluded from the study.

The FSSG has been proven to be a validated questionnaire for the assessment of GERD and is used to determine the prevalence and symptoms of GERD.^2,26 It is also helpful in diagnosing GERD-related cough, particularly in patients with low blood or sputum eosinophil counts. ²⁸ This questionnaire is composed of 12 questions, which are scored to indicate the frequency of symptoms as follows: never = 0, occasionally = 1, sometimes = 2, often = 3, and always = 4. The cut-off score for diagnosis of GERD is defined as 8 points. The Asthma Control Test™ ²⁷ provided a numerical score, which helped to determine if asthma symptoms were well controlled. The patients were categorized into well-controlled asthma, not well-controlled asthma, and very poorly controlled asthma groups according to the ACT score.

Lastly, to evaluate the association of GERD with QoL in asthmatic patients, the short form of the health survey SF-36 questionnaire ²⁹ scores of the patients were analyzed. The SF-36 questionnaire measured the generic QoL, which allowed comparisons between different disease states. It measured health status in eight domains: physical functioning, role limitations—physical, bodily pain, general health, vitality, social functioning, and role limitations—emotional, and mental health. Scores on the SF-36 range from 0 to 100 on each dimension, and on the summary scales, higher scores indicated better QoL. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. ³⁰

Data collection

The method that was used to collect data from the enrolled subjects was an “interview-based technique” by the final-year medical students to avoid bias since multiple interpretations could be made by the patients while filling out the questionnaire by themselves. The questionnaire was generated in English, and then translated to Urdu and then back to English for a better understanding of the patients. Confirmed cases of bronchial asthma above the age group of 18 years were included in this study from the outpatient pulmonology clinic through a convenience sampling technique.

Data analysis

All statistical analyses were conducted by using the Statistical Package for Social Science (SPSS 16.0, Standard Version, Copyright © SPSS; 1989-02). Categorical variables were presented as frequency and percentage, while continuous variables were shown as mean ± standard deviation (SD). For comparison of mean values between GERD positive and GERD negative groups, independent samples t-test was used. Likewise, Chi-square or Fisher’s exact tests were performed, as appropriate, for comparison of categorical variables. Adjusted mean differences for ACT score and QoL between GERD positive and GERD negative groups were compared using analysis of covariance (ANCOVA) test. All p-values were two sided and considered as statistically significant if <0.05.

Results

A total of 190 patients were enrolled in this study. The mean age of the patients was 33.7 ± 13.3 years, of which 55.8% (106) were females and 50.5% (96) of the participants were married. Of 190 patients, 143 (75.2%) had no comorbidities, 50 (26.3%) were students, followed by 42 (22.1%) homemakers. No differences in baseline characteristics were found between GERD positive and negative patients, except gender (p = 0.09) as shown in Table 1.

Table 1.

Characteristics of study patients with and without GERD.

Characteristics	Total	GERD positive	GERD negative	p Value
Age in years (mean ± SD)	33.7 ± 13.3	32.9 ± 13.4	35.9 ± 13.0	0.15
Gender
Male	84 (44.2)	55 (40.4)	29 (53.7)	0.09
Female	106 (55.8)	81 (59.6)	25 (46.3)
Marital status
Married	96 (50.5)	66 (48.5)	30 (55.6)
Single	88 (46.3)	66 (48.5)	22 (40.7)	0.37
Widowed/Divorced	6 (3.1)	4 (3.0)	2 (3.7)
Comorbidities
Hypertension	15 (7.8)	11 (8.0)	4 (7.4)
Diabetes mellitus	14 (7.3)	12 (8.8)	2 (3.7)
Tuberculosis	2 (1.0)	2 (1.4)	0 (0.0)
Two of the above	6 (3.1)	3 (2.2)	3 (5.6)
Three of the above	1 (0.5)	1 (0.7)	0 (0.0)
Others	9 (4.7)	7 (5.1)	2 (3.7)	0.63
None	143 (75.2)	100 (73.5)	43 (79.6)
Occupation
Homemaker	42 (22.1)	31 (22.8)	11 (20.4)
Labor	20 (10.5)	17 (12.5)	3 (5.6)	0.15
Business	22 (11.6)	11 (8.1)	11 (20.4)
Others	6 (3.2)	4 (2.9)	2 (3.7)
Office job	27 (14.2)	21 (15.4)	6 (11.1)
Doctor/Nurse/Teacher	23 (12.1)	14 (10.3)	9 (16.7)
Student	50 (26.3)	38 (27.9)	12 (22.2)
Smoking history	27 (14.2)	19 (14)	8 (14.8)	0.88
Pets	37 (19.5)	31(22.8)	6 (11.1)	0.14
Asthma
Well controlled asthma	59 (31.1)	40 (29.4)	19 (35.2)
Not well controlled asthma	50 (26.3)	34 (25.0)	16 (29.6)	0.43
Very poorly controlled asthma	81 (42.6)	62 (45.6)	19 (35.2)
Drug history
SABA	92 (48.4)	69 (50.7)	23 (42.6)	0.31
ICS/LABA	52 (27.4)	37 (27.2)	15 (27.8)	0.94
ICS	9 (4.7)	6 (4.4)	3 (5.6)	0.72 a
Theophylline	2 (1.1)	2 (1.5)	0 (0.0)	1.000 a
Montelukast	59 (31.1)	38 (27.9)	21 (38.9)	0.14
ICS/SABA	11 (5.8)	7 (5.1)	4 (7.4)	0.51 a
Oral steroids	13 (6.8)	11 (8.1)	2 (3.7)	0.36 a
Other drugs b	36 (18.9)	25 (18.4)	11 (20.4)	0.75

Bold represent significant values.

^aFisher’s exact test.

^bOther drugs included prokinetics, proton pump inhibitors, and intravenous steroids.

GERD, gastro-esophageal reflux disease; ICS, inhaled corticosteroids; ICS/LABA, inhaled corticosteroids/long-acting beta 2-agonists; ICS/SABA, inhaled corticosteroids/short-acting beta-agonists; SD, standard deviation.

According to GERD score, GERD prevalence was 71.6% (136). The ACT score revealed that 59 (31.1%) asthmatic patients had well-controlled asthma (mean GERD score of 11.97 ± 7.39), 50 (26.3%) patients had not well-controlled asthma (mean GERD score of 12.04 ± 7.27), and 81 (42.6%) patients had very poorly controlled asthma (mean GERD score of 13.73 ± 7.66).

We compared ACT score and QoL characteristics between patients with and without GERD. After adjusting for pertinent clinical variables (age, gender, comorbidity, smoking, and asthma, and GERD-related drugs), we found that there was no difference in patients with and without GERD for ACT score (16.54 vs 17.73, p = 0.11). However, GERD patients had statistically lower scores in following domains of QoL: “Role Limitations due to Physical Functioning” (37.78 vs 57.44, p = 0.003), “Energy/Fatigue” (47.47 vs 55.07, p = 0.02), and “Bodily Pain” (63.40 vs 72.84, p = 0.01; Table 2).

Table 2.

Comparison of ACT score and quality of life characteristics between patients with and without GERD.

Characteristics	GERD positive, mean (95% CI)	GERD negative, mean (95% CI)	p Value
Asthma
ACT score	16.54 (15.78–17.30)	17.73 (16.51–18.96)	0.11
Quality of life
General health score	53.07 (49.92–56.23)	54.73 (49.64–59.81)	0.59
Physical functioning	54.62 (49.88–59.36)	60.63 (52.99–68.26)	0.20
Role limitations due to physical functioning	37.78 (31.05–44.51)	57.44 (46.59–68.29)	0.003
Role limitations due to emotional problems	45.74 (37.79–53.70)	40.21 (27.39–53.03)	0.48
Energy/Fatigue	47.47 (44.14–50.80)	55.07 (49.70–60.44)	0.02
Emotional well-being	58.74 (55.37–62.11)	61.66 (56.23–67.09)	0.38
Social functioning	62.35 (58.05–66.65)	65.95 (59.01–72.88)	0.39
Bodily pain	63.40 (59.58–67.22)	72.84 (66.68–79.01)	0.01

ANCOVA was performed and analysis was adjusted for following factors: SABA, ICS/LABA, ICS, theophylline, montelukast, ICS/SABA oral steroids, and other drugs (included prokinetics, proton pump inhibitors, and intravenous steroids). Bold represent significant values.

ACT, Asthma Control Test; ANCOVA, analysis of covariance; CI, confidence intervals; GERD, gastro-esophageal reflux disease.

Discussion

In the present study, the prevalence of GERD in bronchial asthma patients was observed to be 71.6%. GERD was found to be associated with impaired QoL, but no statistically significant relationship was found between GERD and asthma control. We have found a higher incidence of GERD in our asthmatic population. Looking at the previously reported prevalence of GERD in asthma, Amarasiri et al. reported 59.4% among Sri Lankan adults and found that asthmatic patients had a 3.5 times higher risk of GERD symptoms. This study found severity of asthma was linked with GERD symptoms but did not find the influence of asthma medications on GERD symptoms. ³¹ They used the GERD scale for diagnosis of asthma as we did in our study.

A study from India reported a 52% incidence of GERD in asthma compared to a control 28%. ¹ Rameschandra et al. evaluated GERD with a questionnaire but also did endoscopy in all patients. Based on this, they found upper gastrointestinal disorder in 68% of the asthmatics as compared to 37.93% of the controls. While another study from India reported a 40% incidence. ² They used FSSG scores for the diagnosis of GERD as we did, but later, they also performed endoscopy for GERD grading. Although studies vary in their criteria for diagnosing what level of symptoms is pathologic, overall GERD symptoms appear to be more common among asthma populations.

Previous studies suggest that the severity of asthma increases the severity of GERD.^2,31 We did not have spirometry values available for all patients, due to which severity was not assessed based on spirometry testing. We used the ACT™ score ²⁷ to assess the control of asthma. A recent study showed that the prebronchial thermoplasty (BT) ACT score can predict response to BT in younger adult patients with severe asthma and pre-BD %FEV1 ⩾ 70%. ³² High correlations were found between spirometric values and Arabic versions of the ACT and Mini–Asthma Quality of Life Questionnaire (Mini AQLQ) for adults with asthma. The application of these scores can improve the management of asthma not only in Arab countries but also in low- and middle-income countries like Pakistan, where spirometry facilities are not accessible to everyone. ³³ Although 42.6% of patients had very poorly controlled asthma, we found no association of GERD with asthma control in our study.

A recent meta-analysis showed a weak association of GERD with asthma exacerbation in adults. ²¹ However, a study in noncystic fibrosis bronchiectasis showed that the symptoms of airway reflux independently predict severity and exacerbation incidence in noncystic fibrosis bronchiectasis. ³⁴ The effect of GERD on asthma exacerbation is still debatable, yet some studies showed positive results while others showed no effect on asthma control.^18,19,35,36 A study from Hong Kong on asthmatic patients showed that patients with GERD had significantly worse asthma control and worse QoL in all domains of the SF-36. ³⁵ A study showed GERD is associated with not-well-control asthma; they used ACT and reflux diagnostic questionnaire the Reflux Disease Questionnaire (RDQ) scores. ³⁶

Health-related QoL is significantly impaired in patients with chronic cough. The psychosocial influence has generally been under-recognized by physicians, and patients with chronic cough have significant depressive symptoms. ³⁷ GERD also affects the QoL in the general population. ²² It was found that in the adult general population with GERD who had weekly reflux symptoms, most aspects of health-related QoL were compromised (physical functioning, role-physical, bodily pain, general health, and vitality). ³⁸ Among asthma studies have shown a positive correlation between GERD and health-related QoL.^35,39 In Chinese asthmatic patients, those with GERD had worse QoL in all domains of the SF-36 and had more anxiety and depression, as reflected by the Hospital Anxiety and Depression Scale. ³⁵ A study from Japan on asthma and COPD (used GERD (FSSG), the Leicester Cough Questionnaire (LCQ), and ACT and CAT scores) showed impaired cough-related QoL and poor asthma control or more symptoms and impacts of COPD. ³⁹ In our study, we also found GERD patients had lower scores in health-related QoL domains like role limitations due to physical functioning, energy/fatigue, and bodily pain, suggesting a GERD effect on our asthmatic population as well. A systemic review ²³ showed disruptive GERD had 2.4- and 1.5-times higher mean rates of absenteeism and presenteeism, respectively, 1.5-times lower sleep quality scores, 1.1-times lower mean summary scores for physical and mental health, and 1.3-times lower mean scores for psychological and general well-being. However, the treatment of GERD and its impact on asthma is still debatable.^14–16

There are certain limitations to this study. The present study was done in a tertiary care hospital; hence, the results cannot be generalized at a community level. However, these hospitals received major populations from all over the city. Second, silent reflux symptoms cannot be ruled out, as we have not done 24-h pH monitoring of the gastric acid, which is considered the gold standard technique in GERD diagnosis. Obesity is the biggest confounder of GERD and asthma; however, information on BMI is missing in our study. We don’t have data on spirometry for the severity of asthma, the number of exacerbations in past years, and OCS therapy used in past years were also missing. Further larger multicenter studies and randomised controlled trial (RCT) in our population are warranted to clarify this correlation. Considering the high incidence of GERD in our population and its impact on QoL, RCT is required to see whether intervention or adding PPIs in the asthmatic population will have an impact on patients’ lives. These studies will help to provide treatment guidelines for the subset of patients with GERD and asthma. Our study can serve as a base for future studies from Pakistan.

Conclusion

In conclusion, a high prevalence of GERD was found among the asthmatic population with significant lower scores in three domains of health-related QoL: role limitations due to physical functioning, energy/fatigue, and bodily pain in SF36 but did not demonstrate a relationship between GERD and asthma control in our population. Further interventional studies are required to better understand this relationship.