Authors: Nam Xuan Vo  ( Graduate Program in Social, Economic and Administrative Pharmacy, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand )
Thy Bui Xuan Doan  ( Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam )
Di Ngoc Kha Vo  ( Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam )
Tu Kim Tran  ( Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam )
Trung Quang Vo  ( Department of Economic and Administrative Pharmacy (EAP), Faculty of Pharmacy, Pham Ngoc Thach University of Medicine, Ho Chi Minh City 700000, Vietnam )

Objective: One can hypothesize that Mycobacterium genus originated more than 150 million years ago and has evolved to become one of the leading lethal infectious diseases. Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) patients are directly affected by the disease and other subjective issues, such as related diseases, medical costs and social issues, which all have negative impacts on patient quality of life (QOL). Our purpose is to define the status of health-related QOL for international MDR-TB and XDR-TB patients.
Methods: Systematic review is a good method for searching and selecting related researches and articles. As such, we have searched for and cited related articles on reputable databases, such as PubMed, Cochrance, and Google Scholar. A data overview was performed to draw conclusions and results on the QOL of MDR-TB and XDR-TB patients.
Results: A total of 18 articles were included, using instruments from the World Health Organization, Euroqol, Short Form, AQ and the Seattle Obstructive Lung Disease Questionnaire. The QOL of MDR-TB and XDR-TB patients was found to be compromised due to the strong resistance of Mycobacterium tuberculosis, economic pressure and community alienation.
Conclusions: A number of QOL and health-related QOL studies on MDR-TB and XDR-TB patients are limited, especially with XDR-TB patients. Significant numbers of MDR-TB and XDR-TB patients still have sequelae after completing treatment, reducing the health-related QOL among these patients.
Keywords: Extensively drug-resistant tuberculosis, Health-related quality of life, Multidrug-resistant tuberculosis, Quality of life. (JPMA 69: S-137 (Suppl. 2); 2019)

Introduction

Mycobacterium tuberculosis was discovered in monuments and fossil specimens from hundreds of millions of years ago. With strong adaptation throughout geological and climate change stages, as well as the migration of continents, Mycobacterium tuberculosis has spread and eventually become the most dangerous infectious disease in the world known as tuberculosis.^1,2 Due to the mutability and adaptability of tuberculosis bacteria against antibiotics and environment, as well as patient non-compliance with medication regimens, antituberculosis drug resistance has occurred. ² While tuberculosis patients suffer from severe medical pressures, drug-resistance makes it significantly more difficult to manage and successfully treat multi drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) cases. ³  Because of MDR-TB and XDR-TB, these patients must use second-line drugs, which are more expensive, cause more serious side effects and require longer treatment durations. These drugs also cause other health-related, economic and social patient burdens which affect the quality of life (QOL) of these patients. ⁴  There has been some research on the health-related quality of life (HRQOL) of MDR-TB and XDR-TB patients which has shown such patients being significantly affected, but most of these studies were conducted in particular countries.^5-8 Thus, our study shall evaluate QOL among international MDR-TB and XDR-TB cases to produce a positive solution to QOL improvement for MDR-TB and XDR-TB patients.

Methods

A systematic review was conducted from 30 January to 18 April 2019 using the following three databases: PubMed (www.ncbi.nlm.nih.gov/pubmed), Cochrane

(www.cochranelibrary.com) and Google Scholar (www.scholar.google.com.vn). The found articles were sent to Endnote X9 for the creation of citation files. Using Endnote X9, we looked for duplicates and removed them.The syntax we used in the PubMed and Cochrane databases was as follows: ("Health-related quality of life" or "HRQOL" or "HRQoL" or "HRQL" or "Quality of Life"or "QOL" or "QoL") and ("multidrug-resistant tuberculosis"[MeSH Terms] or "extensively drug-resistant tuberculosis"[MeSH Terms]). In the Google Scholar database, we used the following search terms to match the scope of the other database searches: "health-related quality of life", "quality of life", "multidrug-resistant tuberculosis" and "extensively drug-resistant tuberculosis". The Google Scholar search combined the terms with matching words "and" and "or". These found articles were subsequently screened by title, abstract and full-text to determine appropriate articles. The criteria used for selection is shown in



Table-1 and the process selected to identify which articles should be chosen for collecting indispensable information is shown in Figure-1.



Results

Among the databases, 1039 articles were found with 49, 1 and 989 originating from Pubmed, Cochrane and Google Scholar, respectively. After the selection process, 17 duplicates, 96 non-English and 910 unrelated articles were removed. The resulting 16 articles were chosen for review and two additional references were selected to make up the 18 articles included for systematic review. As we summarized these publications, we divided them into three categories: year of publication, the number of study participants and target samples (Table-2).



According to publication years, one study was published in 2004, 2014 and 2019. The other years ranged from two to five articles with the most prolific being 2016 and 2018. The number of participants ranged from under 100 (6 articles), to between 100 and 200 (5 articles) and over 200 (4 articles), with the rest having unlimited participants. There were 11, 1 and 6 publications targeting MDR-TB patients, XDR-TB patients and MDR-TB patients with other subjects, respectively. Furthermore, we also summarized the study designs of these reviewed articles (Table-3)



,obtaining data showing cross-sectional design accounted for more than 10 studies (around 55.56%) while other types of study design represented less than 20%. Among these articles, many HRQOL and QOL instruments were used to evaluate the lives of MDR-TB and XDR-TB patients (Table-4).



The most commonly used instrument was the World Health Organization quality of life (WHOQOL) (used by 5 articles) and the second most common was the SF (using in 3 articles). Most of the 18 reviewed articles researched adult aged subjects (>18 years) and evaluated their lives in four domains: physical, psychological, social and environmental. Instances of depression, anxiety and lack of social support were noted during treatments, which reduced the QOL of MDR-TB patients in all domains.^6,9,10 Moreover, these reductions were dependent on the age and gender of the MDR-TB patients. For instance, the elderly may have a lower HRQOL than thoseaged18-30 years. Females were found more likely to experience poor HRQOL than males. ¹¹  In countries such as India and China, the well-being of living or social support of MDR-TB patients were seen to be comparatively low.^8,12 Therefore, encouragement is a vital factor to enhance the lives of MDR-TB and XDR-TB patients.¹³ India and Africa are two locations that have the most people being affected by this infectious disease. In total, nearly 10 studies (Table-5)



performed their research in these locations (around 50% for each one). Many reasons can explain this preference, but the most prominent are hygiene and health-care systems. Mycobacterium tuberculosis can easily spread from one person to another through air and both India and Africa have large developing populations. As a result, hygiene and healthcare conditions may be of little concern to the citizenry. The results are summarised in greater detail in Table-6.



Discussion

This review indicated the effects on QOL for MDR-TB and XDR-TB patients. There were four domains assessed among the reviewed studies: physical, psychological, social and environmental. The HRQOL of MDR-TB and XDR-TB patients became worse mainly due to physical and psychological problems after completing treatment. Financial damage, social functioning and environmental factors also affected the QOL of MDR-TB and XDR-TB patients. Nevertheless, HRQOL differed regarding gender and age among those patients. HRQOL was higher in the age group of 18 to 30 years11 while QOL in patients 40 years old or older was significantly lower. ⁷  Male patients also had a higher QOL when compared to female patients.11Ten studies focused on the QOL of MDR-TB patients, but different tools were used among these studies (WHOQOLBREF, EQ-5D, SOLDQ, SF-8, SF- 36v2, SOLDQ). Despite the heterogeneity of measurement tools, evidence showed that MDR-TB patients had moderately low HRQOL scores. Five studies compared the HRQOL between MDR-TB patients and other patients, such as PTB, DS-TB, non-DRT Band TB-cured subjects. These studies also used different measurement tools yet visibly indicated that MDR-TB received greater effect on HRQOL from alternative methodology than other groups. Moreover, there was a relation between contracting MDR-TB and being older, less educated, smoking and unemployed. ⁵ However, a conflict remained between two findings about the effects of ADRs on the QOL of MDR-TB patients. One article stated that an increase in total ADRs was considerably associated with a decrease in HRQOL¹⁴  while another study disclaimed this statement. ¹⁵  This may be due to the influence of heterogeneity in measurement instruments, time and execution areas (EQ-5D vs SF-8, 2015 vs 2016, South Africa vs Namibia respectively). On the other hand, we still encountered some limitations while conducting this review. Firstly, our theme is the QOL of MDR-TB and XDR-TB patients, however, most of the studies only researched MDR-TB patients. In particular, we only have one study about the QOL of one XDR-TB patient, ¹⁶  which makes it difficult to provide a proper overview and represent the QOL for international XDR-TB patients. Secondly, many different measurement instruments were used among the reviewed articles, so there was a high level of heterogeneity when pooling the results. We did not possess guidelines for assessing these scores equivalently, which caused summarisation and comparison difficulties. Based on this review, greater attention is recommended for the QOL of MDR-TB andXDR-TB patients. There is also a need for a specific tuberculosis HRQOL tool to standardise finding  interpretation.

Conclusion

In conclusion, this review provides an overview for HRQOLof MDR-TB and XDR-TB patients. Those patients had lower QOL compared to other types of tuberculosis patients. Despite the positive impact of MDR-TB treatment on patients, their physical and mental health remain compromised at the end of treatment. Social functioning, economic and financial challenges also considerably affect their QOL. Further, there is a lack of research that focuses on assessing the HRQOL of MDR-TB patients and XDR-TB patients in particular. The limited number of published studies on this vital topic emphasises a need for greater investment in research concentrating on HRQOL for those patients. Only with such study can health-care professionals and management provide timely, applicable, reliable, and relevant interventions to improve the overall QOL of those patients.

References

1. World Health Organization. WHO treatment guidelines for drug resistant tuberculosis: update 2016. Geneva, Switzerland: WHO Press, 2016; pp 56.

2. Daniel TM. The history of tuberculosis. Respir Med 2006;100:1862 70.

3. World Health Organization. Global Tuberculosis Report [Online] 2018 [Cited 2018 June 25]. Available from URL:

https://www.who.int/tb/publications/global_report/en/

4. Suarez PG, Floyd K, Portocarrero J, Alarcón E, Rapiti E, Ramos G, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002;359:1980-9.

5. Marzook AA. Health-related quality of life of tuberculosis patients in Bagdad and socio-demographic factors associated with multiple drug resistant tuberculosis (MDR TB).Diyala Journal of Medicine 2016;10:9-15.

6. Patel AE, Lalitha K, Rajaram D, Radhika K, Murthy NS. Quality of life among patients on MDR-TB treatment in a district tuberculosis centre of a metropolitan city. Int J Community Med Public Health 2018;5:5355-59.

7. Kittikraisak W, Kingkaew P, Teerawattananon Y, Yothasamut J, Natesuwan S, Manosuthi W, et al. Health related quality of life among patients with tuberculosis and HIV in Thailand. PLoS One 2012;7:e29775.
8. Sharma R Yadav R, Sharma M, Saini V, Koushal V. Quality of life of multi drug resistant tuberculosis patients: a study of north India. Acta Med Iran 2014;52:448-53.

9. Ahmad N, Javaid A, Syed Sulaiman SA, Basit A, Afridi AK, Jaber AA et al. Effects of Multidrug Resistant Tuberculosis Treatment on Patients' Health Related Quality of Life: Results from a Follow Up Study. PloS one 2016;11:e0159560.

10. Alene KA, Clements ACA, McBryde ES, Jaramillo E, Lönnroth K, Shaweno D, et al. Mental health disorders, social stressors, and health-related quality of life in patients with multidrug-resistant tuberculosis: A systematic review and meta-analysis. J Infect 2018;77:357-67.

11. Shinde TN, Dalvi R, Yakkaldevi A. Golden Research Thoughts. Int Multidiscip Res J. [Online] 2015 [Cited 2018 June 20]. Available from URL: https://www.researchgate.net/publication/263653858_Golden_Research_Thoughts 

12. Chen B, Peng Y, Zhou L, Chai C, Yeh HC, Chen S, et al. Social support received by multidrug-resistant tuberculosis patients and related factors: a cross-sectional study in Zhejiang Province, People's Republic of China. Patient Prefer Adherence 2016;10:1063-70.

13. Laxmeshwar C, Stewart AG, Dalal A, Kumar AMV, Kalaiselvi S, Das M, et al. Beyond 'cure' and 'treatment success': quality of life of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2019;23:73-81.

14. Kelly AM. Adverse Drug Reactions and Resultant Health-Related Quality of Life During Multidrug-Resistant Tuberculosis Treatment in South Africa. [Online] 2015 [Cited 2018 June 20]. Available from

URL: https://sigma.nursingrepository.org/handle/10755/579095

15. Sagwa EL, Ruswa N, Mavhunga F, Rennie T, Leufkens HG, Mantel- Teeuwisse AK. Adverse events and patients' perceived health related quality of life at the end of multidrug-resistant tuberculosis treatment in Namibia. Patient Prefer Adherence2016;10:2369-77.

16. Muhammad Redzwan SR, Ralph AP, Sivaraman Kannan KK, William T. Individualised second line anti-tuberculous therapy for an extensively resistant pulmonary tuberculosis (XDR PTB) in East Malaysia. Med J Malaysia 2015;70:200-4.

17. Roba AA, Dasa TT, Weldegebreal F, Asfaw A, Mitiku H, Teklemariam Z, et al. Tuberculosis patients are physically challenged and socially isolated: A mixed methods case-control study of Health Related Quality of Life in Eastern Ethiopia. PloS one 2018;13:e0204697.18. Godoy MD, Mello FC, Lopes AJ, Costa W, Guimarães FS, Pacheco AG, et al. The functional assessment of patients with
pulmonary multidrug-resistant tuberculosis. Respir Care 2012;57:1949-54.
19. Singla R, Mallick M, Mrigpuri P, Singla N, Gupta A. Sequelae of pulmonary multidrug-resistant tuberculosis at the completion of  treatment. Lung India 2018;35:4-8.
20. de Vallière S, Barker RD. Residual lung damage after completion of treatment for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2004;8:767-71.
21. Thomas BE, Shanmugam P, Malaisamy M, Ovung S, Suresh C, Subbaraman R, et al. Psycho-Socio-Economic Issues Challenging Multidrug Resistant Tuberculosis Patients: A Systematic Review. PLoS One 2016;11:e0147397.