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Measuring health-related quality of life in tuberculosis: a systematic review Guo, Na; Marra, Fawziah; Marra, Carlo A Feb 18, 2009

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ralHealth and Quality of Life OutcomesssBioMed CentOpen AcceReviewMeasuring health-related quality of life in tuberculosis: a systematic reviewNa Guo1, Fawziah Marra2 and Carlo A Marra*1,3Address: 1Collaboration for Outcomes Research and Evaluation (CORE), Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C., Canada, 2Faculty of Pharmaceutical Sciences, University of British Columbia; Director, Vaccine and Pharmacy Services, British Columbia Centre for Disease Control (BCCDC), Vancouver, B.C., Canada and 3Centre for Health Evaluation and Outcome Sciences (CHEOS), Providence Health Care Research Institute, Vancouver, B.C., CanadaEmail: Na Guo - naguo@interchange.ubc.ca; Fawziah Marra - Fawziah.Marra@bccdc.ca; Carlo A Marra* - carlo.marra@ubc.ca* Corresponding author    AbstractIntroduction: Tuberculosis remains a major public health problem worldwide. In recent years,increasing efforts have been dedicated to assessing the health-related quality of life experienced bypeople infected with tuberculosis. The objectives of this study were to better understand theimpact of tuberculosis and its treatment on people's quality of life, and to review quality of lifeinstruments used in current tuberculosis research.Methods: A systematic literature search from 1981 to 2008 was performed through a number ofelectronic databases as well as a manual search. Eligible studies assessed multi-dimensional qualityof life in people with tuberculosis disease or infection using standardized instruments. Results ofthe included studies were summarized qualitatively.Results: Twelve original studies met our criteria for inclusion. A wide range of quality of lifeinstruments were involved, and the Short-Form 36 was most commonly used. A validatedtuberculosis-specific quality of life instrument was not located. The findings showed thattuberculosis had a substantial and encompassing impact on patients' quality of life. Overall, the anti-tuberculosis treatment had a positive effect of improving patients' quality of life; their physicalhealth tended to recover more quickly than the mental well-being. However, after the patientssuccessfully completed treatment and were microbiologically 'cured', their quality of life remainedsignificantly worse than the general population.Conclusion: Tuberculosis has substantially adverse impacts on patients' quality of life, whichpersist after microbiological 'cure'. A variety of instruments were used to assess quality of life intuberculosis and there has been no well-established tuberculosis-specific instrument, making itdifficult to fully understand the impact of the illness.IntroductionThe assessment of patient reported outcomes (PROs) haslife (HRQL) is a complex type of PRO that evaluateshealth status. HRQL broadly describes how well individu-Published: 18 February 2009Health and Quality of Life Outcomes 2009, 7:14 doi:10.1186/1477-7525-7-14Received: 27 September 2008Accepted: 18 February 2009This article is available from: http://www.hqlo.com/content/7/1/14© 2009 Guo et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 10(page number not for citation purposes)become more accepted and valued in the disease manage-ment and outcome evaluation. Health-related quality ofals function in daily lives and their own perception ofwell-being in physical, psychological, and social aspectsHealth and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14[1,2]. Although traditional clinical and biological indica-tors are often intrinsically related to patients' quality oflife, they fail to represent one's self-perceived function andwell-being in everyday life settings. It is known thatpatients with chronic diseases place a high value on theirmental and social well-being as well as pure physicalhealth [3]. As a result, HRQL has become an area ofincreasing interest and has been evaluated in many dis-eases, including tuberculosis (TB). To measure HRQL, twokinds of instruments are often used: generic and disease-specific [1,2,4]. Generic instruments are developed tocover the common and important aspects of health andcan be used to assess and compare HRQL across differenthealth conditions and sub-populations [1,4]. In contrast,disease- or condition-specific instruments are designed toreflect unique problems most relevant to a given diseaseand/or its treatment [1,4]. Theoretically, disease-specificinstruments are more precise and more sensitive to smallbut potentially important differences or changes onHRQL, compared to generic instruments [1,4]. One spe-cial category of generic HRQL instruments assesses "pref-erences" for certain health states [2]. These instrumentssummarize quality of life into a single utility score, reflect-ing the 'value' people place on a health state, anchored at0 (death) and 1 (full health). [2]. Health utility measure-ments are often used in health economic studies.Although effective therapy has long been available, TBremains a major public health threat globally, with onethird of the world's population infected [5,6]. Manyaspects of TB along with its treatment could potentiallycompromise patients' HRQL. For example, the standardanti-TB therapy consists of four medications and takes atleast 6 to 9 months to complete, with serious risks ofadverse reactions [6-8]. In some communities, TB patientsare perceived as a source of infection and the resultantsocial rejection and isolation leads to a long-term impair-ment on patients' psychosocial well-being [9-14]. ManyTB patients also report to experience negative emotions,such as anxiety and fear [13,14]. However, the currentgoal of TB management is to achieve microbiological'cure' and there has been little effort taken to considerpatients' HRQL. In 2004, Chang et. al. published a reviewsummarizing the English medical literature on the qualityof life in TB patients [15]. At that time, the authors wereunable to locate studies measuring HRQL using standard-ized instruments. Over the past few years, more effort hasbeen dedicated to this research field. Therefore, thepresent review was performed to identify published origi-nal studies utilizing structured HRQL instruments.ObjectivesThe objectives of this review were: (1) to identify HRQLtreatment on patients' HRQL; and (3) to examine demo-graphic, socio-economic, and clinical factors associatedwith HRQL outcomes in TB patients.MethodsSearch strategies for identification of potential studiesA systematic literature search was performed using the fol-lowing electronic databases: Medline (1950-present),EMBASE (1980-present), Cochrane Register of ControlledTrials (CENTRAL), CINAHL, PsycINFO, and HaPI (1985-present). Key word searching and/or subject searchingwere performed, if applicable. The following keywordswere used: tuberculosis (TB), Quality of Life (QoL), QualityAdjusted Life Years (QALY), health utility, health status, lifequality, and well-being. The limit feature was used to selecthuman studies published between 1981 and 2008 writtenin English or Chinese (traditional or simplified). The lasttime electronic database search was conducted during July22, 2008. The reference sections of the following key jour-nals were manually searched for relevant articles: Interna-tional Journal of Tuberculosis and Lung Disease, Chest,Quality of Life Research, and Health and Quality of Life Out-comes. Reference lists of included studies, review articles,letters, and comments were checked afterwards. We didnot contact the authors of identified studies or relevantexperts to locate unpublished studies. Each stage of the lit-erature searching process is illustrated in Figure 1.Inclusion and exclusion criteriaAll clinical trials and observational studies where multi-dimensional HRQL was evaluated, either as a primary orsecondary outcome, using structured HRQL instrumentswere considered in this review. Participants were thosediagnosed with active TB disease or latent TB infection(LTBI), regardless of the site and stage of the disease andthe treatment status. There were no limitations on age,gender, race, the origin of birth, and other socio-economicstatus.For the purpose of this review, HRQL was defined aspatients' self-evaluations of the impact of either active TBdisease or LTBI and the associated treatments on theirphysical, mental, and social well-being and functioning.The following requirements for HRQL measurement wereset a priori for studies to be included in this review: (1)one multi-dimensional HRQL instrument or a combina-tion of single-dimensional instruments had to be used tocapture the broad framework of HRQL; (2) the HRQLinstruments could be either generic or disease (or condi-tion) -specific; (3) the origin of the applied instrumentshad to be identifiable and traceable; (4) the HRQL instru-ments had to have psychometric properties such as relia-bility and validity reported from previous studies or werePage 2 of 10(page number not for citation purposes)instruments used in TB research; (2) to better understandthe impact of TB disease or infection and the associatedassessed in the specific study being reviewed; (5) HRQLoutcomes had to be self-reported by the specific partici-Health and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14pant, but HRQL measurement that were completed withhelp from proper proxies, such as family members andcaregivers, were also accepted.Studies were excluded if (1) HRQL was evaluated usingqualitative methodologies, such as focus groups; or (2)only one single dimension of HRQL (e.g., depression)was assessed; or (3) HRQL was assessed using instrumentsdesigned for the specific study without psychometricproperties evaluated and reported; or (4) a modified ver-sion of a previously validated instruments (e.g., SF-36)was used as the psychometric properties of the originalinstrument could be changed by the modification.Data extractionIf the study was included in this review, the followinginformation was collected: study design, inclusion andexclusion criteria of subjects, included subjects' socio-instrument(s), administration of HRQL instrument(s),and HRQL outcomes and validation results.ResultsThe literature search identified 2540 articles which werenarrowed to 26 [9-14,16-35] (Figure 1). After reviewingthe full texts, 14 studies were further excluded for variousreasons: 6 studies used qualitative methodologies [9-14];2 studies measured only one single dimension of HRQL[16,17]; 1 study [18] used the Short-Form 36 (SF-36) butthe response options of SF-36 were modified to 3 levels(i.e., the same as before, better, and worse) without pro-viding validation data; 1 study [19] used one single ques-tion from a structured instrument; 1 study was a duplicateand the earlier version was excluded [20,21]; 1 study [22]used a generic instrument, the General Quality of LifeInterview (GQOLI-74), however, no relevant referenceswere provided to track the origin and the psychometricFigure 1Page 3 of 10(page number not for citation purposes)demographic characteristics and clinical features, HRQLinstrument(s) used, the origin and structure of HRQLproperties of this instrument; 2 articles [23,24] were pub-lished from the same study, and therefore only includedHealth and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14as one study for the review; another 2 articles, Marra et. al.[25] and Guo et. al. [26], reported longitudinal and cross-sectional results from one same study respectively, andthus only one study was counted for the review. Therefore,a total of 12 original studies were included in this review[21,23,25,27-35] and an overview is presented in Addi-tional file 1.Of the 12 included studies, one was published in 1998[27] and the remaining 11 were published after 2001[21,23,25,28-35]. Nine studies were published in Englishand 3 in Chinese [27,29,33]. The included studies werecarried out within different countries: 3 in China [27-29];1 in both China and southern Thailand [33]; 2 in India[21,35]; 2 in Turkey [30,31]; 2 in Canada [23-26]; and 2in the USA [32,34]. Seven of the included studies werecross-sectional [27,29-31,33-35] and 4 were prospectivecohort studies [21,23,25,28]. The remaining one studywas a randomized controlled trial (RCT) [32], but onlybaseline HRQL assessment data was reported in the pub-lished article. Among the 12 studies, three studiesincluded a comparison group either from the general pop-ulation [28] or from a "healthy" non-TB sample [27,29];one study used the normative data from the Canadianpopulation as the reference group [23,24]; two studiesincluded people with LTBI as controls [25,34]; one studycompared TB patients with a group of chronic obstructivepulmonary disease (COPD) patients [31]; and theremaining 5 studies did not include proper comparisongroups. Sample size (i.e., number of subjects included inthe statistical analysis) varied among the 12 studies, from46 to 436. Only one study [23] reported how the samplesize was estimated statistically. A wide range of TB patientswere included in this review: pulmonary TB and extra-pul-monary TB, active TB disease and LTBI, and current TB andpreviously treated TB.To measure multiple-dimensional HRQL, a variety ofinstruments were involved in the included studies (Addi-tional file 2). As a result, it was not possible to statisticallysummarize the results and thus a qualitative synthesisapproach was taken for this review.HRQL instruments used in the included studiesNine studies included generic multi-dimensional instru-ments with or without specific single-dimensional ones,one study used a newly developed TB-specific multi-dimensional instrument [21], and two studies used a bat-tery of single-dimensional instruments [31,33].Generic HRQL instrumentsThe SF-36 was used in 6 studies with different languageversions [23-28,33]. It consists of 36 items which arehealth (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH) [36]. From the8 subscales, the physical component summary (PCS) andmental component summary (MCS) scores can be alsocalculated [36]. Duyan et. al. used the 24-item Quality ofLife Questionnaire (QLQ), which covers 7 domains,including living conditions, finances, leisure, family rela-tions, social life, health, and access to health care [30]. The24-item QLQ was first presented by Greenley et. al. in1997 [37]. Finally, the long Medical Outcome Study(MOS) core questionnaire was used in Pasipanodya et. al.[34]. This is a generic instrument covering multipledimensions, including physical function, social function,general health, vitality, and limitations due to physicaland emotional functioning [38]. The well-known SF-36was developed and evolved based on a subset of itemsfrom the MOS core questionnaire [38].Specific HRQL instrumentsDhingra and Rajpal measured HRQL with the DR-12, anew TB-specific instrument, which was developed in Indiaand first published in 2003 [20]. It is composed of 12items, among which 7 cover TB symptoms (i.e., cough andsputum, haemoptysis, fever, breathlessness, chest pain,anorexia, and weight loss) and 5 relate to socio-psycho-logical and exercise adaptation (i.e., emotional symp-toms/depression, interest in work, household activities,exercise activities, and social activities) [20,21]. Allresponse options are presented on 3-point scales andequal weights are given to each item when calculating thetwo domain scores and the total score [20,21]. The St.George Respiratory Questionnaire (SGRQ) used in Pasi-panodya et. al. [34] is a widely used specific instrumentdesigned for measuring HRQL in patients with chronicobstructive pulmonary disease (COPD) and other types ofrespiratory diseases. Three domain (symptom, activity,and impacts) scores and a total score can be generated[39]. It was developed at the St. George's Hospital MedicalSchool at the UK and has been translated into various lan-guages [39].Yang et. al. used two single-dimensional instruments, theChinese version Symptoms Checklist 90 (SCL-90) andSocial Support Rating Scale (SSRS) [29]. The SCL-90 is a90-item symptom inventory designed mainly to evaluatea broad range of psychological problems and symptoms,including 9 dimensions: somatization, obsessive-compul-sive behaviour, interpersonal sensitivity, depression, anx-iety, hostility, phobic anxiety, paranoid ideation, andpsychoticism [40]. The 10-item SSRS was used to measurethe self-perceived availability and use of social supportservices [27]. The study by Aydin and Ulusahin used twosingle-dimensional instruments, the General HealthPage 4 of 10(page number not for citation purposes)aggregated into 8 subscales, including physical function-ing (PF), role-physical (RP), bodily pain (BP), generalQuestionnaire 12 (GHQ-12) and Brief Disability Ques-tionnaire (BDQ) [31]. GHQ-12 is a short version of theHealth and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14GHQ-60, which was developed for screening non-psy-chotic psychiatric disorders in the general population[41]. The BDQ, derived from the MOS short form generalhealth survey, is used to measure patients' physical andsocial disability level [42]. Marra et. al. [25] used the BeckDepression Inventory (Beck-DI), along with the SF-36 anda couple of health utility instruments. The Beck-DI is a 21-item instrument, designed to measure the symptoms anddegree of depression [43].In the USA study, a series of instruments or questions wereused to assess TB-infected homeless individuals' self-per-ceived physical health, psychological profile, emotionalwell-being, social support, and health care access and use[32]. Examples included the 5-item Mental Health Index(MHI-5) and the Center for Epidemiological StudiesDepression Scale (CES-D) [32].Health utility instrumentHealth utility, one generic measure of HRQL, reflects sub-jective preferences for health states and also providesquantitative estimates of HRQL under certain health states[2]. The two studies [23-26] conducted in Canada appliedvarious health utility assessment techniques among TBpatients, including the Health Utility Index (HUI), Euro-Qol (EQ-5D), Short-Form 6D (SF-6D), Visual AnalogueScale (VAS), and Standard Gamble (SG). HUI, SF-6D, andEQ-5D are multi-attribute health status classification sys-tems that indirectly measure preferences for health states[2]. SG and VAS are to directly obtain individuals' prefer-ences using different techniques.HUI currently consists of HUI-2 and HUI-3 [44]. HUI-2and HUI-3 are derived from the same questionnaire butHUI-2 has 7 domains (sensation, mobility, emotion, cog-nition, self-care, pain, and fertility) and HUI-3 contains 8domains (vision, hearing, speech, ambulation, dexterity,emotion, cognition, and pain). EQ-5D consists of 5domains, including mobility, self-care, usual activity,pain, and anxiety/depression [2]. SF-6D is derived from asubset of SF-36 questions. It has 6 dimensions includingphysical functioning, role limitations, social functioning,pain, mental health, and vitality [45].The SG is a classic technique to obtain individual prefer-ences for health outcomes, based on the theory of vonNeumann and Morgenstern [2]. In the study by Dion et.al., the respondent was offered a choice between the cer-tain outcome of a particular health state and a hypotheti-cal gamble, with relative possibilities of perfect health andimmediate death varying. The gamble was terminatedwhen the respondent was indifferent to the choicebetween the given health state and the gamble. The VASdeath" and "perfect health". The respondents were askedto put a mark at the point that represents their currenthealth status [23,24]. Similarly, a 10 cm length of hori-zontal line (anchored at 0 cm = death and 10 cm = perfecthealth) was used by Marra et. al. [25] as VAS.Psychometric properties of HRQL instruments in tuberculosisThe SF-36 was used in 6 studies, and overall it showedacceptable validity and reliability. Chamla [28] validatedthe Chinese version SF-36 among active pulmonary TBpatients and the general population in China. The reliabil-ity was tested by Cronbach's α, ranging form 0.88 to 0.97for the eight SF-36 subscales. All 36 questions of the SF-36had internal item consistency coefficients between 0.56and 0.86. In Dion et. al. [23,24], the reliability of SF-36was evaluated among a mixture of TB patients, including25 with LTBI, 17 with active TB on treatment, and 8 withpreviously treated TB. The internal consistency of the SF-36 responses was strong, with coefficients of 0.86–0.92for the two summary scores and 0.73–0.94 for the sub-scale scores. The test-retest reliability (2-week interval) ofSF-36 was tested by calculating Intraclass Correlation(ICC) coefficients: 0.66–0.79 for the two SF-36 summaryscores. He et. al. [33] also reported good reliability of theChinese version SF-36 (Cronbach' α > 0.7) among the twogroups of TB patients from China and Thailand.Validity of the SF-36 was evaluated by examining the cor-relations between SF-36 outcomes with other external var-iables, including clinical criteria, responses from otherHRQL measures, and physician's evaluations. It wasreported that SF-36 scores were able to discriminatebetween TB patients with different severity levels [21,26]and between patients at different stages of treatment (i.e.,the start, middle, and end of the treatment) [21,25,28]. InGuo et. al. [26], the correlations between SF-36 summaryscores (PCS and MCS) and four utility instruments (SF-6D, HUI-2, HUI-3, and VAS) were tested by calculatingSpearman's coefficients. SF-6D scores were strongly corre-lated with both PCS and MCS (0.79, 0.80), and HUI-2,HUI-3, and VAS scores were more strongly correlated withPCS (0.59, 0.66, and 0.67) than with MCS (0.37, 0.48,and 0.59). Similarly, in the study by Dion et. al. [23,24],SF-36 scores were observed moderately correlated withEQ-5D and VAS scores, but poorly correlated with SGscores (Pearson coefficients < 0.2). Wang et. al. [27]reported that patient-reported SF-36 scores were well cor-related with physician proxy-reported Quality of LifeIndex (QLI) and Karnofsky Performance Status (KPS)scores, with correlation coefficients of 0.78 and 0.89respectively. However, it was not reported which type ofcorrelation coefficient was calculated.Page 5 of 10(page number not for citation purposes)used by Dion et. al. was a 100 cm "feeling thermometer",marked at each end by word descriptions as "immediateHealth and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14The structural validity of SF-36 was tested in two studies,but the results were not consistent. In Chamala [28], fac-tor analysis was applied to evaluate the 2-dimensionalmodel of the SF-36. Two factors (physical health andmental health) were extracted and subjected to orthogo-nal rotation using the Varimax method. The observed pat-tern of correlations between the 8 subscales and the 2factors supported the authors' prior hypothesis. For exam-ple, it was reported that the 4 physical subscales (PF, RP,BP, and GH) were correlated strongly with the physicalhealth factor, but only poorly correlated with the mentalhealth factor. On the other hand, the 4 mental subscales(MH, RE, SF, and VT) were strongly correlated with themental health factor, but not the physical factor. He et. al.[33] used principle component analysis to test the struc-tural validity of SF-36. However, the results showed thatthe 8 subscales were not well independent, and there wereoverlapping items between different subscales. For exam-ple, RE and RP subscales were both strongly correlatedamong the two groups of patients (correlation coefficient0.82 and 0.77). Based on their findings, the authors con-cluded that the SF-36 did not show satisfactory constructvalidity in the studied TB patients.The application of SF-36 among TB patients also revealedsome problems. In the study by Dion et. al. [23,24], SF-36subscales demonstrated a remarkable ceiling effect prob-lem. Over 50% participants with concurrent or previousTB reported the highest scores for 5 of SF-36 subscales (PF,RP, RE, BP, and SF).Ceiling and floor effects are a common problem for theapplication of health utility instruments in TB. In Dion et.al. [23,24], 42–53% participants reported the best possi-ble EQ-5D health state. Guo et. al. also observed ceilingand/or floor effect problems with three commonly usedhealth utility instruments. HUI-2 and HUI-3 sufferedfrom a serious ceiling effect problem, both in global scoreand single dimension level. For example, 25% of active TBpatients scored 1.0 (perfect health) using the HUI-2 and98% of them reported the best level of hearing for HUI-3.SF-6D, on the other hand, was primarily limited by its nar-row range of available utility values, from 0.30 to 1.0.Health states at the lower end may not be adequately rep-resented by the SF-6D. Despite these problems with theapplication among TB patients, some positive aspects ofthese utility instruments were also observed. For example,these utility instruments showed moderate to strong cor-relations with the SF-36 responses as stated before[23,24,26]. Guo et. al. [26] also reported moderate tostrong agreement among SF-6D, HUI-2, HUI-3, and VAS,using ICC: the overall ICC coefficient among these 4instruments was 0.65 and paired ICC coefficients rangedments were all able to discriminate between TB patientswith different severity levels.Pasipanodya et. al. [34] administered the lung disease-specific SGRQ among people with treated pulmonary TBdisease or LTBI. Test-retest reliability of the SGRQ wasexamined by ICC coefficients, 0.93 for the total score and0.83–0.91 for subscale scores. Internal consistency wastested by Cronbach's α, at 0.93. To evaluate its validity,SGRQ responses were correlated with a previously vali-dated MOS core questionnaire and a couple of clinicalpulmonary function tests, such as the forced vital capacity(FVC). Overall, SGRQ scores and MOS scores agreed onsimilar health constructs and diverged on dissimilar con-structs. Low but significant correlations were observedbetween SGRQ scores and pulmonary function test results(-0.12 to -0.29, p < 0.05). On the other hand, a ceilingeffect problem for SGRQ was observed. In both treatedpulmonary TB patients and people with LTBI, the distri-bution of SGRQ scores was skewed toward higher HRQL.In addition, considering varied levels of reading andunderstanding in English in respondents, different lan-guage versions of SGRQ were used, but the potentialimpact of combining results from these on HRQL out-comes was not known.Dhingra and Rajpal [21] applied the new TB-specificinstrument, DR-12, among TB patients under directlyobserved therapy (DOT). It was reported that, at thebeginning of treatment, DR-12 scores demonstrated sig-nificant differences between pulmonary and extra-pulmo-nary TB patients, and between sputum positive andsputum negative patients. Over the treatment period,higher DR-12 score gains were observed among patientswho positively responded to the treatment compared tothose who did not. Based on these evidences, the authorscame to the conclusion that DR-12 had strong constructvalidity in the studied population. However, the clinicalcriteria or indicators were not well defined in the pub-lished work. All comparisons were performed by usingpaired or unpaired t-tests. Potential confounders such associo-demographic and clinical variables were not con-trolled in the final data analysis.Impact of tuberculosis on HRQLOverall, active TB disease had significant and encompass-ing impacts on patients' HRQL. Using the SF-36, Chamla[28] found that, compared to the general population, peo-ple with active TB disease scored significantly lower on PF,RP, GH, BP, and VT (p < 0.05), but no significant differ-ences were observed on RE, SF, and MH subscales (p >0.05). In general, physical health subscales were moreaffected than mental ones. Dion et. al. [23,24] also foundPage 6 of 10(page number not for citation purposes)from 0.53 to 0.67. In addition, these four utility instru- active TB patients scored significantly lower in SF-36 PCSscores, but not in MCS scores, when compared to peopleHealth and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14with LTBI and those with previously treated TB disease. Interms of health utility outcomes, Dion et. al. found thatactive TB patients scored significantly lower in VAS(median 92.5 VS. 97.5, p = 0.02) and SG (median 80.0 VS.90.0, p = 0.002) than others at the baseline assessment.However, no significant difference was observed in EQ-5D scores between active TB patients and others. It islikely that the small sample size and the heterogeneouscomposition of subjects could have prevented the authorsfrom detecting the small but important differences in thesample. Wang et. al. [27] found that active TB patientsreported lower scores (p < 0.01) across all SF-36 subscalesthan healthy non-TB people, with RP and RE being mostaffected. Marra et. al. and Guo et. al. [25,26] found that,compared to those with LTBI, people with active TB scoredsignificantly lower at all SF-36 subscales, SF-6D, HUI-2,HUI-3, and VAS. In contrast, SF-36 scores among peoplewith LTBI before the preventative therapy were very simi-lar to the U.S. norm references.In the study by Marra et. al. [25], Beck-DI scores showedsubstantial impairment on mental well-being in active TBpatients, compared to people with LTBI. However, manyaspects of the Beck-DI (such as fatigue) can also be symp-toms of TB and might not be necessarily indicative ofmental health impairments. Aydin and Ulusahin [31]compared TB patients to COPD patients and found thatTB patients had a lower prevalence of depression and anx-iety and a lower level of disability, suggested by GHQ-12and BDQ scores. The authors postulated that the chronicduration of COPD and the older age of the COPD patientsmay result in a higher prevalence of psychological impair-ments. Within TB patients, multi-drug resistant TBpatients reported the worst disability level, according toBDQ outcomes. Yang et. al. [29] found that pulmonary TBpatients reported more psychological symptoms listed inthe SCL-90 and a lower degree of social support usingSSRS compared to healthy controls. However, SCL-90scores did not show significant correlation with SSRSscores, which is not consistent with the established rela-tionship between social support and health [46], as dis-cussed by the authors.The impaired HRQL experienced by TB patients may be areflection of socio-demographic status (e.g., age, gender,and socio-economic status) and other underlying co-mor-bid conditions, besides TB and its treatment. A fewincluded studies explored the relationship between socio-demographic features and clinical factors and HRQL in TBpatients. In general, the findings were consistent, butsome discrepancies existed. Yang et. al. [29] andNyamatihi et. al. [32] observed that females were morelikely to report poorer health than males, especially ontended to have poorer HRQL than younger ones. ButDuyan et. al. [30] did not find significant associationsbetween gender, age and HRQL in TB patients. On theother hand, they [30] found that better HRQL was corre-lated with higher income, higher education, better hous-ing conditions, better social security, and closerrelationships with family members and friends. Someclinical factors that were observed to correlate with poorerHRQL in TB patients include size of pulmonary TB infec-tion, duration of TB disease, reactivation of previous TBinfection, number of symptoms before treatment, devel-opment of hemoptysis, hospitalization, underlyingchronic conditions, anemia, and count of white bloodcells before treatment [27,28].Effect of anti-tuberculosis treatment on HRQLChamla [28], Dhingra and Rajpal [21], and Marra et. al.[25] prospectively measured active TB patients' HRQL atthe start, middle, and end of treatment. In the study byChamla [28], after the anti-TB treatment, significantimprovement was observed in all physical health sub-scales of the SF-36 (PF, RP, BP, and GH, p < 0.05); twomental health subscales, RE and SF (p < 0.05), improvedsignificantly, but not VT and MH (p > 0.05). During thetreatment, RP, VT and MH scores decreased after the ini-tial 2 months and but showed overall improvement at theend of the treatment, while all other subscale scoresshowed gradual increase over the treatment [28]. Dhingraand Rajpal [21] observed a gradual improvement on DR-12 scores in active TB patients over the course of the treat-ment. Overall, a more identifiable improvement wasobserved in symptom scores than that in socio-psycholog-ical and exercise adaptation scores. Consistently, Marra et.al. [25] also found significant HRQL improvement inactive TB patients over the 6 months of treatment, usingSF-36 and Beck-DI.Although anti-TB treatment improved HRQL overall,active TB patients still had poorer HRQL at the end of thetreatment compared to the general population or peoplewith LTBI, especially in psychological well-being andsocial functioning. Chamla [28] observed that, at the endof the treatment, active TB patients still scored signifi-cantly lower at RP, VT, and MH subscales compared togeneral population comparisons. Marra et. al. [25] foundthat, after the 6 month of treatment, active TB patientsscored significantly lower at SF-36 PCS and MCS sum-mary scores compared to people with LTBI. An interestingfinding by Marra et. al. [25] is that, after the preventivetreatment, MCS scores among people with LTBI decreasedsignificantly, while PCS scores remained unchanged. Pasi-panodya et. al. [34] measured HRQL among pulmonaryTB patients who completed at least 20 weeks of treatment,Page 7 of 10(page number not for citation purposes)mental health problems, such as depression and anxiety.Chamla [28] and Guo et. al. [26] found older peopleusing the SGRQ. Compared with those with LTBI, treatedTB patients had lower SGRQ scores. Those with betterHealth and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14lung functions and/or born in the U.S. (against foreign-born) tended to have better HRQL outcomes. No genderdifference was observed in SGRQ scores.Muniyandi et. al. [35] assessed the HRQL in a sample ofprevious TB patients one year after successful completionof treatment. 40% of these people reported persistentsymptoms, such as breathlessness, cough, chest pain, andoccasional fever. The authors calculated three SF-36 com-ponent scores: the physical well-being, mental well-being,and social well-being. Based on their results, there was nogender difference on physical well-being score; butfemales scored much lower at mental and social well-being scores. Compared with younger people, older oneshad significantly lower physical and mental well-beingscores, but not the social score. They also presented theU.S. general population norms for the three componentscores and concluded that TB patients' HRQL returned tonormal level one year after the completion of treatment.However, the way of calculating the three SF-36 compo-nent scores is not commonly seen in literatures, and thereference regarding the U.S. general population normsprovided in the published paper cannot be located.DiscussionHRQL has been appreciated as an important health out-come measure in clinical research. We identified 12 origi-nal studies where multi-dimensional HRQL was assessedamong people with TB disease or infection using struc-tured instruments around the world. We found that TBand its treatment have a significant impact on patients'quality of life from various aspects and this impact tendsto persist for a long time even after the successful comple-tion of treatment and the microbiological 'cure' of the dis-ease.The results suggest that TB disease has a negative andencompassing impact on active TB patients' self-perceivedhealth status in physical, psychological, and socialaspects. Overall, the anti-TB treatment showed positiveeffect on improving patients' HRQL. It appeared thatphysical health seemed to be more affected by the diseasebut improved more quickly after the treatment, while theimpairment on mental well-being tended to persist for alonger term [21,28]. However, even after the active TBpatients successfully completed the treatment and wereconsidered microbiologically 'cured', their HRQLremained poor as compared to the general population[23-25,28]. The ongoing HRQL impairment may be partlydue to the persistent physical symptoms and residualphysiological damages from the disease and/or the treat-ment. Furthermore, a few qualitative studies [9-14,16-18]have shown that the social stigma attached to the diagno-ence the fear and anxiety of being known by others abouttheir diagnosis. All these consequential impairments alsoneed to be 'cured' and may take a long recovery time.Most studies have focused on assessing HRQL in active TBpatients. Although people with LTBI do not present withclinical disease or symptoms, they are likely to be sub-jected to the same social and psychological impacts asactive TB patients. The knowledge of a deadly and stigma-tized disease lying dormant in his/her body may alsoinduce anxiety and fear. As Marra et. al. [25] observedthat, after receiving 6 months of preventive therapy withisoniazid, the mental well-being of people with LTBIdecreased significantly.HRQL assessment in TB research is still a new area, and avalid and reliable TB-specific instrument is much needed.Currently, a wide range of HRQL instruments were uti-lized in the literature. The SF-36 was the most frequentlyused instrument and it appeared to be a valid and reliabletool to be used in TB. Although the SF-36 has been usedextensively to assess both population health and specifichealth conditions for various medical conditions, as ageneric health assessment instrument, it offers little infor-mation to help understand the unique experiences amongTB patients, such as social stigma and anti-TB treatmentrelated ADRs.Our review identified one TB-specific HRQL instrument,DR-12, which was developed in India [20,21]. Unfortu-nately, its validation study was not conducted in a system-atic fashion and the current evidence provided was notconvincing. Further applications and appropriate meth-odologies are needed to show DR-12 is a psychometricallysound HRQL instrument feasible and valid for TBpatients. In addition, the DR-12 is actually designed spe-cifically for pulmonary TB patients, judging from its itemcontent. TB can affect almost any part of the human body,and in Canada, about 40% of active TB diseases wouldpresent as extra-pulmonary TB [47]. Different types of TBdisease would have very different clinical presentationsand affect people's function differently. This may be achallenge when developing a TB-specific HRQL instru-ment.It should be also noted that most TB patients have verydifferent cultural and socio-demographic backgroundscompared with the population in which many of theseinstruments were originally developed. Also, in the stud-ies done in Canada and the USA [24-26,32,34], most TBpatients were foreign-born and the instruments were nor-mally self-administered in the English language whichwould not have been the respondents' first language.Page 8 of 10(page number not for citation purposes)sis of TB in some cultures is significant. People with TBmay feel isolated from their family and friends or experi-Thus, the results of these studies may not be valid if care-ful translation and cultural adaptation of the instrumentHealth and Quality of Life Outcomes 2009, 7:14 http://www.hqlo.com/content/7/1/14was not done to accommodate the multi-cultural popula-tion.Particular attention should be given to some methodolog-ical issues on assessing HRQL among people with activeTB disease or LTBI. To comprehensively examine theimpact of TB and its treatment on patients' HRQL, it isvery important to include a proper comparison groupfrom a similar demographic and socio-economic back-ground. When conducting the study, researchers are rec-ommended to seek statistical consultation regardingproper sample size estimating, missing data handling, andadjusting for potential confounders, such as socio-demo-graphic status and presence of co-morbidities. Anotherconcern is the lack of interpretation of HRQL outcomes interms of clinical meaningfulness. Statistical significance isa useful way to interpret the result, but it fails to relate theHRQL outcome with clinical relevance. As such, morework needs to be done to relate changes in HRQL assess-ment in TB to concepts such as the minimal clinical differ-ence [48,49].ConclusionOur review of the literature shows that TB diminishespatients' HRQL, as measured by various instruments.However, due to the heterogeneity of HRQL measure-ments, it was difficult to assimilate results across studies.A few studies used the SF-36 which appeared to be a validinstrument in the measurement of HRQL in TB. Otherinstruments require further psychometric testing to deter-mine their suitability in measurement in this context. Ourreview suggests that HRQL assessment in people with TBis a growing research area and a psychometrically soundTB-specific HRQL instrument is lacking. A critical step inthe future would be to design an applicable, reliable, andvalid TB-specific HRQL instrument. Particular attentionshould be given to address the methodological issueswhen conducting a HRQL assessment study in TBpatients.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsAll authors contributed to the conception and design ofthe review. NG acquired and analyzed the data anddrafted the manuscript. CAM and FM contributed to theanalysis and interpretation of the data and finalizing themanuscript. All authors read and gave approval of thefinal manuscript.Additional materialReferences1. Guyatt GH, Feeny DH, Patrich DL: Measuring health-relatedquality of life.  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