Health-Related Quality of Life (HRQoL) in Tuberculosis Patients: a Cross-Sectional Study Using the EuroQoL EQ-5D-3L Scale

The measurement of health-related quality of life (HRQoL) of pulmonary tuberculosis (TB) patients is important since TB significantly affects the patient’s health and sufferings worldwide. HRQoL indicates the consciousness of patients regarding their physical and mental health. It is, therefore, very relevant in comprehending and measuring the exact impact of the disease state. The current study assessed the HRQoL of TB patients and the correlation between the EQ-5D index score and visual analogue scale (VAS) score. A prospective, cross-sectional study was conducted in February–March, 2022, at Rawalpindi Leprosy Hospital. A total of 400 patients with TB were included in the study. HRQoL was measured by using a validated Urdu version of EuroQol 5 dimensions 3 level (EQ-5D-3L) and visual analogue scale (EQ-VAS). The overall mean score of EQ-5D and the visual analogue scale (VAS) score were (0.56 ± 0.43) and (65.56 ± 17.02), respectively. The correlation coefficient of r = 0.521 between VAS and EQ-5D indicates that our results are statistically significant. Multivariate linear regression analysis implied that gender and education have a significant impact on the patient quality of life. The current study indicated that tuberculosis negatively affects the mental health, social function, and emotional aspects of the patient’s quality of life. The HRQoL data from this study could be used to design future interventions and help prescribers to gain insight into the factors in which patient’s health-related quality of life can be improved.


Background
Tuberculosis (TB) is a matter of concern for global public health [1,2]. Regardless of advancements in the identification and management of TB, approximately 10 million people developed TB, and an estimated 1.4 million people died from TB globally in 2019 [3]. The prevalence of tuberculosis in Pakistan is alarmingly high, and it ranked 6th among the highest burden country in the world for tuberculosis cases. It was estimated that annually 1.5 million people suffer from tuberculosis in Pakistan [4]. TB is an infectious disease that can affect any organ in the human body [5]. In most cases, it affects the lungs, and whenever it affects the lungs, it is referred to as pulmonary tuberculosis (PTB). TB is a curable disease. Despite the availability of effective medication, TB remains a major health concern worldwide [6]. TB patients may undergo several psychological problems, including depression, fear, and anxiety, and socioeconomic issues, in addition to clinical problems because of societal discrimination and extended 6-month period of treatment during the management of TB [3,7].
Health-related quality of life (HRQoL) is the person's perception of HRQoL, showing comfort in the areas that are influenced by their health status [8,9]. A prolonged treatment period for TB can have detrimental effects on the HRQoL of the patients. Low HRQoL is due to the symptoms of TB, side effects of medication therapy, societal stigma, economic costs, anxiety, and depression during the process of treatment [10,11]. Thus, in addition to the treatment of TB, it is crucial to address the psychological and social problems of patients as well [6].
Pakistan is ranked 5th among 22 countries with the highest burden of TB and 27th among high multidrug-resistant (MDR) TB countries in the world, contributing about 60% of the total TB burden in the Eastern Mediterranean Region. Every year, approximately 510,000 new cases of tuberculosis are reported in the country [11,12]. TB diagnosis and treatment in Pakistan have not been thoroughly researched. TB patients reported a lack of treatment services rather than a refusal to take medication [10]. In contrast, another study concludes that lack of adherence is mainly due to poor access to treatment and limited interaction between patients and clinicians [13]. It was reported that clinicians underestimate the effect of prolonged TB treatment on the physical and psychological domains of the patient. Therefore, a more accurate picture can be provided through measures of patients' perception of health [14]. HRQoL is an important metric for helping healthcare workers understand their patients' levels of satisfaction and illness. The HRQoL of TB patients undergoing treatment is critical for tracking the impact of drug therapy on disease progression. To the best of our knowledge, no research has been conducted to evaluate HRQoL and the factors that influence it in TB patients in Pakistan's Potohar region. Therefore, the present survey aimed to assess self-reported HRQoL of pulmonary TB patients in Rawalpindi, Pakistan, utilizing the EQ-5D-3L and EQ-VAS (Urdu version) to investigate the impact of TB on HRQoL of the patients.

Study Designs and Settings
This descriptive, cross-sectional study was conducted at the outpatient department of Rawalpindi Leprosy Hospital, the oldest facility dedicated to the treatment of leprosy in Pakistan and particularly a treatment center for TB. The hospital was developed in 1965 by the Association of German Leprosy and Tuberculosis Relief Association. The hospital has 3 wards with a 97-bed facility providing diagnostic and treatment services for more than 100,000 patients per year.

Inclusion/Exclusion Criteria and Participants Characteristics
The following criteria were selected for inclusion in the study: the patient's age should be 16 or above, diagnosed with TB disease, and the patient can speak or write Urdu (the official language of Pakistan). In this study, only those TB patients were included who were receiving TB therapy. The examination was conducted during the treatment of TB. The patients had different schemes and duration of treatment. Patients were diagnosed through chest X-ray, sputum smear microscopy, and sputum for gene expert tests. Patients with the presence of MDR strains were also included in the study.
The patients with ages below 16 and the patients with comorbidities such as hypertension and diabetes, dementia, immigrants, and those unable to complete the survey were excluded from the study.

Sample Size and Sampling Technique
A simple random sampling technique was used to collect the data from the patients suffering from TB. All the TB patients who fulfilled the outlined criteria have equal chances of being enrolled in the study. The sample size was calculated by using the Rao soft calculator, and the required sample size by this software came out to be 377. The 377-sample size was generated by taking 20,000 TB patients with a 95% confidence interval and a 5% margin of error. We adjusted the sample size by using the following formula: n = n / (1 − d), where n = 384 and d = 5%. The required sample size by this formula came out to be 397. For the prevention of any error or missing rate, we approached 400 TB patients at the Rawalpindi Leprosy Hospital.

Study Instrument and Data Collection Procedure
The EuroQoL health-related quality of life scale (EQ-5D-3L) and visual analogue scale (VAS) were calculated to measure the HRQoL of TB patients. The protocol of the study was registered with the EuRoQoL registration foundation (registration ID: 46,800) [9], and we got the validated Urdu version of the EQ-5D-3L questionnaire. The 5 health domains were assessed by EQ-5D: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension had three levels, viz., no problem, some or moderate, problems, and extreme problems corresponding to levels 1, 2, and 3, respectively [15]. The participant's health state was described in 243 different health states. These health states' score ranges from 1 to − 0.594, where 1 indicates the best health state (1111) and − 0.594 for the worse health state (3333). The visual analogue scale (EQ-VAS) was also included in EQ-5D-3L. The visual analogue scale (EQ-VAS) is a calibrated line, and it determined the respondent's self-rated status of health on a graduated (0-100) scale, where 0 indicates feeble health and 100 for the good health of patients [16]. The EQ-5D-3L and VAS are being used for many years for determining the HRQOL of different diseases such as tuberculosis [11], hypertension [17], liver disease [18], HIV/AIDS [9], diabetes [19], and cancer [20].
The data was collected for a period of 2 months (February 2022-March 2022) by using the designed questionnaire which accesses the HRQoL of the patients suffering from TB. The internal consistency and reliability of the questionnaire were validated by using Cronbach's alpha, and it came out to be 0.809. The 0.809 value of Cronbach indicates that our questionnaire was highly reliable. The questionnaire consisted of 2 parts [16]. The first part comprised sociodemographic characteristics of the patients' (age, gender, marital status, level of education, occupation, and locality of the patients) parameters. The information obtained from the patient was also confirmed by the patient's medical record. The second part comprised of EuroQoL HRQoL scale (EQ-5D-3L) and a visual analogue scale (VAS). The study participants were requested to self-assess their health states and rate their health score by using the EuroQoL HRQoL scale (EQ-5D-3L) and visual analogue scale (VAS). The investigator ensures that all the participants understand the nature and purpose of the study. If the participants face any difficulty related to understanding the question, then the investigator assists the patients and makes sure that the patient understands the question. The participants were encouraged to fill all the questions in chronological order and instructed to not skip any question. The patients completed the questionnaire in 20-30 min.

Statistical Analysis
The data was compiled in MS Excel and then analyzed by using the Statistical Package for Social Sciences (SPSS) software version 21.0. The Shapiro-Wilk test was used to determine normality. There was a normal distribution of data; therefore, parametric tests were applied on the collected data. Descriptive and inferential statistics were applied to summarize the characteristics of the data set and to make predictions about a larger population based on the representative sample, respectively.
Descriptive statistics were used to summarize and describe the demographic information and disease-related characteristics of TB patients. The categorical variables were represented in percentages and frequencies, while the continuous variables were described in the means and standard deviations. The mentioned 5 health domains of HRQoL were described as no problems, some problems, and severe problems. For the Pakistani population, EQ-5D preference utility score data were not available for each state of health. Therefore, the HRQoL index value was calculated by using the time trade-off (TTO) tariff method from the representative sample of the UK population [18,21]. The chi-square test was used to measure the level of association between study variables. Pearson correlation test was applied to determine any correlation between health-related quality of life (HRQoL) and the visual analogue scale (VAS). Independent sample t-tests and ANOVA were applied to determine the statistically significant differences in HRQoL (EQ-5D and EQ-VAS scores) related to the characteristics of TB patients. For regression analysis, only those variables include that show significant variation in HRQoL in univariate analysis. The significant predictor of HRQoL of TB patients was determined by applying a multivariable regression model. Moreover, the impact of two or more independent factors on the dependent variable was predicted using multiple regression analysis. A P value of < 0.05 was considered significant at a 95% confidence interval.

Ethical Considerations
This study was ethically approved by the institutional review board (IRB) of Rawalpindi Leprosy Hospital (approval no. RLH-097-2022). The objective and purpose of the study were verbally explained by the principal investigator to the patients. Informed consent was obtained from the patients. The patients were assured that their health information should be kept confidential and disclosed only to the research team. Data were collected after they signed the consent form. The patient's involvement in the study was fully voluntary and without remuneration. All the participants filled out the questionnaire and participated in the study. The study was accomplished according to ethical principles as described in the Helsinki Declaration of 1964, which was revised in 2013 [22], and also follows the rules and regulations of Pakistan for research that involves the human subject.

Health-Related Quality of Life
Regarding mobility, 206 (51.5%) patients responded that they had no problem while walking, 138 (34.5%) patients had some problems in walking, and 56 (14%) were confined to bed. Regarding self-care, 272 (68%) patients could take care of themselves, and 92 (23%) patients had some problem while washing or dressing, whereas 36 (9%) were unable to wash or dress. Regarding usual activities, 239 (59.8%) patients could perform their usual activities without any problem, whereas 114 (28.5%) had some problem with performing their daily activities, and 47 (18%) patients were unable to perform their usual activities. Regarding the dimension of pain/discomfort, 145 (36.3%) had no pain, and 190 (47.5%) had moderate pain, whereas 65 (16.3%) patients had extreme pain or discomfort because of the disease. Regarding anxiety/depression, 220 (55%) patients had no anxiety or depression because of the disease, and 135 (33.8%) had some sort of depression because of the disease, whereas 45 (11.3%) were extremely anxious or depressed because of this disease ( Table 2).

EQ-5D Health Scores
The EQ-5D index score shows a significant difference between different groups of age (P = 0.000), marital status (P = 0.013), level of education (P < 0.05, P = 0.000), and different groups of occupation, whereas the EQ-5D score has  an insignificant difference ((P > 0.05) between the gender group and related to the locality. Similarly, the VAS score has significant differences related to the different groups of occupation, levels of education, and insignificant differences (P < 0.05) for the gender group and locality group. In contrast to the EQ-5D index score, the VAS score indicates an insignificant difference regarding marital status (P = 0.177) and between the different groups of age (P = 0.094) ( Table 3).

EQ-5D Health States
Ninety-six different EQ-5D states of health were mentioned by patients with TB. The results showed that 82 (20.5%) patients had a health state of 11,111, 32 (8.0%) patients had a health state of 11,121, and 35 (8.8%) patients had a health state of 11,122. The EQ-5D states of health with maximum frequencies were included (Table 4).

Correlation Between EQ-5D Index and VAS Scores
The correlation between the EQ-5D index score and VAS was measured by using Pearson's correlation. The range of correlation values is between + 1 and − 1. The coefficient of correlation was r = 0.521 (P 0.000) which indicated a statistically significant and moderate linear relationship ( Table 5).

The Multivariate Linear Regression Model
The multiple regression table shows the impact of independent variables on health index scores. The table shows that all independent variables have an insignificant impact on the dependent variable except gender and education. Gender has a positive and significant impact on health index score (P < 0.05), and education also has a positive and significant impact on health index score (P < 0.05) ( Table 6). The multiple regression table shows the impact of independent variables on the VAS score. The table shows that all independent variables have an insignificant impact on the dependent variable except education. Education has a positive and significant impact on VAS (P < 0.05) ( Table 7).

Discussion
Tuberculosis is a major public health concern around the world. The prolonged therapy and infectious nature of the disease are the reasons for social, physical, and mental distress and the poor health quality of TB patients. Unfortunately, a few studies have been conducted in Pakistan to access the impact of disease burden and its prolonged therapy on the HRQoL of patients with TB [2]. The current study was conducted to assess the HRQoL of TB patients at the Rawalpindi Leprosy Hospital's outpatient department (OPD).
The mean EQ-5D score for TB patients was 0.56 ± 0.43, while the mean EQ-VAS score was 65.56 ± 17.02. EQ and VAS scores in our study are better than the other study conducted in Pakistan in 2018, which reported a 0.43 score on EQ-5D and a 54.73 score on the VAS [11]. A study conducted in Sri Lanka reported that the mean EQ-VAS score of TB patients at the start of therapy was 59.64 and this mean EQ-VAS score was lower than our study score. But in the Sri Lankan study, the mean EQ-VAS score increased to 78 scores at the end of the 2-month therapy (intensive phase) and increased to 83.4 after 6 months of therapy [6]. The results of our study indicate that most of the patients suffering from TB showed some/moderate problems in the domains of mobility, pain/discomfort, and anxiety/depression which leads to poor HRQoL in TB patients. The prior studies also reported that the physical and psychological domains of HRQoL were affected by TB. These studies mentioned that the social and mental health of people are equally valuable and affected in chronic disease patients along with physical health and these factors attribute to the poor health-related quality of life of TB patients [14,23,24]. The result of this study is consistent with the earlier studies conducted in different countries, and these studies concluded that patients' QOL was affected by prolonged TB therapy. The extended duration of TB therapy, the complex drug combination, the adverse drug effects, and the fear of losing the job decrease the health-related quality of life of TB patients. These studies also mention that TB patients have lower HRQoL compared to healthy individuals [25][26][27]. The poor HRQoL in TB patients might be due to lack of knowledge, loss of income, stigma, and lack of social support, drug side effects, and long treatment duration emerged as important barriers to treatment adherence [28,29]. A case-control study    [30]. The current study indicates that patient education and age group have a positive effect on the HRQoL, and these results are very similar to the study conducted in Thailand [31]. The education level leads to better HRQoL, and these results were also supported by the prior study [2]. The current study indicates that 33% of patients have moderate anxiety/depression levels, while 11% are extremely depressed patients, and these results are lower than the previous study conducted by Atif et al. which reported that 67% of patients have depression at the start of the treatment and 23% patients still have depression at the end of the treatment [10]. A study conducted in Yemen observed poor QoL in TB patients, with a significant likelihood of depression, and these findings are consistent with the present study. Hospitalization, social stigma, and difficulty in maintaining family life are some of the factors that contribute to anxiety or depression in tuberculosis patients [23,32]. In another study, about half of the assessed patients indicated bad or very bad general HRQoL [33]. The previous study conducted to access HRQoL on both inpatient and outpatient reported that the inpatients (n = 197) displayed lower HRQoL scores compared to outpatients [34]. Similarly, a study was conducted in Eritrea to assess HRQoL among rifampicin/multidrug-resistant TB (RR/MDR-TB) in comparison to drug-susceptible TB (DS-TB) patients. HRQOL was impaired in both groups, but RR/MDR-TB patients had a worse HRQoL [35]. The HRQoL was diminished in the TB patients [36]. The previous studies reported that HRQoL was poor in TB patients, but after treatment progression, both EQ-5D health utility and EQ-VAS scores were increased [11,37,38] Evidence suggests that improved awareness regarding TB leads to better treatment outcomes and better control over the spread of TB [12]. It has been found that healthcare programs that include holistic assessment of social and psychological aspects of treatment in physical disorders are more likely to be successful [39]. The presence of a pharmacist in an inpatient setting has contributed to the prevention and resolution of problems related to the pharmacotherapeutic management of TB. Pharmacists can position themselves as major players in the therapeutic management of TB inpatients in resource-limited settings [40]. HRQoL was significantly improved in the interventional group that comprised the pharmacist-led interventional program which advocates the vital role of pharmacists in patients' education and a better healthcare system in Pakistan [41].

Clinical Implications
This study has practical implications as its findings highlight the current status of HRQoL among TB patients in Pakistan. The prescriber will be able to gain insight into possible factors that may influence HRQoL among TB patients as a result of the current analysis. In addition, it will be helpful for designing interventions aimed at improving HRQoL in tuberculosis patients. The current study suggests that specialized centers and programs should be developed to provide TB patients with awareness about healthy activities and enhance their life status.
The HRQoL of TB patients during and after therapy will need to be measured in future studies. As in the present study, the HRQoL of TB patients was measured during the treatment, but not after the treatment was completed. The HRQoL level was certainly better after the treatment compared to during the treatment. The other suggestion is that researchers should conduct further studies in the future to evaluate the HRQoL of TB patients who have comorbidities.

Strengths and Limitations of the Study
The strength of the study was that the investigators make sure that patients understand all the questions so that we can get a more accurate finding of HRQoL level. Moreover, a generic and disease-specific validated questionnaire EuRoQoL EQ-5D VAS was used to measure the HRQoL of the TB patients.
The study also has some limitations. This study was conducted in one city in Pakistan, and the results may not be generalizable to the whole areas and population of the country. Time and financial constraints were also faced during the conduction of the study.

Conclusion
The study participants showed poor EQ-5D index and VAS scores which indicate poor HRQoL in TB patients. VAS score and the EQ-5D index showed a moderate and statistically significant linear relationship. The poor HRQoL among TB patients in Pakistan raises serious concerns, and the finding of this study suggests that the management of TB patients should focus on strategies addressing HRQoL problems. Health education programs and interventions involving pharmacists should also be provided especially in rural areas.