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Research Article| Volume 127, P93-105, February 2023

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The effect of undernutrition on sputum culture conversion and treatment outcomes among people with multidrug-resistant tuberculosis: a systematic review and meta-analysis

Open AccessPublished:December 05, 2022DOI:https://doi.org/10.1016/j.ijid.2022.11.043
The effect of undernutrition on sputum culture conversion and treatment outcomes among people with multidrug-resistant tuberculosis: a systematic review and meta-analysis
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      Highlights

      • •
        An estimated 1.9 million tuberculosis cases are attributable to undernutrition.
      • •
        A comprehensive systematic review containing 63 published articles was conducted.
      • •
        Undernutrition was associated with prolonged time to sputum culture conversion.
      • •
        Undernutrition increased the risk of unsuccessful treatment outcomes and mortality.
      • •
        Nutritional support may be beneficial for people with multidrug-resistant tuberculosis.

      Abstract

      Objectives

      We aimed to evaluate the effect of undernutrition on sputum culture conversion and treatment outcomes among people with multidrug-resistant tuberculosis (MDR-TB).

      Methods

      We searched for publications in the Medline, Embase, Scopus, and Web of Science databases. We conducted a random-effect meta-analysis to estimate the effects of undernutrition on sputum culture conversion and treatment outcomes. Hazard ratio (HR) for sputum culture conversion and odds ratio (OR) for end-of-treatment outcomes, with 95% CI, were used to summarize the effect estimates. Potential publication bias was checked using funnel plots and Egger's tests.

      Results

      Of the 2358 records screened, 63 studies comprising a total of 31,583 people with MDR-TB were included. Undernutrition was significantly associated with a longer time to sputum culture conversion (HR 0.7, 95% CI 0.6-0.9, I2 = 67·1%), and a higher rate of mortality (OR 2.8, 95% CI 2.1-3.6, I2 = 21%) and unsuccessful treatment outcomes (OR 1.8, 95% CI 1.5-2.1, I2 = 70%). There was no significant publication bias in the included studies.

      Conclusion

      Undernutrition was significantly associated with unsuccessful treatment outcomes, including mortality and longer time to sputum culture conversion among people with MDR-TB. These findings have implications for supporting targeted nutritional interventions alongside standardized TB drugs.

      Keywords

      Introduction

      Multidrug-resistance tuberculosis (MDR-TB) is a major public health problem affecting approximately half a million people globally. MDR-TB is defined as tuberculosis (TB) that is resistant to at least the two most effective first-line TB drugs, rifampicin and isoniazid [
      World Health Organization. Global tuberculosis report
      Geneva: World Health Organization, 2021.
      2021
      ]. According to the recent World Health Organization (WHO) Global TB report, a total of 132,222 MDR-TB cases were identified in 2020 and of these, 25,861 had extensive drug resistance (XDR)-TB [
      World Health Organization. Global tuberculosis report
      Geneva: World Health Organization, 2021.
      2021
      ]. In addition, approximately 19 million individuals have latent MDR-TB infection globally [
      • Knight GM
      • McQuaid CF
      • Dodd PJ
      • Houben RMGJ.
      Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.
      Lancet Infect Dis. 2019; 19: 903-912https://doi.org/10.1016/S1473-3099(19)30307-X
      ]. Treatment of MDR-TB is more challenging than treatment of drug-susceptible TB (DS-TB) as it requires lengthy (from a minimum of 9 up to 20 months), arduous, expensive, and more toxic medications [
      World Health Organization. Global tuberculosis report
      Geneva: World Health Organization, 2021.
      2021
      ,
      World Health Organization
      Global Plan to Stop TB 2011–2015: transforming the fight towards elimination of tuberculosis.
      World Health Organization, Geneva2010
      ]. The treatment success rate reported globally is 59% for MDR-TB, much lower than for people with DS-TB at 86% [
      World Health Organization. Global tuberculosis report
      Geneva: World Health Organization, 2021.
      2021
      ].
      The MDR-TB situation in the past 2 years is thought to have worsened because of the COVID-19 pandemic that compromised TB services [
      • McQuaid CF
      • Vassall A
      • Cohen T
      • Fiekert K
      • White RG.
      The impact of COVID-19 on TB: a review of the data.
      Int J Tuberc Lung Dis. 2021; 25: 436-446https://doi.org/10.5588/ijtld.21.0148
      ,
      • Migliori GB
      • Marx FM
      • Ambrosino N
      • Zampogna E
      • Schaaf HS
      • van der Zalm MM
      • et al.
      Clinical standards for the assessment, management and rehabilitation of post-TB lung disease.
      Int J Tuberc Lung Dis. 2021; 25: 797-813https://doi.org/10.5588/ijtld.21.0425
      ], including TB notifications [
      • Tadolini M
      • Codecasa LR
      • García-García JM
      • Blanc FX
      • Borisov S
      • Alffenaar JW
      • et al.
      Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases.
      Eur Respir J. 2020; 56https://doi.org/10.1183/13993003.01398-2020
      ] and treatment success [
      World Health Organization. Global tuberculosis report
      Geneva: World Health Organization, 2021.
      2021
      ]. Unsuccessful treatment outcomes for people with MDR-TB can be associated with various factors including patients’ socioeconomic status such as low levels of education or income, alcohol use disorder, and unemployment [
      • Gulpe T
      • Ciobanu A
      • Iavorschi C
      • Gozalov O
      • Dadu A
      • et al.
      Risk factors associated with loss to follow-up among multidrug-resistant tuberculosis patients in the Republic of Moldova in 2014–2016.
      Public Health Panorma. 2019; 5: 493-502
      ,
      • Pradipta IS
      • Forsman LD
      • Bruchfeld J
      • Hak E
      • Alffenaar JW.
      Risk factors of multidrug-resistant tuberculosis: a global systematic review and meta-analysis.
      J Infect. 2018; 77: 469-478https://doi.org/10.1016/j.jinf.2018.10.004
      ], and comorbidities such as cancer, diabetes mellitus, and HIV. Previous history of TB and TB program-related factors such as treatment regimens [
      • Burhan E
      • Soepandi PZ
      • Isbaniah F
      • Damayanti K
      • Edwar SQ
      • Maruli MF
      • et al.
      Determinants of treatment outcomes in patients with multidrug-resistant TB.
      Int J Tuberc Lung Dis. 2022; 26: 126-132https://doi.org/10.5588/ijtld.21.0351
      ,
      • Kurbatova EV
      • Dalton T
      • Ershova J
      • Tupasi T
      • Caoili JC
      • Van Der Walt M
      • et al.
      Additional drug resistance of multidrug-resistant tuberculosis in patients in 9 countries.
      Emerg Infect Dis. 2015; 21: 977-983https://doi.org/10.3201/eid2106.141329
      ] can also affect the treatment outcomes of people with MDR-TB.
      Undernutrition, which includes low body mass index (BMI) in adults, is one of the most important public health issues affecting more than 768 million people worldwide in 2019 [
      Food and Agriculture Organization of the United Nations
      The state of food security and nutrition in the world 2020: transforming food systems for affordable healthy diets.
      Food and Agriculture Organization of the United Nations, Rome2020
      ]. Although the burden of undernutrition has declined in the last few decades, it still disproportionately affects children and adults in low and middle-income countries [
      • Black RE
      • Allen LH
      • Bhutta ZA
      • Caulfield LE
      • De Onis M
      • Ezzati M
      • et al.
      Maternal and child undernutrition: global and regional exposures and health consequences.
      Lancet. 2008; 371: 243-260https://doi.org/10.1016/S0140-6736(07)61690-0
      ]. More than half of the global burden of undernutrition is reported in Asia (418 million people) and nearly one-third in Africa (282 million people) [
      Food and Agriculture Organization of the United Nations
      The state of food security and nutrition in the world 2020: transforming food systems for affordable healthy diets.
      Food and Agriculture Organization of the United Nations, Rome2020
      ]. This high burden of undernutrition poses significant challenges to the future economic growth, human well-being, and health system including the control and prevention of TB programs.
      Undernutrition is the most important driver of the TB epidemic [
      • Lönnroth K
      • Jaramillo E
      • Williams BG
      • Dye C
      • Raviglione M.
      Drivers of tuberculosis epidemics: the role of risk factors and social determinants.
      Soc Sci Med. 2009; 68: 2240-2246https://doi.org/10.1016/j.socscimed.2009.03.041
      ]. According to the WHO Global TB Report 2021 [
      World Health Organization. Global tuberculosis report
      Geneva: World Health Organization, 2021.
      2021
      ], an estimated 1.9 million TB cases (19%) are attributable to undernutrition in 2020. In particular, the prevalence of undernutrition among people with MDR-TB in low- and middle-income countries is high ranging from 35-75% [
      • Baluku JB
      • Namiiro S
      • Nabwana M
      • Muttamba W
      • Kirenga B.
      Undernutrition and treatment success in drug-resistant tuberculosis in Uganda.
      Infect Drug Resist. 2021; 14: 3673-3681https://doi.org/10.2147/IDR.S332148
      ,
      • Magassouba AS
      • Touré AA
      • Diallo BD
      • Camara LM
      • Touré D
      • Conté N
      • et al.
      Malnutrition prevalence and associated biochemical factors among drug-resistance tuberculosis (DR-TB) patients at key treatment sites in Conakry City, Republic of Guinea.
      Pan Afr Med J. 2021; 38: 279https://doi.org/10.11604/pamj.2021.38.279.27270
      ,
      • Whitehouse ER
      • Perrin N
      • Levitt N
      • Hill M
      • Farley JE.
      Cardiovascular risk prevalence in South Africans with drug-resistant tuberculosis: a cross-sectional study.
      Int J Tuberc Lung Dis. 2019; 23: 587-593https://doi.org/10.5588/ijtld.18.0374
      ]. This could lead to worse outcomes in people with MDR-TB by weakening the innate and adaptive cell-mediated immunity, decreasing Th1 cytokines, and diminishing phagocytic function [
      • Cegielski JP
      • Arab L
      • Cornoni-Huntley J.
      Nutritional risk factors for tuberculosis among adults in the United States, 1971–1992.
      Am J Epidemiol. 2012; 176: 409-422https://doi.org/10.1093/aje/kws007
      ,
      • Paton NI
      • Castello-Branco LR
      • Jennings G
      • Ortigao-de-Sampaio MB
      • Elia M
      • Costa S
      • et al.
      Impact of tuberculosis on the body composition of HIV-infected men in Brazil.
      J Acquir Immune Defic Syndr Hum Retrovirol. 1999; 20: 265-271https://doi.org/10.1097/00042560-199903010-00008
      ]. As well, undernutrition is likely to be linked to a decreased drug absorption because of altered intestinal absorption area [
      • Pinheiro VG
      • Ramos LM
      • Monteiro HS
      • Barroso EC
      • Bushen OY
      • Façanha MC
      • et al.
      Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis.
      Braz J Infect Dis. 2006; 10: 374-379https://doi.org/10.1590/s1413-86702006000600003
      ]. People with undernutrition are more likely to have severe diseases such as lung cavitation and lung involvement [
      • Hoyt KJ
      • Sarkar S
      • White L
      • Joseph NM
      • Salgame P
      • Lakshminarayanan S
      • et al.
      Effect of malnutrition on radiographic findings and mycobacterial burden in pulmonary tuberculosis.
      PLoS One. 2019; 14e0214011https://doi.org/10.1371/journal.pone.0214011
      ] as well as TB relapse [
      • Khan A
      • Sterling TR
      • Reves R
      • Vernon A
      • Horsburgh CR.
      Lack of weight gain and relapse risk in a large tuberculosis treatment trial.
      Am J Respir Crit Care Med. 2006; 174: 344-348https://doi.org/10.1164/rccm.200511-1834OC
      ]. Furthermore, as well as increasing the risk of infection, some previous studies have provided evidence that undernutrition is related to poor MDR-TB treatment outcomes including death, and loss to follow-up [
      • Gonah L
      • Maphosa TM.
      Association of MDR-TB treatment outcomes and HIV status in Zimbabwe: a retrospective study.
      Cogent Med. 2020; 71783129https://doi.org/10.1080/2331205X.2020.1783129
      ,
      • Kwon YS
      • Kim YH
      • Suh GY
      • Chung MP
      • Kim H
      • Kwon OJ
      • et al.
      Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis.
      Clin Infect Dis. 2008; 47: 496-502https://doi.org/10.1086/590005
      ,
      • Magee MJ
      • Kempker RR
      • Kipiani M
      • Tukvadze N
      • Howards PP
      • Narayan KM
      • et al.
      Diabetes mellitus, smoking status, and rate of sputum culture conversion in patients with multidrug-resistant tuberculosis: a cohort study from the country of Georgia.
      PLOS ONE. 2014; 9: e94890https://doi.org/10.1371/journal.pone.0094890
      ]. However, other studies have reported that undernutrition is not associated with poorer treatment outcomes [
      • Ejo M
      • Hassane-Harouna S
      • Souleymane MB
      • Lempens P
      • Dockx J
      • Uwizeye C
      • et al.
      Multidrug-resistant patients receiving treatment in Niger who are infected with M. tuberculosis Cameroon family convert faster in smear and culture than those with M. tuberculosis Ghana family.
      Tuberculosis (Edinb). 2020; 122101922https://doi.org/10.1016/j.tube.2020.101922
      ,
      • Kempker RR
      • Kipiani M
      • Mirtskhulava V
      • Tukvadze N
      • Magee MJ
      • Blumberg HM.
      Acquired drug resistance in Mycobacterium tuberculosis and poor outcomes among patients with multidrug-resistant tuberculosis.
      Emerg Infect Dis. 2015; 21: 992-1001https://doi.org/10.3201/eid2106.141873
      ]. This conflicting and inconsistent evidence in the existing literature indicates that a more comprehensive systematic review and meta-analysis is needed to quantify the effect of undernutrition on sputum culture conversion and treatment outcomes.
      Understanding the effect of nutritional status on treatment outcomes and disease progression is particularly important for people with MDR-TB because of the long duration of treatment. Although the WHO published guidelines on TB and nutrition 2013 [
      World Health Organization
      Nutritional care and support for patients with tuberculosis.
      World Health Organization, Geneva2013
      ], less attention has been paid to undertaking nutritional counseling and assessments and implementing targeted nutritional interventions for people with TB or MDR-TB. Although few meta-analyses have been conducted on various aspects of TB treatment outcomes and its associated factors in some parts of the African region [
      • Assemie MA
      • Alene M
      • Petrucka P
      • Leshargie CT
      • Ketema DB
      Time to sputum culture conversion and its associated factors among multidrug-resistant tuberculosis patients in eastern Africa: a systematic review and meta-analysis.
      Int J Infect Dis. 2020; 98: 230-236https://doi.org/10.1016/j.ijid.2020.06.029
      ,
      • Alemu A
      • Bitew ZW
      • Worku T.
      Poor treatment outcome and its predictors among drug-resistant tuberculosis patients in Ethiopia: a systematic review and meta-analysis.
      Int J Infect Dis. 2020; 98: 420-439https://doi.org/10.1016/j.ijid.2020.05.087
      ], there is limited evidence assessing the impacts of undernutrition on sputum culture conversion and treatment outcomes among people with MDR-TB. Therefore, a comprehensive meta-analysis that quantifies the effect of undernutrition on treatment outcomes for people with MDR-TB could provide important evidence for decision-making and service provision to improve the management and prevention of MDR-TB [
      • Podewils LJ
      • Holtz T
      • Riekstina V
      • Skripconoka V
      • Zarovska E
      • Kirvelaite G
      • et al.
      Impact of malnutrition on clinical presentation, clinical course, and mortality in MDR-TB patients.
      Epidemiol Infect. 2011; 139: 113-120https://doi.org/10.1017/S0950268810000907
      ]. We conducted this systematic review and meta-analysis to synthesize and determine the effects of undernutrition on sputum culture conversion and treatment outcomes for people with MDR-TB.

      Methods

      The protocol for this systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (CRD42022320754). It was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines (see details in S1: PRISMA checklist) [
      • Page MJ
      • McKenzie JE
      • Bossuyt PM
      • Boutron I
      • Hoffmann TC
      • Mulrow CD
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      Syst Rev. 2021; 10: 89https://doi.org/10.1186/s13643-021-01626-4
      ].

      Study selection and eligibility criteria

      Eligible studies were included as per our research question formulated using the Population, Exposure, Comparator, Outcomes, and Studies (PECOS) format.
      Population: Adults with MDR-TB/rifampicin-resistant TB aged 15 years and above, with bacteriologically confirmed MDR/ rifampicin-resistant-TB on phenotypic drug susceptibility testing, molecular methods using Xpert® MTB/RIF or line probe assay.
      Exposure: Undernutrition was considered an exposure, which was defined as BMI <18.5 kg/m2 [
      Centers for Disease Control and Prevention (U.S.)
      Body mass index (BMI): the Global Health Observatory: about Adult BMI.
      Centers for Disease Control and Prevention, Atlanta2021
      ]. BMI is the most reliable and inexpensive tool recommended by the Centers for Disease Control and WHO for measuring adult undernutrition [
      Centers for Disease Control and Prevention (U.S.)
      Body mass index (BMI): the Global Health Observatory: about Adult BMI.
      Centers for Disease Control and Prevention, Atlanta2021
      ]. BMI is computed by dividing the weight (in kilograms) by the square of height (in meters).
      Comparator: The comparator was people who had a normal BMI value (i.e., between 18.5 to 24.9 kg/m2) [
      Centers for Disease Control and Prevention (U.S.)
      Body mass index (BMI): the Global Health Observatory: about Adult BMI.
      Centers for Disease Control and Prevention, Atlanta2021
      ].
      Outcomes: The primary outcomes of interest were mortality and unsuccessful treatment outcome. Mortality was defined as a patient who died for any reason during MDR-TB treatment. Unsuccessful treatment outcome was defined as the sum of treatment failure, loss to follow-up, and death according to the WHO definitions [
      World Health Organization
      Definitions and reporting framework for tuberculosis–2013 revision: updated 2014 and January 2020.
      World Health Organization, Geneva2013
      ]. Whereas, a successful treatment outcome was defined as the sum of cure and treatment completion [
      World Health Organization
      Definitions and reporting framework for tuberculosis–2013 revision: updated 2014 and January 2020.
      World Health Organization, Geneva2013
      ].
      The secondary outcome of interest was sputum culture conversion—the transition in sputum culture results from a sample positive for Mycobacterium tuberculosis growth to two consecutive negative culture results at least 30 days apart.
      Studies: Interventional studies and observational studies such as cross-sectional, case-control, and cohort studies which provided sufficient data to determine the effect of undernutrition on treatment outcomes in people with MDR-TB were included. Both peer-reviewed articles and grey literature were included.

      Exclusion criteria

      Conference and meeting abstracts or papers published in languages other than English, qualitative, and animal studies were excluded. In addition, studies conducted among adults living with DS-TB or studies conducted exclusively among children or pregnant women were excluded.

      Search strategy

      We searched Embase (Ovid), Medline (Ovid), Scopus, and Web of Science databases from the inception of each database through to September 01, 2022, for peer-reviewed articles without restriction on geography and year of publication. Grey literature and reference lists of included studies were also retrieved. We used boolean operators and truncations during the searches. We utilized medical subject headings and relevant keywords to articulate the search map in the selected databases. The keywords used in the search strategy include “drug-resistant tuberculosis, undernutrition, BMI, underweight, nutritional deficiency, cure, treatment outcomes, death, and sputum culture conversion”. The search strategies for all databases are provided in Supplementary File 1.

      Screening of articles

      The articles retrieved from the databases were imported to Endnote, and then duplicates were removed. Titles, abstracts, and full-text screening were performed by the two independent authors (FW and KAA) as per a priori criteria. Any discrepancies were discussed and resolved by consensus.

      Risk of bias assessment

      The same two authors independently assessed the risk of bias for each included study using a modified version of the Newcastle-Ottawa Assessment scale [
      • Wells GA
      • Shea B
      • O'Connell D
      • Peterson J
      • Welch V
      • Losos M
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
      The Ottawa Hospital Research Institute, Oxford2000
      ]. The scores range from zero to nine for cohort studies and zero to ten for cross-sectional surveys, with three main sections: selection of study groups (four points); comparability of groups (two points); and ascertainment of exposure and outcomes (three points). A score below four was considered low quality, between five and seven, was considered moderate quality, and eight and above were considered high quality. The risk of bias assessment results is provided in the Supplementary File 2.

      Data extraction

      A standardized Joanna Briggs Institute data extraction form was used for data extraction. The tool was pilot-tested with a subset of eligible studies. It was refined based on the pilot testing. Data were extracted into a Microsoft Excel spreadsheet (Microsoft, Redmond, Washington, USA). Two authors (FW and KAA) independently extracted the necessary information from the included studies. Any dispute in extracted variables was adjudicated through discussion to reach a consensus. Where there was incomplete data, we contacted the corresponding authors via email and requested the missing data; one out of three authors answered.
      The following study variables were extracted: first author, year of publication, accrual period, country, region, study design, sample size, the mean or median age of participants, types of TB, and odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI). Where ORs with 95% CI were not reported in the eligible articles, we used numerator and denominator data and beta coefficients and their standard errors (if given) to calculate them.

      Data synthesis and analysis

      The characteristics of the included articles were summarized descriptively in tables, and outcomes were illustrated by forest plots. A random-effects meta-analysis model with a DerSimonian-Laird statistical method was used to pool the results of the included studies. The effect estimates were summarized using the HR for sputum culture conversion and OR for end-of-treatment outcomes, with 95% CI.
      Heterogeneity across the selected studies was examined quantitatively by calculating the heterogeneity squared index (I2) with corresponding P-values and qualitatively by visual inspection of forest plots [
      • Higgins JP
      • Thompson SG
      • Deeks JJ
      • Altman DG.
      Measuring inconsistency in meta-analyses.
      BMJ. 2003; 327: 557-560https://doi.org/10.1136/bmj.327.7414.557
      ]. The I2 statistic value –the proportion of total variation across studies attributable to heterogeneity but not chance– below 25% represents as low, between 25 to 75% represents moderate and above 75% represents as high heterogeneity across the studies. In the presence of substantial heterogeneity across the included studies, we performed a subgroup analysis based on the treatment regimen type, HIV prevalence, sample size, and the WHO regions to investigate the potential sources of heterogeneity.
      Visual inspection of Funnel plots and Egger's weighted regression test at a 5% significance level were used to test for potential publication bias and small-study effects. Data analyses were performed using STATA version 16.1 (STATA Corporation, College Station, TX, USA).

      Results

      Our search yielded 2358 publications. After removing 186 duplicates, 2172 unique articles were screened by reviewing their titles and abstracts, resulting in 92 potential full-text articles. After review, 63 studies comprising a total of 31,583 participants met our eligibility criteria (Figure 1).
      Figure 1
      Figure 1Flow diagram showing the study selection process for systematic review and meta-analysis of the effect of undernutrition on sputum culture conversion and treatment outcomes among people with multidrug-resistant-tuberculosis.

      Characteristics of the included studies

      The characteristics of the included studies are outlined in Table 1. All 63 included studies were published between 2005 and 2022. Study-specific sample sizes ranged from 60 in Bangladesh [
      • Heysell SK
      • Ahmed S
      • Ferdous SS
      • Khan MSR
      • Rahman SM
      • Gratz J
      • et al.
      Quantitative drug-susceptibility in patients treated for multidrug-resistant tuberculosis in Bangladesh: implications for regimen choice.
      PLoS One. 2015; 10e0116795https://doi.org/10.1371/journal.pone.0116795
      ] to 3712 in India [
      • Parmar MM
      • Sachdeva KS
      • Dewan PK
      • Rade K
      • Nair SA
      • Pant R
      • et al.
      Unacceptable treatment outcomes and associated factors among India's initial cohorts of multidrug-resistant tuberculosis (MDR-TB) patients under the revised national TB control programme (2007–2011): evidence leading to policy enhancement.
      PLoS One. 2018; 13e0193903https://doi.org/10.1371/journal.pone.0193903
      ]. The articles were from the six WHO regions: 28 from Africa [
      • Gonah L
      • Maphosa TM.
      Association of MDR-TB treatment outcomes and HIV status in Zimbabwe: a retrospective study.
      Cogent Med. 2020; 71783129https://doi.org/10.1080/2331205X.2020.1783129
      ,
      • Ejo M
      • Hassane-Harouna S
      • Souleymane MB
      • Lempens P
      • Dockx J
      • Uwizeye C
      • et al.
      Multidrug-resistant patients receiving treatment in Niger who are infected with M. tuberculosis Cameroon family convert faster in smear and culture than those with M. tuberculosis Ghana family.
      Tuberculosis (Edinb). 2020; 122101922https://doi.org/10.1016/j.tube.2020.101922
      ,
      • Alakaye OJ.
      Time to sputum culture conversion of multidrug-Resistant tuberculosis in HIV positive versus HIV negative patients in Lesotho [dissertation].
      University of Pretoria, Pretoria2018
      ,
      • Alene KA
      • Viney K
      • McBryde ES
      • Tsegaye AT
      • Clements AC.
      Treatment outcomes in patients with multidrug-resistant tuberculosis in north-west Ethiopia.
      Trop Med Int Health. 2017; 22: 351-362https://doi.org/10.1111/tmi.12826
      ,
      • Aragaw N
      • Teferi M
      • Ali O
      • Tesema E
      • Ayele S
      • Jarso H
      • et al.
      Treatment outcomes and predictors of outcome in multidrug resistance tuberculosis (MDR-TB) cohort of patients in Addis Ababa.
      Ethiopia. Am J Health Res. 2021; 9: 204-212https://doi.org/10.11648/j.ajhr.20210905.19
      ,
      • Bade AB
      • Mega TA.
      Survival status and its predictors among multi-drug resistance tuberculosis treated patients in Ethiopia: multicenter observational study.
      PLoS One. 2020; 15e0241684https://doi.org/10.1371/journal.pone.0241684
      ,
      • Bade AB
      • Mega TA
      • Negera GZ.
      Malnutrition is associated with delayed sputum culture conversion among patients treated for MDR-TB.
      Infect Drug Resist. 2021; 14: 1659-1667https://doi.org/10.2147/IDR.S293461
      ,
      • Bakare AM
      • Udunze OC
      • Bamidele JO
      • Omoniyi A
      • Osman E
      • Daniel OJ.
      Outcome of community-initiated treatment of drug-resistant tuberculosis patients in Lagos, Nigeria.
      Trans R Soc Trop Med Hyg. 2021; 115: 1061-1065https://doi.org/10.1093/trstmh/traa188
      ,
      • Belachew T
      • Yaheya S
      • Tilahun N
      • Gebrie E
      • Seid R
      • Nega T
      • et al.
      Multidrug-resistant tuberculosis treatment outcome and associated factors at the university of Gondar comprehensive specialized hospital: a ten-year retrospective study.
      Infect Drug Resist. 2022; 15: 2891-2899https://doi.org/10.2147/IDR.S365394
      ,

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      • Cegielski JP
      • Kurbatova E
      • Van Der Walt M
      • Brand J
      • Ershova J
      • Tupasi T
      • et al.
      Multidrug-resistant tuberculosis treatment outcomes in relation to treatment and initial versus acquired second-line drug resistance.
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      • Diallo A
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      ] to 52.9 years [
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      ] (Table 1).
      Table 1Summary of included studies reporting the effect of undernutrition on mortality, unsuccessful outcome and sputum culture conversions among people with MDR-TB.
      NoNameYearStudy designCountryRegion by World Health OrganizationSample sizeOutcomesMean/ median, ageType of TBOdds ratio for outcomesHIV prevalenceTreatment regimen
      1Bade and Mega
      • Bade AB
      • Mega TA.
      Survival status and its predictors among multi-drug resistance tuberculosis treated patients in Ethiopia: multicenter observational study.
      PLoS One. 2020; 15e0241684https://doi.org/10.1371/journal.pone.0241684
      		2019Retrospective cohortEthiopiaAfrica200Mortality32.9 yrs
      mean age the participants;
      		MDR-TB2.4622.00%Longer regimen
      2Woldeyohannes et al.
      • Woldeyohannes D
      • Assefa T
      • Aman R
      • Tekalegn Y
      • Hailemariam Z.
      Predictors of time to unfavorable treatment outcomes among patients with multidrug resistant tuberculosis in Oromia region.
      Ethiopia. PLoS One. 2019; 14e0224025https://doi.org/10.1371/journal.pone.0224025
      		2012-2017Retrospective cohortEthiopiaAfrica406Mortality28.0 yrs
      median age of the participants. D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.
      		All DR-TB1.450.50%Longer regimen
      3Kassa et al.
      • Kashongwe IM
      • Mbulula L
      • Mawete F
      • Anshambi N
      • Maingowa N
      • Kaswa M
      • et al.
      Implementing a short regimen for multidrug-resistant tuberculosis in Kinshasa, Democratic Republic of Congo: a cohort study 2014–2017.
      J Tuberc Res. 2020; 08: 111-126https://doi.org/10.4236/jtr.2020.83010
      		2010-2017Retrospective cohortEthiopiaAfrica451Mortality31.3 yrs
      mean age the participants;
      		All DR-TB2.3926.00%Both
      4Gebre, 2019
      • Diallo A
      • Diallo BD
      • Camara LM
      • Kounoudji LAN
      • Bah B
      • N'Zabintawali F
      • et al.
      Different profiles of body mass index variation among patients with multidrug-resistant tuberculosis: a retrospective cohort study.
      BMC Infect Dis. 2020; 20: 315https://doi.org/10.1186/s12879-020-05028-0
      		2012-2017Retrospective cohortEthiopiaAfrica362Mortality31.0 yrs
      median age of the participants. D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.
      		All DR-TB2.3521.00%Longer regimen
      5Alene et al.
      • Alene KA
      • Viney K
      • McBryde ES
      • Tsegaye AT
      • Clements AC.
      Treatment outcomes in patients with multidrug-resistant tuberculosis in north-west Ethiopia.
      Trop Med Int Health. 2017; 22: 351-362https://doi.org/10.1111/tmi.12826
      		2010-2015Retrospective cohortEthiopiaAfrica189Unsuccessful30.0 yrsMDR-TB1.4422.20%Longer regimen
      6Woldeyohannes et al.
      • Tekalegn Y
      • Woldeyohannes D
      • Assefa T
      • Aman R
      • Sahiledengle B.
      Predictors of time to sputum culture conversion among drug-resistant tuberculosis patients in Oromia region hospitals.
      Ethiopia. Infect Drug Resist. 2020; 13: 2547-2556https://doi.org/10.2147/IDR.S250878
      		2012-2017Retrospective cohortEthiopiaAfrica415Unsuccessful28.0 yrs
      median age of the participants. D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.
      		MDR-TB3.2618.60%Longer regimen
      7Samali
      • Piubello A
      • Souleymane MB
      • Hassane-Harouna S
      • Yacouba A
      • Lempens P
      • Assao-Neino MM
      • et al.
      Management of multidrug-resistant tuberculosis with shorter treatment regimen in Niger: nationwide programmatic achievements.
      Respir Med. 2020; 161105844https://doi.org/10.1016/j.rmed.2019.105844
      		2009-2016Retrospective cohortTanzaniaAfrica583Mortality37.4 yrs
      mean age the participants;
      		MDR-TB3.0134.80%Longer regimen
      8Chung-Delgado et al.
      • Yu MC
      • Chiang CY
      • Lee JJ
      • Chien ST
      • Lin CJ
      • Lee SW
      • et al.
      Treatment outcomes of multidrug-resistant tuberculosis in Taiwan: tackling loss to follow-up.
      Clin Infect Dis. 2018; 67: 202-210https://doi.org/10.1093/cid/ciy066
      		2000-2012Retrospective cohortPeruAmerica1232Mortality30.9 yrs
      mean age the participants;
      		MDR-TB2.541.62%Not specify
      9Leimane et al.
      • Khachatryan L
      • Grigoryan R
      • Dadu A
      • Kumar AMV
      • Akopyan K
      • Dumchev K
      • et al.
      Factors associated with unfavourable treatment outcomes among people with rifampicin-resistant tuberculosis in Armenia, 2014–2017.
      Monaldi Arch Chest Dis. 2021; 91: 1677https://doi.org/10.4081/monaldi.2021.1677
      		2000Retrospective cohortLatviaEurope172UnsuccessfulMale: 43.0 yrs
      median age of the participants. D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.


      female:39.0 yrs      		All DR-TB2.000.58%Longer regimen
      10Schwœbel et al.
      • Samali A.
      Predictors of mortality among multidrug resistance tuberculosis patients admitted at Kibong'oto hospital from 2009–2016[dissertation].
      Muhimbili University of Health and Allied Sciences, Tanzania2017
      		2013-2015Retrospective cohort9 Africa countriesAfrica1006UnsuccessfulNAAll DR-TB1.9119.90%

      		Shorter regimen
      11du Cros et al.
      • Velayutham B
      • Nair D
      • Kannan T
      • Padmapriyadarsini C
      • Sachdeva KS
      • Bency J
      • et al.
      Factors associated with sputum culture conversion in multidrug-resistant pulmonary tuberculosis.
      Int J Tuberc Lung Dis. 2016; 20: 1671-1676https://doi.org/10.5588/ijtld.16.0096
      		2013-2015Prospective cohortUzbekistanEurope128Unsuccessful30.1 yrs
      median age of the participants. D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.
      		All DR-TB0.940.00%Shorter regimen
      12Mengistu
      • Kassa GM
      • Teferra AS
      • Wolde HF
      • Muluneh AG
      • Merid MW.
      Incidence and predictors of lost to follow-up among drug-resistant tuberculosis patients at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia: a retrospective follow-up study.
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      Infect Drug Resist. 2021; 14: 1659-1667https://doi.org/10.2147/IDR.S293461
      		2013-2019Retrospective cohortEthiopiaAfrica200Culture conversion32.9 yrs
      mean age the participants;
      		MDR-TBNA22.00%Longer regimen
      56Diallo et al.
      • Cegielski JP
      • Kurbatova E
      • Van Der Walt M
      • Brand J
      • Ershova J
      • Tupasi T
      • et al.
      Multidrug-resistant tuberculosis treatment outcomes in relation to treatment and initial versus acquired second-line drug resistance.
      Clin Infect Dis. 2016; 62: 418-430https://doi.org/10.1093/cid/civ910
      		2016-2018Retrospective cohortGuineaAfrica165Culture conversion34.0 yrs
      mean age the participants;
      		All DR-TBNA25.50%Shorter regimen
      57Podewils et al.
      • Podewils LJ
      • Holtz T
      • Riekstina V
      • Skripconoka V
      • Zarovska E
      • Kirvelaite G
      • et al.
      Impact of malnutrition on clinical presentation, clinical course, and mortality in MDR-TB patients.
      Epidemiol Infect. 2011; 139: 113-120https://doi.org/10.1017/S0950268810000907
      		2000-2004Retrospective cohortLatviaEurope995Culture conversion-MDR-TBNA3.20%Longer regimen
      58Velayutham et al.
      • Soeroto AY
      • Pratiwi C
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      Factors affecting outcome of longer regimen multidrug-resistant tuberculosis treatment in west Java Indonesia: a retrospective cohort study.
      PLoS One. 2021; 16e0246284https://doi.org/10.1371/journal.pone.0246284
      		2009-2011Retrospective cohortIndiaSouth-East Asia787Culture conversion-All DR-TBNA3.83%Longer regimen
      59Kassa et al.
      • Kassa GM
      • Tadesse A
      • Gelaw YA
      • Alemayehu TT
      • Tsegaye AT
      • Tamirat KS
      • et al.
      Predictors of mortality among multidrug-resistant tuberculosis patients in central Ethiopia: a retrospective follow-up study.
      Epidemiol Infect. 2020; 148: e258https://doi.org/10.1017/S0950268820002514
      		2010-2017Retrospective cohortEthiopiaAfrica332Loss to follow-up30.0
      median age of the participants. D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.
      		All DR-TB1.31UnknownLonger regimen
      60Tupasi et al.
      • Tang S
      • Tan S
      • Yao L
      • Li F
      • Li L
      • Guo X
      • et al.
      Risk factors for poor treatment outcomes in patients with MDR-TB and XDR-TB in China: retrospective multi-center investigation.
      PLoS One. 2013; 8: e82943https://doi.org/10.1371/journal.pone.0082943
      		20212-2014Case-controlPhilippinesWestern Pacific273Loss to follow-up40.0
      median age of the participants. D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.
      		MDR-TB1.17UnknownLonger regimen
      61Yu et al.
      • Tupasi TE
      • Garfin AMCG
      • Kurbatova EV
      • Mangan JM
      • Orillaza-Chi R
      • Naval LC
      • et al.
      Factors associated with loss to follow-up during treatment for multidrug-resistant tuberculosis, the Philippines, 2012–2014.
      Emerg Infect Dis. 2016; 22: 491-502https://doi.org/10.3201/eid2203.151788
      		2007-2012Retrospective cohortTaiwanWestern Pacific686Loss to follow-up52.9
      mean age the participants;
      		MDR-TB1.03UnknownLonger regimen
      62Soedarsono et al.
      • Sharma N
      • Khanna A
      • Chandra S
      • Basu S
      • Chopra KK
      • Singla N
      • et al.
      Trends & treatment outcomes of multidrug-resistant tuberculosis in Delhi, India (2009–2014): a retrospective record-based study.
      Indian J Med Res. 2020; 151: 598-603https://doi.org/10.4103/ijmr.IJMR_1048_18
      		2017-2021Cross-sectionalIndonesiaSouth-East Asia280Loss to follow-upNAAll DR-TB1.58UnknownLonger regimen
      63Belachew et al.
      • Belachew T
      • Yaheya S
      • Tilahun N
      • Gebrie E
      • Seid R
      • Nega T
      • et al.
      Multidrug-resistant tuberculosis treatment outcome and associated factors at the university of Gondar comprehensive specialized hospital: a ten-year retrospective study.
      Infect Drug Resist. 2022; 15: 2891-2899https://doi.org/10.2147/IDR.S365394
      		2011-2021Retrospective cohortEthiopiaAfrica389Unsuccessful32.4
      mean age the participants;
      		MDR-TB1.7825.00%Not specify
      a mean age the participants;
      b median age of the participants.D: article reporting two outcomes; HR: hazard ratio; MDR-TB: multidrug-resistant TB; NA: not available; TB, tuberculosis; yrs: years.

      Effect of undernutrition on sputum culture conversion

      Eleven cohort studies [
      • Magee MJ
      • Kempker RR
      • Kipiani M
      • Tukvadze N
      • Howards PP
      • Narayan KM
      • et al.
      Diabetes mellitus, smoking status, and rate of sputum culture conversion in patients with multidrug-resistant tuberculosis: a cohort study from the country of Georgia.
      PLOS ONE. 2014; 9: e94890https://doi.org/10.1371/journal.pone.0094890
      ,
      • Podewils LJ
      • Holtz T
      • Riekstina V
      • Skripconoka V
      • Zarovska E
      • Kirvelaite G
      • et al.
      Impact of malnutrition on clinical presentation, clinical course, and mortality in MDR-TB patients.
      Epidemiol Infect. 2011; 139: 113-120https://doi.org/10.1017/S0950268810000907
      ,
      • Parmar MM
      • Sachdeva KS
      • Dewan PK
      • Rade K
      • Nair SA
      • Pant R
      • et al.
      Unacceptable treatment outcomes and associated factors among India's initial cohorts of multidrug-resistant tuberculosis (MDR-TB) patients under the revised national TB control programme (2007–2011): evidence leading to policy enhancement.
      PLoS One. 2018; 13e0193903https://doi.org/10.1371/journal.pone.0193903
      ,
      • Alakaye OJ.
      Time to sputum culture conversion of multidrug-Resistant tuberculosis in HIV positive versus HIV negative patients in Lesotho [dissertation].
      University of Pretoria, Pretoria2018
      ,
      • Bade AB
      • Mega TA
      • Negera GZ.
      Malnutrition is associated with delayed sputum culture conversion among patients treated for MDR-TB.
      Infect Drug Resist. 2021; 14: 1659-1667https://doi.org/10.2147/IDR.S293461
      ,
      • Diallo A
      • Diallo BD
      • Camara LM
      • Kounoudji LAN
      • Bah B
      • N'Zabintawali F
      • et al.
      Different profiles of body mass index variation among patients with multidrug-resistant tuberculosis: a retrospective cohort study.
      BMC Infect Dis. 2020; 20: 315https://doi.org/10.1186/s12879-020-05028-0
      ,
      • Shibabaw A
      • Gelaw B
      • Wang SH
      • Tessema B.
      Time to sputum smear and culture conversions in multidrug resistant tuberculosis at University of Gondar Hospital, Northwest Ethiopia.
      PLoS One. 2018; 13e0198080https://doi.org/10.1371/journal.pone.0198080
      ,
      • Tekalegn Y
      • Woldeyohannes D
      • Assefa T
      • Aman R
      • Sahiledengle B.
      Predictors of time to sputum culture conversion among drug-resistant tuberculosis patients in Oromia region hospitals.
      Ethiopia. Infect Drug Resist. 2020; 13: 2547-2556https://doi.org/10.2147/IDR.S250878
      ,
      • Park HO
      • Kim SH
      • Moon SH
      • Byun JH
      • Kim JW
      • Lee CE
      • et al.
      Association between body mass index and sputum culture conversion among South Korean patients with multidrug resistant tuberculosis in a tuberculosis referral hospital.
      Infect Chemother. 2016; 48: 317-323https://doi.org/10.3947/ic.2016.48.4.317
      ,
      • Velayutham B
      • Nair D
      • Kannan T
      • Padmapriyadarsini C
      • Sachdeva KS
      • Bency J
      • et al.
      Factors associated with sputum culture conversion in multidrug-resistant pulmonary tuberculosis.
      Int J Tuberc Lung Dis. 2016; 20: 1671-1676https://doi.org/10.5588/ijtld.16.0096
      ,
      • Tierney DB
      • Franke MF
      • Becerra MC
      • Alcántara Virú FA
      • Bonilla CA
      • Sánchez E
      • et al.
      Time to culture conversion and regimen composition in multidrug-resistant tuberculosis treatment.
      PLoS One. 2014; 9e108035https://doi.org/10.1371/journal.pone.0108035
      ] reported the effect of undernutrition on sputum culture conversion. Five cohort studies were not suited to meta-analysis because they considered BMI as a continuous variable or they used different categories of BMI (Table 1). Of these, three studies [
      • Bade AB
      • Mega TA
      • Negera GZ.
      Malnutrition is associated with delayed sputum culture conversion among patients treated for MDR-TB.
      Infect Drug Resist. 2021; 14: 1659-1667https://doi.org/10.2147/IDR.S293461
      ,
      • Velayutham B
      • Nair D
      • Kannan T
      • Padmapriyadarsini C
      • Sachdeva KS
      • Bency J
      • et al.
      Factors associated with sputum culture conversion in multidrug-resistant pulmonary tuberculosis.
      Int J Tuberc Lung Dis. 2016; 20: 1671-1676https://doi.org/10.5588/ijtld.16.0096
      ,
      • Tierney DB
      • Franke MF
      • Becerra MC
      • Alcántara Virú FA
      • Bonilla CA
      • Sánchez E
      • et al.
      Time to culture conversion and regimen composition in multidrug-resistant tuberculosis treatment.
      PLoS One. 2014; 9e108035https://doi.org/10.1371/journal.pone.0108035
      ] determined that undernutrition was significantly associated with delayed sputum culture conversion. The other two studies [
      • Podewils LJ
      • Holtz T
      • Riekstina V
      • Skripconoka V
      • Zarovska E
      • Kirvelaite G
      • et al.
      Impact of malnutrition on clinical presentation, clinical course, and mortality in MDR-TB patients.
      Epidemiol Infect. 2011; 139: 113-120https://doi.org/10.1017/S0950268810000907
      ,
      • Diallo A
      • Diallo BD
      • Camara LM
      • Kounoudji LAN
      • Bah B
      • N'Zabintawali F
      • et al.
      Different profiles of body mass index variation among patients with multidrug-resistant tuberculosis: a retrospective cohort study.
      BMC Infect Dis. 2020; 20: 315https://doi.org/10.1186/s12879-020-05028-0
      ] indicated that patients with low BMI were associated with delayed sputum culture conversion.
      Our meta-analysis showed that undernutrition was significantly associated with a longer time to sputum culture conversion at the end of treatment (HR 0.7, 95% CI 0.6-0.9, I2 = 67.1%) (Figure 2).
      Figure 2
      Figure 2The pooled effect of undernutrition on sputum culture conversion among people with multidrug-resistant-tuberculosis.
      REML, Restricted maximum likelihood.

      Effect of undernutrition on mortality

      Nine studies representing 4904 people with MDR-TB were included in the meta-analysis to determine the effect of undernutrition on mortality among people with MDR-TB. Patients with a BMI of less than 18.5 kg/m2 had 2.8 times higher odds of death compared to those patients with normal BMI values (OR 2.8, 95% CI 2.1-3.6, I2 = 21%) (Figure 3).
      Figure 3
      Figure 3The pooled effect of undernutrition on mortality among people with multidrug-resistant-tuberculosis.
      REML, Restricted maximum likelihood.

      The effect of undernutrition on unsuccessful treatment outcomes

      We identified 43 studies representing 21,266 people with MDR-TB which reported the association between undernutrition and unsuccessful treatment outcomes. Among these, three studies were not suited for inclusion in the meta-analysis as they considered BMI as a continuous variable or used different BMI categories than the ones used in our study [
      • Heysell SK
      • Ahmed S
      • Ferdous SS
      • Khan MSR
      • Rahman SM
      • Gratz J
      • et al.
      Quantitative drug-susceptibility in patients treated for multidrug-resistant tuberculosis in Bangladesh: implications for regimen choice.
      PLoS One. 2015; 10e0116795https://doi.org/10.1371/journal.pone.0116795
      ,
      • Bakare AM
      • Udunze OC
      • Bamidele JO
      • Omoniyi A
      • Osman E
      • Daniel OJ.
      Outcome of community-initiated treatment of drug-resistant tuberculosis patients in Lagos, Nigeria.
      Trans R Soc Trop Med Hyg. 2021; 115: 1061-1065https://doi.org/10.1093/trstmh/traa188
      ,
      • Jeon DS
      • Shin DO
      • Park SK
      • Seo JE
      • Seo HS
      • Cho YS
      • et al.
      Treatment outcome and mortality among patients with multidrug-resistant tuberculosis in tuberculosis hospitals of the public sector.
      J Korean Med Sci. 2011; 26: 33-41https://doi.org/10.3346/jkms.2011.26.1.33
      ]. Of the 40 included studies, 22 showed that undernutrition was associated with unsuccessful treatment outcomes, whereas 18 studies found no association.
      When the study results were pooled together using meta-analysis, those patients with undernutrition were 1.8 times more likely to have unsuccessful treatment outcomes (OR 1.8, 95% CI 1.5-2.1, I2 = 70%) than those patients with normal BMI values (Figure 4).
      Figure 4
      Figure 4The pooled effect of undernutrition on unsuccessful treatment outcomes among people with multidrug-resistant-tuberculosis.
      REML, Restricted maximum likelihood.

      The effect of undernutrition on loss to follow-up and treatment failure

      In total, six studies [
      • Cegielski JP
      • Kurbatova E
      • Van Der Walt M
      • Brand J
      • Ershova J
      • Tupasi T
      • et al.
      Multidrug-resistant tuberculosis treatment outcomes in relation to treatment and initial versus acquired second-line drug resistance.
      Clin Infect Dis. 2016; 62: 418-430https://doi.org/10.1093/cid/civ910
      ,
      • Kassa GM
      • Teferra AS
      • Wolde HF
      • Muluneh AG
      • Merid MW.
      Incidence and predictors of lost to follow-up among drug-resistant tuberculosis patients at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia: a retrospective follow-up study.
      BMC Infect Dis. 2019; 19: 817https://doi.org/10.1186/s12879-019-4447-8
      ,
      • Soedarsono S
      • Mertaniasih NM
      • Kusmiati T
      • Permatasari A
      • Juliasih NN
      • Hadi C
      • et al.
      Determinant factors for loss to follow-up in drug-resistant tuberculosis patients: the importance of psycho-social and economic aspects.
      BMC Pulm Med. 2021; 21: 360https://doi.org/10.1186/s12890-021-01735-9
      ,
      • Tupasi TE
      • Garfin AMCG
      • Kurbatova EV
      • Mangan JM
      • Orillaza-Chi R
      • Naval LC
      • et al.
      Factors associated with loss to follow-up during treatment for multidrug-resistant tuberculosis, the Philippines, 2012–2014.
      Emerg Infect Dis. 2016; 22: 491-502https://doi.org/10.3201/eid2203.151788
      ,
      • Yu MC
      • Chiang CY
      • Lee JJ
      • Chien ST
      • Lin CJ
      • Lee SW
      • et al.
      Treatment outcomes of multidrug-resistant tuberculosis in Taiwan: tackling loss to follow-up.
      Clin Infect Dis. 2018; 67: 202-210https://doi.org/10.1093/cid/ciy066
      ,
      • Wahid A
      • Ahmad N
      • Ghafoor A
      • Latif A
      • Saleem F
      • Khan S
      • et al.
      Effectiveness of shorter treatment regimen in multidrug-resistant tuberculosis patients in Pakistan: a multicenter retrospective record review.
      Am J Trop Med Hyg. 2021; 104: 1784-1791https://doi.org/10.4269/ajtmh.20-1134
      ] reported the effect of undernutrition on loss to follow-up and three [
      • Diallo A
      • Diallo BD
      • Camara LM
      • Kounoudji LAN
      • Bah B
      • N'Zabintawali F
      • et al.
      Different profiles of body mass index variation among patients with multidrug-resistant tuberculosis: a retrospective cohort study.
      BMC Infect Dis. 2020; 20: 315https://doi.org/10.1186/s12879-020-05028-0
      ,
      • Ige OM
      • Oladokun RE.
      Time to sputum culture conversion and treatment outcome among the first cohort of multidrug resistant tuberculosis patients in a high burden country.
      Indian J Tuberc. 2018; 65: 322-328https://doi.org/10.1016/j.ijtb.2018.07.006
      ,
      • Kurbatova EV
      • Taylor A
      • Gammino VM
      • Bayona J
      • Becerra M
      • Danilovitz M
      • et al.
      Predictors of poor outcomes among patients treated for multidrug-resistant tuberculosis at DOTS-plus projects.
      Tuberculosis (Edinb). 2012; 92: 397-403https://doi.org/10.1016/j.tube.2012.06.003
      ] studies reported the effects of undernutrition on treatment failure. The pooled effect size estimate showed that undernutrition had no significant impact on loss to follow-up (OR 1.0, 95% CI 0.8-1.4, I2 = 27%) but was associated with a higher risk of treatment failure (OR 3.2, 95% CI 1.1-9.3, I2 = 75%) (Figures S1 and S2)

      Subgroup analyses

      We performed subgroup analyses based on the treatment regimen used, HIV prevalence in the study setting, sample size, and the WHO region where research was conducted, as there was substantial heterogeneity across included studies. The pooled effect of undernutrition on mortality and unsuccessful outcomes did not differ significantly by study characteristics. However, there was no significant association between undernutrition and unsuccessful treatment outcomes among people with MDR-TB who received only the short treatment regimen (OR 1.27, 95% CI 0.9-1.82, I2 = 62%) (Table 2).
      Table 2Pooled effect of undernutrition on mortality and unsuccessful treatment outcomes among people with MDR-TB by study characteristics (subgroup analysis).
      MortalityUnsuccessful
      CategoryNo of studiesPooled effect size OR (95% CI), I2 heterogeneityNo of studiesPooled effect size OR (95% CI), I2 heterogeneity
      World Health Organization regions
       Africa62.48 (1.74, 3.55), I2 = 0%151.57 (1.22, 2.01), I2 = 66%
       South-East Asia--132.33 (1.77, 3.07), I2 = 77%
       Europe--61.53 (1.12, 2.09), I2 = 52%
       Western Pacific12.28 (1.34, 3.84), I2 =.%41.63 (1.2, 2.24), I2 = 43%
       Eastern Mediterranean--21.22 (0.39, 3.79), I2 = 68%
       Americas12.54 (1.45, 4.44), I2 =.%--
       Mixed regions14.11 (2.69, 6.27), I2 =.%--
      Sample size
       <38533.10 (1.78, 5.38), I2 = 0%231.88 (1.44, 2.45), I2 =65%
       ≥38562.66 (1.95, 3.62), I2 = 33%171.69 (1.43, 1.99), I2 = 70%
      HIV prevalence
      median HIV prevalence. OR: odds ratio; I2: % indicates that the subcategory only included one study.
       HIV negative--52.12 (1.05, 4.25), I2 = 81%
       <9.7%32.64 (1.49, 4.68), I2 = 67%151.82 (1.63, 2.02), I2 = 3%
       ≥ 9.7%52.89 (1.93, 4.34), I2 = 0%151.73 (1.27, 2.34), I2 = 80%
       Unknown12.28 (1.34, 3.89), I2 =.%51.56 (1.1, 2.52), I2 = 49%
      Treatment regimen
      Short--81.27 (0.9, 1.82), I2 = 62%
      Long72.81 (2.01, 3.93), I2 = 33%261.9 (1.62, 2.31), I2 = 71%
      Both12.39 (1.04, 5.49), I2 =.%31.49 (1.06, 2.09), I2 = 16%
      Not specify12.54 (1.45, 4.44), I2 =.%32.27 (1.65, 3.11), I2 = 0%
      a median HIV prevalence.OR: odds ratio; I2: % indicates that the subcategory only included one study.

      Publication bias and study quality

      Overall, three studies were low, 45 studies were moderate and 15 studies were high quality (Supplementary File 2).
      There was no statistically significant publication bias for the outcomes of interest, as determined by Funnel plots and Egger's test (Figures S3, S4, S5).

      Discussion

      We analyzed data from 63 studies comprising 31,583 people with MDR-TB. The results of this meta-analysis showed that undernutrition was significantly associated with unsuccessful treatment outcomes, mortality, and delayed sputum culture conversion among people with MDR-TB.
      Bacteriological sputum conversion status is a marker of the response to treatment [
      • Kanda R
      • Nagao T
      • Tho NV
      • Ogawa E
      • Murakami Y
      • Osawa M
      • et al.
      Factors affecting time to sputum culture conversion in adults with pulmonary tuberculosis: a historical cohort study without censored cases.
      PLoS One. 2015; 10e0142607https://doi.org/10.1371/journal.pone.0142607
      ]. Delayed time to sputum culture conversion could potentially increase the risk of transmission in the community. Our systematic review and meta-analysis found that undernutrition was associated with delayed sputum culture conversion among people with MDR-TB at the end of treatment, which is in line with a previous meta-analysis [
      • Assemie MA
      • Alene M
      • Petrucka P
      • Leshargie CT
      • Ketema DB
      Time to sputum culture conversion and its associated factors among multidrug-resistant tuberculosis patients in eastern Africa: a systematic review and meta-analysis.
      Int J Infect Dis. 2020; 98: 230-236https://doi.org/10.1016/j.ijid.2020.06.029
      ]. A study carried out in India has also reported that undernutrition has heightened the disease severity, the radiographic extent of the disease, and long-term pulmonary complications such as chronic sequelae [
      • Hoyt KJ
      • Sarkar S
      • White L
      • Joseph NM
      • Salgame P
      • Lakshminarayanan S
      • et al.
      Effect of malnutrition on radiographic findings and mycobacterial burden in pulmonary tuberculosis.
      PLoS One. 2019; 14e0214011https://doi.org/10.1371/journal.pone.0214011
      ]. The association between undernutrition and chronic sequelae may be because of high mycobacterium load, bilateral cavitation, and far-advanced lung disease [
      • Van Lettow M
      • Kumwenda JJ
      • Harries AD
      • Whalen CC
      • Taha TE
      • Kumwenda N
      • et al.
      Malnutrition and the severity of lung disease in adults with pulmonary tuberculosis in Malawi.
      Int J Tuberc Lung Dis. 2004; 8: 211-217
      ]. A severe form of pulmonary TB may create bilateral cavitation in the lung parenchyma, which can be associated with a higher mycobacterium load [
      • Perrin FM
      • Woodward N
      • Phillips PP
      • McHugh TD
      • Nunn AJ
      • Lipman MC
      • et al.
      Radiological cavitation, sputum mycobacterial load and treatment response in pulmonary tuberculosis.
      Int J Tuberc Lung Dis. 2010; 14: 1596-1602
      ] and increase the likelihood of having a prolonged time to sputum culture conversion. Therefore, nutritional counseling and supplementation during TB treatment might be associated with boosted immune function and bacterial clearance which might improve early sputum culture conversion [
      • Paton NI
      • Chua YK
      • Earnest A
      • Chee CB.
      Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting.
      Am J Clin Nutr. 2004; 80: 460-465https://doi.org/10.1093/ajcn/80.2.460
      ].
      Our study found that undernutrition was significantly associated with increased mortality and unsuccessful treatment outcomes. This finding is in line with previous systematic reviews reporting higher mortality in people living with MDR-TB and undernutrition [
      • Alemu A
      • Bitew ZW
      • Worku T.
      Poor treatment outcome and its predictors among drug-resistant tuberculosis patients in Ethiopia: a systematic review and meta-analysis.
      Int J Infect Dis. 2020; 98: 420-439https://doi.org/10.1016/j.ijid.2020.05.087
      ,
      • Johnston JC
      • Shahidi NC
      • Sadatsafavi M
      • Fitzgerald JM.
      Treatment outcomes of multidrug-resistant tuberculosis: a systematic review and meta-analysis.
      PLoS One. 2009; 4: e6914https://doi.org/10.1371/journal.pone.0006914
      ]. Another report by the WHO indicated that low BMI and lack of weight gain during treatment follow-up are associated with an increased risk of death, TB relapse, and adverse drug reactions [
      World Health Organization
      Nutritional care and support for patients with tuberculosis.
      World Health Organization, Geneva2013
      ]. There are several explanations for these unsuccessful outcomes. First, undernutrition alters the immune status of people with TB, rendering them prone to severe TB infection [
      • Podewils LJ
      • Holtz T
      • Riekstina V
      • Skripconoka V
      • Zarovska E
      • Kirvelaite G
      • et al.
      Impact of malnutrition on clinical presentation, clinical course, and mortality in MDR-TB patients.
      Epidemiol Infect. 2011; 139: 113-120https://doi.org/10.1017/S0950268810000907
      ,
      • Scrimshaw NS
      • SanGiovanni JP.
      Synergism of nutrition, infection, and immunity: an overview.
      Am J Clin Nutr. 1997; 66 (464S–77S)https://doi.org/10.1093/ajcn/66.2.464S
      ]. Undernutrition also decreases the concentration of interleukin-2 receptors and interferon-γ, immunoglobulins, and T-helper cells [
      • Scrimshaw NS
      • SanGiovanni JP.
      Synergism of nutrition, infection, and immunity: an overview.
      Am J Clin Nutr. 1997; 66 (464S–77S)https://doi.org/10.1093/ajcn/66.2.464S
      ]. Second, undernutrition may result in supra-therapeutic or sub-therapeutic serum concentration of TB medicines [
      • Ahmad N
      • Javaid A
      • Basit A
      • Afridi AK
      • Khan MA
      • Ahmad I
      • et al.
      Management and treatment outcomes of MDR-TB: results from a setting with high rates of drug resistance.
      Int J Tuberc Lung Dis. 2015; 19: 1109-1114https://doi.org/10.5588/ijtld.15.0167
      ,
      • Javaid A
      • Shaheen Z
      • Shafqat M
      • Khan AH
      • Ahmad N.
      Risk factors for high death and loss-to-follow-up rates among patients with multidrug-resistant tuberculosis at a programmatic management unit.
      Am J Infect Control. 2017; 45: 190-193https://doi.org/10.1016/j.ajic.2016.07.026
      ,
      • Khan I
      • Ahmad N
      • Khan S
      • Muhammad S
      • Ahmad Khan SA
      • Ahmad I
      • et al.
      Evaluation of treatment outcomes and factors associated with unsuccessful outcomes in multidrug resistant tuberculosis patients in Baluchistan province of Pakistan.
      J Infect Public Health. 2019; 12: 809-815https://doi.org/10.1016/j.jiph.2019.04.009
      ,
      • Ter Beek L
      • Alffenaar J-WC
      • Bolhuis MS
      • van der Werf TS
      • Akkerman OW
      Tuberculosis-related malnutrition: public health implications.
      J Infect Dis. 2019; 220: 340-341https://doi.org/10.1093/infdis/jiz091
      ]. Undernutrition is thought to be a contributing factor for adverse drug reactions throughout treatment by decreasing fat-free mass and TB drug bioavailability. Adverse drug reactions can often lead to non-compliance or treatment interruptions [
      • Ter Beek L
      • Alffenaar J-WC
      • Bolhuis MS
      • van der Werf TS
      • Akkerman OW
      Tuberculosis-related malnutrition: public health implications.
      J Infect Dis. 2019; 220: 340-341https://doi.org/10.1093/infdis/jiz091
      ,
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      Patient and provider reported reasons for lost to follow up in MDRTB treatment: a qualitative study from a drug resistant TB Centre in India.
      PLoS One. 2015; 10e0135802https://doi.org/10.1371/journal.pone.0135802
      ]. Third, patients with undernutrition may have a shortage of essential micronutrients, making them more vulnerable to severe disease [
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      J Nutr. 2009; 139: 113-119https://doi.org/10.3945/jn.108.095091
      ,
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      Impact of micronutrients on respiratory infections.
      Nutr Rev. 2011; 69: 259-269https://doi.org/10.1111/j.1753-4887.2011.00386.x
      ].
      Our subgroup analysis found that undernutrition was significantly associated with mortality and unsuccessful outcomes in the studies with HIV-positive or HIV-negative individuals. In addition, undernutrition was associated with unsuccessful outcomes in the longer or both treatment regimen studies but not in the shorter treatment regimen studies, which merits further examination. These observed variations might be because our subgroup analysis comprised a small number of studies in the shorter regimen group. Thus, a meta-analysis of individual participant data with a large sample size would be necessary to understand the association between undernutrition and unsuccessful treatment outcomes among people with MDR-TB who only received the shorter treatment regimen.
      Previous studies have suggested that nutritional supplements and regular counseling can be provided as part of treatment support for people with TB, notably among undernourished patients to improve sputum culture conversion at 2 months and weight gain [
      • Khan A
      • Sterling TR
      • Reves R
      • Vernon A
      • Horsburgh CR.
      Lack of weight gain and relapse risk in a large tuberculosis treatment trial.
      Am J Respir Crit Care Med. 2006; 174: 344-348https://doi.org/10.1164/rccm.200511-1834OC
      ,
      • Andrade BKC
      • Garcia-Perdomo HA.
      Effectiveness of micronutrients supplement in patients with active tuberculosis on treatment: systematic review/meta-analysis.
      Complement Ther Med. 2020; 48102268
      ,
      • Koethe JR
      • Von Reyn CF.
      Protein-calorie malnutrition, macronutrient supplements, and tuberculosis.
      Int J Tuberc Lung Dis. 2016; 20: 857-863https://doi.org/10.5588/ijtld.15.0936
      ]. Contrasting findings were also reported in previous clinical trials which showed that micronutrient supplementation did not affect sputum culture conversion and treatment outcomes [
      • Grobler L
      • Nagpal S
      • Sudarsanam TD
      • Sinclair D.
      Nutritional supplements for people being treated for active tuberculosis.
      Cochrane Database Syst Rev. 2016; 2016CD006086https://doi.org/10.1002/14651858.CD006086.pub4
      ,
      • Range N
      • Andersen AB
      • Magnussen P
      • Mugomela A
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      The effect of micronutrient supplementation on treatment outcome in patients with pulmonary tuberculosis: a randomized controlled trial in Mwanza, Tanzania.
      Trop Med Int Health. 2005; 10: 826-832https://doi.org/10.1111/j.1365-3156.2005.01463.x
      ].
      Monitoring and restoring nutritional status by nutrition support in undernourished individuals may enhance the efficacy of TB drugs by boosting immunity as well as increasing drug absorption [
      • Ter Beek L
      • Alffenaar J-WC
      • Bolhuis MS
      • van der Werf TS
      • Akkerman OW
      Tuberculosis-related malnutrition: public health implications.
      J Infect Dis. 2019; 220: 340-341https://doi.org/10.1093/infdis/jiz091
      ]. However, this strategy has not been practiced in many countries with developed National Strategic Plans for ending TB [
      Ministry of Health
      National Strategic Plan to End TB 2017–2023.
      Ministry of Health, Bhutan2017
      ,
      Ministry of Health
      National tuberculosis programme strategic Plan, 2017–2021.
      Ministry of Health, South Africa2019
      ].
      Our study has some important limitations. The included primary studies were exclusively published in English, which means that our review may not be representative of the global literature on this topic. In addition, since the majority of the included studies used secondary data, some important nutritional determinants such as dietary diversity and food insecurity were not considered in this analysis.

      Implications for future research

      Altogether, our findings suggest that the WHO end-TB strategy by 2035 could be more challenging to achieve without focusing on undernutrition, particularly in countries where the twin epidemics of MDR-TB and undernutrition coexist. Program planners and decision-makers should give greater attention to reducing undernutrition at the population level and to providing nutritional support when it is needed. Further research on targeted nutritional interventions alongside standardized TB drugs is strongly needed as a striking association has been found between undernutrition and poor MDR-TB treatment outcomes.

      Conclusion

      Undernutrition was significantly associated with a higher mortality rate, poorer treatment outcomes, and longer time to sputum culture conversion among people with MDR-TB. Therefore, our findings suggest the need for urgent expansion of access to nutritional support to improve the nutritional status of people living with MDR-TB, notably at the early stage of treatment.

      Declaration of competing interest

      The authors have no competing interests to declare.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethics approval and consent to participate

      Not applicable.

      Acknowledgments

      We thank the Australian National University library for offering us a wide range of available online databases. The authors additionally acknowledge Dr. Kerri Viney, of the Global Tuberculosis Programme, World Health Organization, Switzerland, who provided constructive and helpful comments during the development of this manuscript.

      Authors contributions

      FW: Conception of the research protocol, study design, quality assessment, data extraction, data analysis, interpretation, and drafting the manuscript. FW and KAA: study design, data extraction, quality assessment, data analysis, and reviewing and editing the manuscript. DG and MK: Interpretation of the data, reviewing and editing the manuscript. The manuscript has been read and approved by all the authors.

      Availability of data and material

      All data generated or analyzed during this study are included in this article and its supplementary information files.

      Appendix. Supplementary materials

      • Download .zip (.04 MB)
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        Figure S3. Funnel plot with pseudo 95% confidence limits and Egger's test for the pooled effect of undernutrition on sputum culture conversion in people with ect of undernutrition on treatment failure among people with multidrug-resistant-tuberculosis.

      • Download .zip (.04 MB)
        Help with zip files

        Figure S5. Funnel plot with pseudo 95% confidence limits and Egger's test for the pooled effect of undernutrition on unsuccessful outcomes in people with multidrug-resistant-tuberculosis.

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