European Journal of Clinical Nutrition (2006) 60, 163–171 & 2006 Nature Publishing Group All rights reserved 0954-3007/06 $30.00 www.nature.com/ejcn

ORIGINAL ARTICLE Wasting and body composition of adults with pulmonary in relation to HIV-1 coinfection, socioeconomic status, and severity of tuberculosis

E Villamor1, E Saathoff1, F Mugusi2, RJ Bosch3,4, W Urassa5 and WW Fawzi1,6

1Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; 2Department of Internal Medicine, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania; 3Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA; 4Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA, USA; 5Department of Microbiology and Immunology, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania and 6Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

Objective: To examine the impact of HIV coinfection, socioeconomic status (SES) and severity of tuberculosis (TB) on the body composition and anthropometric status of adults with pulmonary TB. Design: Cross-sectional study. Setting: Five TB clinics in Dar es Salaam, Tanzania. Subjects: A total of 2231 adult men and women diagnosed with pulmonary TB, prior to the initiation of anti-TB therapy. Methods: We compared the distribution of anthropometric characteristics including body mass index (BMI), mid-upper arm circumference (MUAC), triceps skin-fold (TSF), and arm muscle circumference (AMC) by HIV status, SES characteristics, and indicators of TB severity (bacillary density in sputum and Karnofsky performance score). Similar comparisons were carried out with body composition variables from bioelectrical impedance analysis and albumin concentrations, in a subsample of 731 subjects. Results: In multivariate analysis, HIV was significantly associated with lower MUAC and AMC in both men and women, but not with BMI or TSF. Compared to HIV-uninfected women, those who were HIV infected had lower body cell mass (BCM) (adjusted difference ¼À0.85 kg, P ¼ 0.04), intracellular water (À0.68 l, P ¼ 0.04), and phase angle (À0.52, P ¼ 0.02). Albumin concentrations were significantly lower in both men and women infected with HIV. Among HIV-infected men, CD4 cell counts o200/mm3 were related to lower intracellular water, BCM, -free mass and phase angle. Independent of HIV infection, BMI and MUAC were positively related to SES indicators and the Karnofsky performance score; and inversely related to bacillary density. Conclusions: HIV infection is associated with indicators of low lean body mass in adults with TB; socioeconomic factors and TB severity are important correlates of wasting, independent of HIV. Sponsorship: The National Institute of Allergy and Infectious (UO1 AI 45441-01). European Journal of Clinical Nutrition (2006) 60, 163–171. doi:10.1038/sj.ejcn.1602281; published online 12 October 2005

Keywords: tuberculosis; HIV; body composition; wasting; bioelectrical impedance analysis

Correspondence: Dr E Villamor, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. E-mail: [email protected] Introduction Guarantor: E Villamor. Contributors: WWF, FM, WU, and EV contributed to the study design. EV and ES participated in the study implementation and field supervision. RJB Tuberculosis (TB) is among the foremost infectious causes of participated in statistical data analyses. EV carried out the data analyses, mortality worldwide, with 2–3 million deaths reported each interpreted the results, and wrote the initial draft of the manuscript. All year. The incidence of TB also remains high, with 8.8 million authors participated in data interpretation and contributed to the final version new cases found in 2002 only (World Health Organization, of the manuscript. WWF and FM are Principal Investigators of the study. Received 24 March 2005; revised 8 July 2005; accepted 2 August 2005; 2004). In sub-Saharan Africa, where the prevalence and published online 12 October 2005 incidence of TB are among the highest in the world, between Wasting in adults with tuberculosis E Villamor et al 164 25 and 75% of adults with TB are also infected with HIV Methods (World Health Organization, 2004), which results in elevated mortality. We conducted a cross-sectional study among TB-infected TB is often associated with severe wasting (Harries et al., adults who attended five outpatient TB clinics in Dar es 1988; Macallan et al., 1998), a progressive loss of body Salaam, Tanzania, and who were evaluated for inclusion in a mass that increases the risk of death (Zachariah et al., 2002). clinical trial. Since HIV-related wasting is also a strong risk factor for mortality (Tang et al., 2002; Van Lettow et al., 2004), it is relevant to know whether HIV infection contributes Study population and procedures to wasting in patients with TB, especially in settings where Between March 2000 and January 2004, 70 828 sputum TB-HIV coinfection is highly prevalent. This question smears were obtained at the five outpatient clinics and sent was addressed in anthropometric studies that yielded to the laboratory for microscopic analyses of acid fast bacilli inconsistent results. While HIV infection was related to (AFB). Among the 6515 patients who tested positive, we decreased BMI among TB-infected adults from Burundi evaluated the following eligibility criteria: age between 18 (Niyongabo et al., 1994, 1999) and Tanzania (Kennedy and 65 years, Karnofsky performance score (The Karnofsky et al., 1996), no association was found in Uganda (Shah score is an indicator of general performance status of an et al., 2001), Ethiopia (Madebo et al., 2003) or Malawi individual (Karnofsky et al., 1948) and can be used as an (Van Lettow et al., 2004). The majority of these studies indicator of the severity of a pathological process. A score failed to adjust the association between HIV infection above 70% indicates the ability to carry on normal activity, and wasting for the potential confounding effects of 70% indicates the ability to care for self but the inability socioeconomic characteristics and the severity of TB to carry on normal activity or work, 40-60% indicates the infection. requirement of different degrees of assistance from others, In addition to assessing the impact of HIV infection and 10–30% indicates severe disability.) X40%, residence on the anthropometric status of TB-infected persons, it is within the clinic area where the Directly Observed Treat- important to ascertain which body compartments are ment, Short-course (DOTS) was to be administered, plan to more likely to be affected by HIV, since the influence on stay in the study area for 2 years, not being pregnant, and survival and the response to interventions may be different not having received anti-TB treatment during the previous for lean and fat mass (FM) depletion. For example, year. Among the 3349 subjects who fulfilled all criteria among HIV-infected adults, loss of metabolically active we obtained two additional early morning sputum samples lean tissue, as measured with body cell mass (BCM), has to confirm the smear results at the Muhimbili National been found to be a strong predictor of mortality, indepen- Hospital microbiology laboratory using Ziehl Neelsen stain- dent of FM (Kotler et al., 1989) or total body weight ing of smears, and sought informed consent for HIV testing. (Suttmann et al., 1995). In addition, lean mass of TB-infected Smear-positive TB was confirmed in 2960 people and 2360 adults may increase after nutritional supplementation consented for pretest counseling and HIV testing. Infection (Paton et al., 2004). A few cross-sectional studies examined with HIV-1 was assessed using two ELISA tests (Wellcozyme, the impact of HIV infection on body composition of Murex Biotech Ltd, Dartford, UK) (Urassa et al., 1994); adults with TB and yielded divergent results; BCM was found discrepant results were resolved by Western blot test (Genetic to be lower in coinfected men from Malawi (Van Lettow Systems, Redmond, WA, USA). et al., 2004), but not in patients from Uganda (Shah We provided post-test counseling and recruited tested et al., 2001) or Burundi (Niyongabo et al., 1994, 1999). In subjects who returned for their HIV results (n ¼ 2231). Malawi and Uganda, HIV coinfection was related to Trained research nurses collected information on age, level decreased phase angle, an indicator of cell membrane of education, marital status, and indicators of the socio- integrity that has been reported to be predictive of mortality economic status (SES) including type of household amenities (Ott et al., 1995; Schwenk et al., 2000). One of the reasons (Schellenberg et al., 2003), and frequency of meat purchase that could explain differences in the results across studies (red meat, fish or poultry) (Macdonald et al., 2004); and is that they did not take into account the influence of obtained anthropometric measurements using calibrated confounding factors that affect body composition and which instruments. There were two study nurses per clinic; they may also be associated with HIV infection in persons with underwent anthropometric training and standardization TB. Also, some of these studies are limited by relatively small (Lohman et al., 1988) in workshops conducted before the sample sizes. beginning of recruitment and every year into the study. We conducted a cross-sectional study in Dar es Salaam, Within- and between-observer variations in anthropometric Tanzania, to examine the contribution of HIV to wasting measurements were monitored during these workshops, among adults infected with TB. We identified correlates of and were kept to a minimum through the identification of wasting among socioeconomic characteristics and indicators specific problems in the measuring technique and retraining. of TB severity, and considered them as adjustment factors of Height was measured to the nearest 0.1 cm using SECA the association between HIV infection and wasting. Bodymeter 206 stadiometers, weight to the nearest 100 g in

European Journal of Clinical Nutrition Wasting in adults with tuberculosis E Villamor et al 165 SECA 700 balance beam scales, left mid-upper arm circum- adjusted differences between categories of the predictors ference (MUAC) at the midpoint between the acromion and were obtained from multivariate linear regression models. olecranon to the nearest 0.1 cm using nonstretchable tailor’s Confidence intervals for the differences were constructed tapes, and left triceps skin-fold (TSF) thickness with Holtain using robust estimates of the variance (White, 1980), to calipers. Arm muscle circumference (AMC) was calculated overcome potential deviations from normality in the as MUAC – (p  TSF) (World Health Organization Expert distributions of continuous outcomes. Committee on Physical Status, 1995), and body mass index We next compared the distributions of anthropometric (BMI) as weight/height2. measures by HIV status using the Wilcoxon rank-sum test, We performed bioelectrical impedance analysis (BIA) in a separately in men and women. Adjusted differences by HIV subsample of 731 subjects who had consented to participate were obtained from multivariate linear regression models in in a nutrition intervention trial. This sub-sample included which sociodemographic and TB-severity indicators were both HIV-negative (n ¼ 336) and HIV-positive (n ¼ 395) included as covariates. subjects. Single frequency BIA was carried out with tetrapolar In the subsample of subjects in whom body composition lead placement at 50 kHz and 800 mA using BIA-101Q and albumin concentration were measured, we tested analyzers (RJL Systems, Detroit, MI, USA). The analyzers differences in these outcomes by HIV status within genders. were recalibrated for each subject using the manufacturer’s Given that the subsample differed significantly from the device. BCM (BCM), fat-free mass (FFM), total body water original study population in various characteristics, the (TBW), and intracellular water (ICW) were estimated from associations between HIV and body composition variables the values of resistance and reactance obtained through BIA, were adjusted for those selection factors in a multivariate using sex-specific equations validated by Kotler et al. (1996) linear regression model. in a sample of white, black, and Hispanic patients that Finally, among HIV-infected participants in whom BIA was included HIV-infected individuals. These formulas had been performed, we examined the associations between CD4 cell previously used in African adults with pulmonary TB (Shah counts and body composition characteristics. et al., 2001; Van Lettow et al., 2004). FM was calculated Differences were considered to be statistically significant at as weight minus FFM, and extracellular water (ECW) as Pp0.05. All P-values are from two-sided tests. All analyses TBW minus ICW. Phase angle a was calculated as were carried out using the Statistical Analysis Systems (reactance  180)/(p  resistance) (Ott et al., 1995). Also in statistical software package version 8.0 (SAS Institute, Cary, this subsample, we examined CD4 T-lymphocyte cell counts NC, USA). using the FACScount system (Becton-Dickinson, San Jose, The study protocol was approved by the Research and CA, USA), and measured the concentration of serum Publications Committee at Muhimbili University College of albumin. All measurements in this cross-sectional study Health Sciences, and the Institutional Review Board of the were obtained immediately prior to the beginning of anti-TB Harvard School of Public Health. Each participant provided therapy. None of the HIV-infected subjects were receiving informed consent. antiretroviral medications since the anthropometric evalua- tion coincided with the time of HIV diagnosis. Results

Data analyses Of 2231 subjects included in the study, 69% (n ¼ 1545) were Anthropometric and body composition variables and men and 31% women, comparably with figures reported albumin were treated as continuous outcomes. The main previously by the National Tuberculosis and Leprosy Pro- predictor of interest was HIV status. Sociodemographic gramme: 61 and 39%, respectively (Range et al., 2001). The predictors were age, cohabiting with a partner, education average ages were 32 (s.d. ¼ 10) for men and 30 (s.d. ¼ 8) years level, frequency of meat purchase in the household, and for women. The majority (80%) had complete primary number of household assets from a list that included schooling and came from households with fewer than two sofa, television, radio, refrigerator, and fan. Indicators of assets from a list that included sofa, television, radio, the severity of TB were the Karnofsky performance score and refrigerator, and fan (59%). The prevalence of HIV infection the number of Mycobacterium tuberculosis bacilli per sputum was higher among women (50%) than men (24%), also in smear field (bacillary density according to the World Health agreement with a previous report (Range et al., 2001). Organization classification (World Health Organization, Compared to women, men were taller, and had greater MUAC 1998)). For each client, we chose the maximum density and AMC; in contrast, their average BMI and TSFs were lower. from all available baseline smears, prior to the initiation of anti-TB treatment. We compared the distribution of anthropometric out- Anthropometric differences by sociodemographic characteristics comes (height, BMI, TSF, MUAC, and AMC) by categories of and severity of TB (Table 1) sociodemographic variables and TB-severity indicators using Height. Height (data not shown) was significantly lower in the Kruskal–Wallis test. For each anthropometric outcome, men 450 years of age compared to men 21–30 years

European Journal of Clinical Nutrition 166 uoenJunlo lnclNutrition Clinical of Journal European

Table 1 Adjusted differences (95% CI) in anthropometric variables by sociodemographic characteristics of adult men (M) and women (W) with pulmonary tuberculosis in Tanzania*

Characteristic N BMI (kg/m2) Triceps skin-fold (mm) MUAC (cm) AMC (cm)

MWMWMWMWMW

Age (years) P ¼ 0.01 P ¼ 0.0004 P ¼ 0.34 P ¼ 0.02 P ¼ 0.44 Po0.0001 P ¼ 0.86 Po0.0001 p20 106 55 À0.4 (À0.9, 0.0) À0.6 (À1.4, 0.2) À0.1 (À0.9, 0.6) À0.6 (À1.9, 0.6) À0.6 (À1.1, À0.1) À1.1 (À1.8, À0.3) À0.5 (À1.0, 0.0) À0.8 (À1.4, À0.2) 21–30 678 384 Reference Reference Reference Reference Reference Reference Reference Reference 31–40 489 166 0.0 (À0.2, 0.3) 0.7 (0.1, 1.4) 0.0 (À0.5, 0.4) 0.6 (À0.4, 1.5) À0.1 (À0.4, 0.2) 0.9 (0.3, 1.5) À0.1 (À0.4, 0.2) 0.7 (0.3, 1.2) 41–50 174 58 0.1 (À0.3, 0.5) 0.6 (À0.6, 1.8) 0.3 (À0.4, 1.0) 1.1 (À0.5, 2.6) 0.0 (À0.4, 0.5) 0.8 (À0.2, 1.8) 0.0 (À0.5, 0.4) 0.3 (À0.3, 1.0) X

51 93 20 0.7 (0.1, 1.4) 2.2 (0.6, 3.7) 0.3 (À0.5, 1.1) 1.2 (À0.9, 3.4) 0.0 (À0.6, 0.6) 2.0 (0.5, 3.6) À0.2 (À0.7, 0.3) 1.8 (0.6, 3.0) tuberculosis with adults in Wasting

Education level P ¼ 0.26 P ¼ 0.80 P ¼ 0.53 P ¼ 0.08 P ¼ 0.88 P ¼ 0.75 P ¼ 0.99 P ¼ 0.39 None formal 120 114 0.1 (À0.4, 0.6) À0.3 (À1.4, 0.7) À0.1 (À1.1, 0.8) À2.0 (À3.8, À0.3) À0.1 (À0.6, 0.5) À0.2 (À1.2, 0.8) À0.1 (À0.6, 0.5) 0.4 (À0.4, 1.1) Low o5 years 139 70 0.5 (À0.1, 1.0) À0.6 (À1.7, 0.6) À0.5 (À1.3, 0.3) À1.2 (À3.0, 0.6) 0.0 (À0.5, 0.6) 0.2 (À0.8, 1.2) 0.2 (À0.3, 0.8) 0.6 (À0.1, 1.4) Primary 5–8 years 1085 439 0.1 (À0.3, 0.4) À0.8 (À1.7, 0.2) À0.2 (À0.8, 0.4) À1.4 (À2.8, 0.1) 0.0 (À0.4, 0.4) À0.4 (À1.2, 0.5) 0.1 (À0.3, 0.4) 0.3 (À0.3, 0.9) Secondary 48 years 195 61 Reference Reference Reference Reference Reference Reference Reference Reference Villamor E Cohabits with a partner P ¼ 0.002 P ¼ 0.33 P ¼ 0.20 P ¼ 0.51 P ¼ 0.002 P ¼ 0.22 P ¼ 0.06 P ¼ 0.14 No 847 320 Reference Reference Reference Reference Reference Reference Reference Reference Yes 695 365 0.4 (0.1, 0.6) 0.3 (À0.3, 0.8) 0.3 (À0.1, 0.7) À0.3 (À1.0, 0.5) 0.4 (0.2, 0.7) 0.3 (À0.2, 0.8) 0.3 (0.0, 0.5) 0.3 (À0.1, 0.6) tal et

Number of household assetsa Po0.0001 P ¼ 0.003 P ¼ 0.02 P ¼ 0.52 P ¼ 0.005 P ¼ 0.07 P ¼ 0.06 P ¼ 0.13 None 490 267 À1.2 (À1.8, À0.7) À1.3 (À2.3, À0.3) À1.2 (À2.0, À0.3) À0.8 (À2.2, 0.6) À0.9 (À1.4, À0.4) À1.0 (À1.9, À0.2) À0.7 (À1.1, À0.2) À0.6 (À1.2, 0.0) 1 394 162 À1.3 (À1.8, À0.7) À1.1 (À2.2, 0.0) À1.3 (À2.2, À0.4) À0.5 (À2.0, 1.0) À1.1 (À1.6, À0.6) À0.7 (À1.6, 0.2) À0.7 (À1.2, À0.3) À0.5 (À1.2, 0.2) 2–3 518 196 À1.0 (À1.5, À0.4) À0.6 (À1.6, 0.4) À1.0 (À1.8, À0.1) À0.8 (À2.2, 0.6) À0.8 (À1.3, À0.3) À0.8 (À1.7, 0.0) À0.6 (À1.1, À0.2) À0.5 (À1.1, 0.1) 4–5 143 61 Reference Reference Reference Reference Reference Reference Reference Reference

Frequency of meat purchase P ¼ 0.08 P ¼ 0.92 P ¼ 0.13 P ¼ 0.03 P ¼ 0.30 P ¼ 0.73 P ¼ 0.84 P ¼ 0.65 o1/month 85 36 À0.7 (À1.3, À0.1) À0.8 (À2.6, 1.1) À0.7 (À1.7, 0.4) À2.8 (À5.4, À0.2) À0.8 (À1.4, À0.2) À0.9 (À2.4, 0.6) À0.6 (À1.3, 0.0) À0.2 (À1.5, 1.0) 1–3/month 394 193 À0.4 (À0.9, 0.1) À0.4 (À2.1, 1.3) À0.7 (À1.4, 0.1) À2.0 (À4.5, 0.4) À0.5 (À0.9, 0.0) À0.7 (À1.9, 0.4) À0.3 (À0.8, 0.3) À0.3 (À1.2, 0.6) 1/week 349 177 À0.5 (À1.0, 0.0) À0.6 (À2.3, 1.1) À0.2 (À1.1, 0.6) À2.0 (À4.5, 0.4) À0.5 (À1.0, À0.1) À0.9 (À2.0, 0.3) À0.5 (À1.0, 0.0) À0.5 (À1.3, 0.4) 2–4/week 608 251 À0.3 (À0.8, 0.1) À0.6 (À2.2, 1.1) À0.4 (À1.1, 0.3) À1.4 (À3.8, 0.9) À0.6 (À1.0, À0.1) À0.8 (À1.9, 0.3) À0.5 (À1.0, 0.0) À0.5 (À1.3, 0.4) 5–7/week 106 27 Reference Reference Reference Reference Reference Reference Reference Reference

Karnofsky score Po0.0001 Po0.0001 Po0.0001 Po0.0001 Po0.0001 Po0.0001 Po0.0001 Po0.0001 X70% 1355 552 Reference Reference Reference Reference Reference Reference Reference Reference o70% 172 131 À1.5 (À1.8, À1.2) À1.8 (À2.3, À1.2) À0.6 (À1.2, 0.0) À1.5 (À2.4, À0.5) À1.6 (À2.0, À1.3) À2.1 (À2.7, À1.6) À1.5 (À1.9, À1.2) À1.6 (À2.0, À1.2)

Bacillary density in AFB smear P ¼ 0.0008 P ¼ 0.50 Po0.0001 P ¼ 0.002 P ¼ 0.0007 P ¼ 0.03 P ¼ 0.55 P ¼ 0.13 o1/field 354 215 Reference Reference Reference Reference Reference Reference Reference Reference 1–10/field 443 170 À0.2 (À0.5, 0.2) À0.2 (À0.9, 0.4) À0.2 (À0.8, 0.4) À1.0 (À2.0, 0.0) À0.1 (À0.5, 0.2) À0.5 (À1.1, 0.1) À0.1 (À0.4, 0.3) À0.2 (À0.6, 0.3) 410/field 744 296 À0.5 (À0.8, À0.2) 0.2 (À0.4, 0.8) À1.4 (À1.9, À0.9) À1.4 (À2.3, À0.6) À0.5 (À0.8, À0.2) À0.6 (À1.2, À0.1) À0.1 (À0.4, 0.2) À0.3 (À0.7, 0.1)

*Differences and 95% confidence intervals (CI) are from linear regression models (one for each anthropometric outcome, separately for men and women) that included HIV status and all the sociodemographic characteristics presented in the table as covariates. P-values are for trend tests and correspond to each sociodemographic characteristic when introduced into the model as a continuous predictor representing the ordinal categories. For the partner variable, P-value corresponds to ‘yes’ vs ‘no’. aFrom a list that included sofa, television, radio, refrigerator, and fan. Wasting in adults with tuberculosis E Villamor et al 167 (adjusted difference ¼À1.8 cm, P ¼ 0.02). Women p20 years Anthropometric differences by HIV status (Table 2) were À3.5 cm significantly shorter than those 21–30 years After adjusting for sociodemographic potential confounders (P ¼ 0.0002). The level of education (P for trend ¼ 0.0005 and and TB severity, HIV-infected men had significantly lower 0.06 in men and women, respectively) and the frequency of MUAC (P ¼ 0.05) and AMC (P ¼ 0.02) than those who were meat purchase at home (P for trend ¼ 0.01 and 0.03) were HIV-uninfected men (difference in each ¼À0.3 cm). Simi- positively related to height in both men and women, after larly, HIV infection was associated with significantly lower adjustment for age and other sociodemographic character- MUAC (À0.6 cm, P ¼ 0.02) and AMC (À0.3 cm, P ¼ 0.05) in istics. There was a strong inverse association between height women. TSF appeared to be lower among HIV-infected and bacillary density in women (adjusted difference between women compared to HIV-uninfected women, but this 410/field and o1/field ¼À2.1 cm, P ¼ 0.0005, P for tren- association was only marginally significant after adjustment d ¼ 0.0007). for other factors (P ¼ 0.07). HIV was not related to BMI.

Body mass index. In multivariate analyses among men, BMI was positively associated with age, cohabiting with a Differences in body composition and albumin concentrations by partner, the number of assets, the frequency of meat purchase, HIV status and the Karnofsky performance score, and inversely with The subsample of subjects in whom we measured body bacillary density in the AFB smear, an indicator of the composition and albumin (n ¼ 731) differed in various severity of TB infection; in women, BMI was positively aspects from the group that was not measured (Table 3). By related to age, the number of household assets, and the design, HIV-positive subjects were over-represented in this Karnofsky score. subsample. HIV-infected persons in the subsample had lower bacillary density and higher average weight, BMI, triceps, Triceps skin-fold. TSF was positively and significantly asso- MUAC, and AMC than nonincluded HIV-positive subjects. ciated with the number of household assets in men. In In contrast, HIV-negative subjects in the subsample had women, it was directly related to age, education level, and greater bacillary density and lower weight, BMI, MUAC, frequency of meat purchase. In both men and women, TSF and AMC than the HIV-negative individuals who were not was independently associated with decreased severity of TB included. There were also differences in the distributions of infection as indicated by higher Karnofsky scores and lower gender, age, cohabiting with a partner, and socioeconomic bacillary density. indicators. Owing to these disparities, the differences in body composition variables by HIV status were adjusted for the Mid-upper arm and AMCs. In both men and women, MUAC characteristics that were known to differ between the and AMC were each positively associated with the number subsample and the subjects who were not measured. of household assets and the Karnofsky score. MUAC but Among men, HIV infection appeared to be significantly not AMC was negatively related to bacillary density. MUAC associated with increased TBW, but not with other measure- was significantly higher among men who lived with a ments of body composition (Table 4). In women, by contrast, partner; whereas in women both MUAC and AMC increased HIV infection was related to significantly lower mean ICW significantly with age. (À0.7 L, P ¼ 0.04), ICW to ECW ratio (À0.04, P ¼ 0.01), BCM

Table 2 Anthropometric characteristics by HIV status in adult men and women infected with tuberculosis, Tanzania

Characteristic* Men Women

w w HIV-positive HIV-negative Adjusted difference (95% CI) HIV-positive HIV-negative Adjusted difference (95% CI)

N 376 1169 344 342 Height (cm) 166.977.2 167.176.6 0.0 (À0.9, 0.8) 156.376.5 156.576.5 À0.8 (À1.7, 0.2) Weight (kg) 52.877.4 52.677.0 À0.1 (À1.0, 0.7) 47.179.2 47.378.0 À0.3 (À1.6, 1.0) BMI (kg/m2) 19.072.4 18.972.2 À0.1 (À0.3, 0.2) 19.373.7 19.373.0 0.1 (À0.4, 0.6) Triceps skin-fold (mm) 7.074.2 6.873.5 0.1 (À0.4, 0.6) 10.074.9 10.574.6 À0.7 (À1.4, 0.1) y MUAC (cm) 23.172.5 23.372.4 À0.3 (À0.6, 0.0)z 22.673.3 23.273.2 À0.6 (À1.0, À0.1) y AMC (cm) 20.872.3 21.272.3 À0.3 (À0.6, 0.0) 19.572.3 19.872.4 À0.3 (À0.7, 0.0)z

*Values are mean7s.d. w From linear regression models (one for each outcome, separately for men and women) that included HIV status and the following covariates: age group in decades (p20, 21–30, 31–40, 41–50, X51; four indicator variables), education level (none, o5, 5–8, 48 years; three indicators), whether the subject cohabits with a partner (Y/N), the number of household assets from a list that included sofa, television, radio, refrigerator, and fan (0, 1, 2–3, 4–5; three indicators), the frequency of meat purchase at home (o1/mo, 1–3/mo, 1/wk, 2–4/wk, 5–7/wk; four indicators), the Karnofsky performance score (Xvs :o 70%), and the bacillary density in AFB smear (o1/field, 1–10/field, 410/field; two indicators). Significant P-values: z¼0.05; y ¼ 0.02.

European Journal of Clinical Nutrition Wasting in adults with tuberculosis E Villamor et al 168 Table 3 Characteristics of the subsample with body composition (BC) assessment in comparison to subjects without assessment

Characteristic HIV-positive HIV-negative

BC assessed BC not assessed P* BC assessed BC not assessed P*

n 395 325 336 1175 % Female 41.8 55.1 0.0004 22.6 22.6 0.99 Mean age7s.d. 34.078.4 32.277.6 0.03 30.378.9 30.8710.0 0.87 % Low or no education 20.3 21.8 0.61 22.0 18.7 0.18 % With partner 55.9 50.0 0.12 51.5 43.0 0.006 Mean of number household assets7s.d. 1.771.5 1.471.4 0.01 1.471.3 1.471.4 0.42

Frequency of meat purchase, % 0.31 0.14 o 1/week 30.9 34.8 29.0 32.1 1/week 23.8 25.5 20.9 23.8 41/week 45.3 39.7 50.2 44.1 % With Karnofsky performance score o70% 15.2 21.4 0.03 9.3 12.4 0.12

Bacillary density, % 0.03 o0.0001 o1/field 33.8 27.8 10.8 26.6 1–10/field 28.1 24.4 12.2 32.7 410/field 38.1 47.8 77.0 40.8

Anthropometry – mean7s.d. Height (cm) 162.078.8 161.678.5 0.25 164.478.0 164.877.9 0.32 Weight (kg) 51.078.9 48.978.5 0.001 50.677.4 51.677.6 0.05 BMI (kg/m2) 19.473.0 18.773.1 0.0001 18.772.6 19.072.4 0.03 Mid-upper arm circumference (cm) 23.372.7 22.373.0 o0.0001 22.972.5 23.472.6 0.002 Triceps skin-fold (mm) 9.174.9 7.774.5 o0.0001 7.774.3 7.673.9 0.39 Arm muscle circumference (cm) 20.572.3 19.872.4 0.002 20.572.3 21.072.4 0.0006

*The Wilcoxon rank-sum and w2 tests were used for continuous and categorical characteristics, respectively.

(À0.9 kg, P ¼ 0.04), and phase angle a (À0.5, P ¼ 0.02). Mean prevents us from formally testing whether there is synergism serum albumin concentrations of HIV-infected men and between HIV and TB in the pathogenesis of women were significantly lower than those of HIV-un- wasting. However, our findings provide indirect support for infected subjects; the association was stronger in women. such synergism. On the one hand, the mean BMI and MUAC We next examined differences in body composition and in this group of TB-infected adults were much lower than albumin concentrations by CD4 cell counts among HIV- those recently reported for the general population in the infected subjects. In men, low CD4 cell counts (o200/mm3) city of Dar es Salaam (Bovet et al., 2002; Villamor et al., were significantly related to decreased TBW (adjusted 2002). On the other, HIV/TB coinfected subjects in our study difference (AD) between o and X200/mm3 ¼À1.23 l; 95% had significantly lower MUAC and AMC than those who CI ¼À2.44, À0.01; P ¼ 0.05), ICW (AD ¼À1.23 l; 95% were only TB positive. CI ¼À2.28, À0.19; P ¼ 0.02), ICW to ECW ratio (AD ¼À0.15; Longitudinal studies of presumably TB-uninfected subjects 95% CI ¼À0.29, À0.01; P ¼ 0.03), BCM (AD ¼À1.54 kg; 95% suggest that the impact of HIV infection on body composi- CI ¼À2.84, À0.23; P ¼ 0.02), FFM (AD ¼À1.38 kg; 95% tion strongly depends on gender and the baseline distribu- CI ¼À2.66, À0.10; P ¼ 0.04), and phase angle a (AD ¼À0.53; tion of fat and lean mass. In men with low baseline fat, 95% CI ¼À1.04, À0.02; P ¼ 0.04). In HIV-positive women, HIV infection results in a preferential loss of lean mass; by there were no significant differences in body composition contrast, in men with high baseline fat HIV infection variables by CD4 cell counts, after adjusting for a number of induces greater loss of fat than lean mass (Mulligan et al., covariates. Albumin concentrations were not associated with 1997; Forrester et al., 2002). In general, women have greater CD4 cell counts in HIV-positive subjects. fat percentage than men and the impact of HIV on wasting of lean mass appears to be independent of their initial fat percentage (Forrester et al., 2002); HIV-infected women with Discussion high initial fat percentage seem to lose more fat than lean mass (Kotler et al., 1999; Forrester et al., 2002). Whether In this cross-sectional study of adults with pulmonary TB, these relations exist among subjects who are infected with coinfection with HIV was related to indicators of low lean TB is not known. One major consideration is that TB- body mass including AMC and, among women, BCM. The infected subjects are expected to have lower baseline BMI lack of inclusion of TB-uninfected subjects in the study and FM than those who are TB uninfected. In studies of

European Journal of Clinical Nutrition Wasting in adults with tuberculosis E Villamor et al 169 Table 4 Body composition and albumin concentrations by HIV status in a sample of adults with pulmonary tuberculosis, Dar es Salaam, Tanzania

Characteristic (mean7s.d.) Men Women

HIV-positive HIV-negative Adjusted difference (95% CI)a HIV-positive HIV-negative Adjusted difference (95% CI)a

N 230 260 165 76

Body composition Reactance (O) 520781 537779 — 624798 6097108 — Resistance (O)57711 58710 — 61710 63712 — TBW (l) 35.274.5 34.274.2 0.77 (0.04, 1.50)w 28.274.1 28.573.5 À0.81 (À1.85, 0.22) ICW (l) 19.873.7 19.273.6 0.56 (À0.09, 1.21) 12.772.3 13.072.0 À0.68 (À1.32, À0.04)w ECW (l) 15.472.4 14.972.0 0.21 (À0.20, 0.62) 15.572.1 15.571.9 À0.13 (À0.62, 0.36) ICW:ECW ratio 1.370.5 1.370.6 0.04 (À0.04, 0.13) 0.870.1 0.870.1 À0.04 (À0.07, À0.01)z BCM (kg) 24.774.6 24.074.5 0.70 (À0.11, 1.51) 15.872.9 16.272.6 À0.85 (À1.65, À0.06)w Fat mass (kg) 4.574.0 4.173.2 À0.38 (À0.85, 0.10) 12.678.2 11.378.0 0.91 (À0.20, 2.02) FFM (kg) 48.975.1 47.874.7 0.80 (À0.01, 1.60) 35.274.6 35.673.9 À0.96 (À2.16, 0.25) Percent fat (g/100g) 7.976.2 7.575.5 À0.82 (À1.70, 0.05) 24.7711.7 22.4712.6 2.02 (À0.27, 4.31) Phase angle a 6.471.8 6.371.7 0.13 (À0.20, 0.47) 5.771.3 6.071.4 À0.52 (À0.95, À0.09)y

Serum albumin (g/l) 28710 32711 À2.9 (À5.1, À0.7)z 29711 34711 À5.7 (À9.6, À1.9)z aFrom linear regression models (one for each characteristic, separately for men and women) with predictors that included: HIV status, age (five categories), education level (four categories), whether the person cohabits with a partner (Y/N), number of household assets (four categories), frequency of meat purchase at home (five categories), Karnofsky performance score (Xvs o70%), bacillary density in AFB smear (three categories), and body mass index (continuous). 95% confidence intervals (CI) were constructed using empirical variances. Significant P-values: w ¼ 0.04; z¼0.01; y ¼ 0.02; z ¼ 0.004.

TB þ /HIVÀ African adults with pulmonary TB (Shah et al., tions. In our study, a decrease in lean mass among men could 2001; Van Lettow et al., 2004), including ours, the typical have been underestimated by relative increases in ECW, average BMI is around 18–19 kg/m2 in both men and which have been reported to occur in TB þ /HIV þ subjects women. Also, fat percent is usually o8% in men and (Paton et al., 1999); we observed a nonsignificant positive 20–24% in women, compared to E15 and E31% in TB- relation between HIV infection and ECW. Varying sample uninfected men and women from other African settings sizes and confounding patterns could also account for (Kotler et al., 1999). Results on the additional impact of HIV differences across studies; it is also possible that among on wasting at these low levels of fat percent in TB-infected individuals infected with TB, factors other than gender or subjects are inconsistent. HIV infection was related to lower the baseline size of the fat compartment modify the effect of BMI in some (Niyongabo et al., 1994, 1999; Kennedy et al., HIV infection on wasting. The estimation of body compart- 1996) but not all (Shah et al., 2001; Madebo et al., 2003; Van ments using BIA in the context of TB needs to be interpreted Lettow et al., 2004) these previous studies. We did not find with caution as it is subjected to assumptions that may not associations between HIV and anthropometric indicators hold in this severely wasted subpopulation. of FM such as BMI or TSF; however, we found that HIV The phase angle is an indicator of water distribution infection was associated with decreased indicators of lean between intra- and extracellular compartments, and mem- mass such as the AMC, in both men and women. Studies in brane integrity. Among HIV-infected individuals, the phase England (Onwubalili, 1988) and Haiti had also reported such angle has been inversely related to the risk of death (Ott an association (Scalcini et al., 1991). et al., 1995; Schwenk et al., 2000), although a precise From the anthropometric evidence, it is tempting to mechanism is not known yet. In this study, the average speculate that among TB patients with low BMI and FM, phase angle in both HIV-positive and -negative subjects HIV coinfection induces a preferential loss of lean mass. was lower than the means reported among healthy adults Cross-sectional studies of body composition provide partial (Ellis, 2000). We found that HIV infection was associated support to this possibility; an inverse association between with lower phase angle in women, while in the Malawi and BCM and HIV infection was found among TB-coinfected Uganda studies an association in the same direction was Malawian men (Van Lettow et al., 2004), and in women from observed only in men. We also found that HIV-infected men our Tanzanian population, without an apparent impact on with lower CD4 cell counts had decreased phase angle, FM. Also, both in our study and Uganda (Shah et al., 2001), suggesting that it is related to progression. Future severity of HIV infection as measured with CD4 cell counts studies are warranted on the value of phase angle to predict was associated with loss of lean mass. It is not clear why the mortality and other adverse outcomes in patients with TB. apparent effect of HIV infection on lean body mass among Consistent with previous reports from Burundi (Niyongabo adults with TB appears to differ by gender across popula- et al., 1999), Uganda (Shah et al., 2001), and Haiti

European Journal of Clinical Nutrition Wasting in adults with tuberculosis E Villamor et al 170 (Scalcini et al., 1991), albumin concentrations were inversely In conclusion, HIV infection is associated with indicators related to HIV infection in our study. Although these results of decreased lean body mass in patients with pulmonary TB. suggest that hypoalbuminemia is a frequent finding among The degree of wasting correlates with the severity of both HIV/TB coinfected adults, its usefulness as an indicator of HIV and TB infections. Whether loss of lean body mass is poor nutritional status is questionable in persons with severe associated with adverse health and survival outcomes among infections since concentrations can be downregulated by patients with TB needs to be examined in longitudinal cytokines IL-1 and IL-6 during the acute phase response. It is studies. Independent of HIV infection, poor socioeconomic likely that hypoalbuminemia reflects a generalized state of status is an important predictor of anthropometry in inflammation instead. patients with TB. The efficacy of nutritional interventions Independent of HIV infection, wasting among subjects as adjuvants of antimicrobial therapy on wasting and clinical with TB in our study was strongly associated with the outcomes requires evaluation in future trials. severity of TB. BMI, TSF, and MUAC were each significant and positively related to the Karnofsky score and inversely associated with bacillary density, consistent with a recent study in Malawi where BMI, FM, and phase angle were Acknowledgements inversely related to the radiological severity of TB (Van Lettow et al., 2004). Anthropometric indicators were also We thank the study participants, and the study coordinator, strongly related to the socioeconomic status. It is funda- supervisors, nurses, and laboratory technicians who made mental to consider insufficient dietary intake due to poverty this research possible. This study was supported by the among the causes of wasting in sub-Saharan Africa. Dietary National Institute of Allergy and Infectious Diseases (UO1 AI assessment and food security studies should provide clues 45441-01) of the United States of America. to the potential of protein and energy supplementation to TB-infected persons as a public health strategy to improve clinical outcomes. The main strengths of our study are its large sample size References and the inclusion of important correlates of wasting as Bovet P, Ross AG, Gervasoni JP, Mkamba M, Mtasiwa DM, Lengeler C adjustment covariates for the impact of HIV. Nevertheless, et al. (2002). Distribution of blood pressure, body mass index and the study has some limitations. 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