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The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA;
Tuberculosis Research Unit, Department of Epidemiology, Case Western Reserve University, Cleveland, OH;
Division of Gastroenterology, Department of Medicine, St. Luke’s-Roosevelt Hospital Center, New York, NY;
Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD; and
Department of Medicine, Makerere University, Kampala, Uganda
**
*
2To whom correspondence should be addressed. E-mail: rdsemba{at}jhmi.edu
ABSTRACT
Although coinfection with tuberculosis and human immunodeficiency virus
(HIV) is emerging as a major problem in many developing countries,
nutritional status has not been well characterized in adults with
tuberculosis and HIV infection. We compared nutritional status between
261 HIV-positive and 278 HIV-negative adults with pulmonary
tuberculosis in Kampala, Uganda, using anthropometry and bioelectrical
impedance analysis. Among 163 HIV-positive and 199 HIV-negative
men, intracellular water–to–extracellular water (ICW:ECW) ratio was
1.48 ± 0.26 and 1.59 ± 0.48 (P = 0.006)
and phase angle was 5.42 ± 1.05 and 5.76 ± 1.30
(P = 0.009), respectively. Among 98
HIV-positive and 79 HIV-negative women, ICW:ECW was 1.19
± 0.16 and 1.23 ± 0.15 (P = 0.11) and
phase angle was 5.35 ± 1.27 and 5.43 ± 0.93
(P = 0.61), respectively. There were no significant
differences in BMI, body cell mass, fat mass or fat-free mass
between HIV-positive and HIV-negative adults. Among
HIV-positive subjects, BMI, ICW:ECW, body cell mass, fat mass and
phase angle were significantly lower among those with CD4+
lymphocytes 
200 cells/µL compared with those who had >200
cells/µL. In sub-Saharan Africa, coinfection with pulmonary
tuberculosis and HIV is associated with smaller body cell mass and
intracellular water, but not fat-free mass, and by large
differences in ICW:ECW and phase angle 
.
KEY WORDS: • acquired immune deficiency syndrome • AIDS • human immunodeficiency virus infection • HIV • malnutrition • body composition • bioelectrical impedance • tuberculosis
There are an estimated 1.86 billion individuals, or nearly one-third
of the world’s population, infected with Mycobacterium
tuberculosis, and the majority of these individuals live in
developing countries where human immunodeficiency
(HIV)3 is a major public health problem
(1
). Tuberculosis accounts for three million deaths a
year, making it the leading infectious cause of death, far surpassing
measles (two million deaths per year) and malaria (one million deaths
per year) (2
). In 1997 there were 7.96 million new cases
and 16.2 million existing cases of tuberculosis, and 8% of incident
cases of tuberculosis were coinfected with HIV (1
). Among
the major infectious diseases, tuberculosis has long been associated
with malnutrition, a factor that is known to play a role in the
reactivation of latent tuberculosis infection (3
).
In sub-Saharan Africa, tuberculosis is one of the most common
opportunistic infections among HIV-infected adults
(4
). Although malnutrition is associated with
tuberculosis, there have been few studies addressing nutritional status
in HIV-infected adults with tuberculosis. These studies have been
limited to assessment of body weight (5
) and serum albumin
concentrations (6
). A recent study from Burundi among
adults with tuberculosis, including pulmonary, extra-pulmonary and
disseminated infection, suggests that those infected with HIV have
significantly lower weight, BMI and fat-free mass compared with
individuals without concurrent HIV infection (7
).
Moreover, there appears to be a relationship between BMI, host
immune function and the natural history of HIV in adults with
tuberculosis (8
).
Bioelectrical impedance analysis (BIA) has been proposed for
nutritional studies in HIV-infected individuals and has been shown
to be sufficiently precise for clinical investigation (9
).
Phase angle , the relationship between two vector components of
resistance and reactance that is considered to indicate water
distribution between extra- and intracellular spaces, has been shown to
be an independent predictor of mortality during HIV infection
(10
, 11
). Body cell mass also appears to be an independent
predictor of mortality among HIV-infected adults in the era before
highly active antiretroviral therapy (12
). To gain further
insight into body composition in adults with pulmonary tuberculosis, we
conducted a study that compared nutritional status between
HIV-infected and uninfected adults with pulmonary tuberculosis in
Kampala, Uganda using BIA.
MATERIALS AND METHODS
The study population consisted of adults who presented with sputum-positive pulmonary tuberculosis to the National Tuberculosis and Leprosy Program at the Tuberculosis Clinic of Old Mulago Hospital, Kampala, Uganda between February 1999 and January 2000. Subjects were offered HIV testing and were screened for HIV-1 antibodies after oral informed consent. All subjects were given appropriate pre- and post-test HIV counseling and AIDS education. At enrollment, basic demographic information and a medical history were collected, and a standardized physical examination was conducted by a medical officer. Subjects received standard four-drug chemotherapy for tuberculosis per guidelines of the Ugandan Ministry of Health. Adults with a previous history of treated pulmonary tuberculosis were excluded. The study was approved by the institutional review boards at Case Western Reserve University and the Ugandan National AIDS Research Subcommittee, with final approval by the Office for Protection from Research Risk of the National Institutes of Health.
Single-frequency BIA was performed at 50 kHz and 800 µA (RJL Systems,
Detroit, MI) with standard tetrapolar lead placement (13
).
Before performing measurements on each subject, the BIA instrument was
calibrated using the manufacturer’s recalibration device. The
resistance (R) and reactance
(Xc) are based on measures of a series
circuit (9
). BIA measurements were performed in triplicate
for each subject. The reproducibility of the R and
Xc measurements on repeated
measurement in the clinic was <1%. Body weight was determined to the
nearest 0.1 kg using a SECA adult balance, and standing height was
determined to the nearest 2 mm. Triceps skinfold thickness was measured
using Holtain calipers. Total body water (TBW), body cell mass (BCM),
fat-free mass (FFM) and intracellular water (ICW) were calculated
from BIA measurements using equations that were previously
cross-validated in a sample of patients (white, black and Hispanic)
with and without HIV infection (9
). Extracellular water
(ECW) was calculated as TBW minus ICW, and fat mass (FM) was calculated
as body weight minus FFM. HIV-1 infection was diagnosed on the basis of
a positive enzyme-linked immunosorbent assay for HIV-1 antibodies
(Recombigen; Cambridge Biotech, Cambridge, MA). At enrollment, a
complete blood count and differential white blood cell count were done
using an automated cell counter (T540 Coulter, Hialeah, FL), and
CD4+ lymphocytes were measured using standard
two-color flow cytometry (14
).
Student’s t test was used to compare normally distributed
variables between groups. Men and women were analyzed separately. Exact
and 
2 tests were used for comparisons of
categorical variables between groups. HIV-infected adults were
divided into two groups based upon CD4+
lymphocyte count above and below 200 cells/µL, per convention. BMI
< 19 kg/m2 was considered consistent with
malnutrition (15
). Phase angle < 5.3° was used
because this cutoff was previously shown to be predictive of mortality
in HIV-infected adults (11
).
RESULTS
There were 278 HIV-negative and 261 HIV-positive adults
with pulmonary tuberculosis enrolled in the study, and demographic
characteristics and some laboratory variables are shown in Table 1
. Among both men and women with pulmonary tuberculosis, HIV-positive
individuals were older and had a lower mean CD4+
lymphocyte count, serum albumin level and hemoglobin level than
HIV-negative individuals. A larger proportion of HIV-positive
individuals with pulmonary tuberculosis were female compared with
HIV-negative individuals. CD4+ lymphocytes,
serum albumin and hemoglobin were not measured on 5, 15 and 5 of the
539 total participants in the study, respectively, because of lack of
availability of an adequate blood sample for analysis.
|
. Among both men and women, there were no significant differences in BMI
or the proportion of individuals with BMI < 19
kg/m2 by HIV status. Intracellular to
extracellular water ratio (ICW:ECW) and phase angle were
significantly lower in HIV-positive than in HIV-negative men
with pulmonary tuberculosis. The proportion of adults with phase angle
< 5.3° was significantly higher in HIV-positive
compared with HIV-negative men. There were no significant
differences in BMI or indicators from BIA between HIV-positive
compared with HIV-negative women.
|
200 and >200 cells/µL (Table 3
). Among both men and women, those with CD4+
lymphocyte counts 200 cells/µL had significantly lower mean BMI,
reactance, ICW, ICW:ECW, BCM, fat mass and phase angle than
individuals with CD4+ lymphocyte counts >200
cells/µL. The proportion of individuals with BMI < 19
kg/m2 and with phase angle <5.3° was
significantly higher with CD4+ lymphocyte count
200 than >200 cells/µL among both men and women.
|
DISCUSSION
This study demonstrates that poor nutritional
status is common among adults with pulmonary tuberculosis in Uganda.
The mean BMI in this population was 18.1 among both HIV-positive
and HIV-negative men and 19.8 and 19.3 among HIV-positive and
HIV-negative women, respectively. In comparison, in the era before
highly active antiretroviral therapy in other populations, adults with
advanced AIDS in Germany in 1993 had mean BMI of 21.4
kg/m2 (12
), men with AIDS in San
Francisco had mean BMI of 22.6 kg/m2
(16
) and men with advanced HIV disease in the U.K. had
mean BMI of 21.4 kg/m2 (17
). Mean
BMI and the proportion of individuals with BMI <19
kg/m2 were not significantly different between
HIV-positive and HIV-negative adults who were newly diagnosed
with pulmonary tuberculosis in Kampala, Uganda. These findings raise
the possibility that generalized malnutrition may be a greater risk
factor for developing pulmonary tuberculosis than HIV infection alone.
The present study was limited by not having a group of control subjects
who were HIV-negative and had no pulmonary tuberculosis. However,
we have previously studied a control group of 569 healthy men and women
in sub-Saharan Africa using the same instrument and methods
(18
). Among 297 men, mean BCM (± SD), FFM and fat mass
were 26.9 ± 4.3, 54.3 ± 7.2 and 10.4 ± 5.6,
respectively. Among 272 women, mean BCM, FFM and fat mass were 19.7
± 2.5, 41.7 ± 4.5 and 20.3 ± 10.5, respectively. In
comparison with these healthy control subjects from sub-Saharan
Africa, the men and women with pulmonary tuberculosis in the present
study had lower mean BCM, FFM and fat mass.
In the present study, results were reported separately for men and
women, as there are large differences in BMI, BCM, fat mass and FFM by
sex (18
). The results of the present study do not
corroborate the findings of a previous study from Burundi, in which BMI
was significantly lower in 22 HIV-positive than in 11
HIV-negative adults with pulmonary tuberculosis, but there were
disproportionate numbers of men and women in each group
(7
). The present study compared HIV-positive and
HIV-negative adults who all presented with pulmonary tuberculosis.
A study from Brazil showed that BCM was significantly lower among 12
HIV-positive men with tuberculosis than among 11 HIV-positive
men without tuberculosis (19
).
The present study shows that among adults with pulmonary tuberculosis,
the main alterations in body composition associated with concurrent HIV
infection are lower ICW:ECW ratio and lower phase angle . Among
HIV-positive adults with pulmonary tuberculosis, lower BMI, lower
ICW:ECW, lower phase angle and loss of BCM and fat mass were
associated with more advanced HIV infection, i.e.,
CD4+ lymphocyte count <200 cells/µL. Depletion
of BCM has been associated with an increased risk of death among adults
with HIV infection (20
). Body composition as reflected by
a low phase angle has been shown to be an important determinant of
survival during HIV infection (10
, 11
). The phase angle
represents that distribution of water between intracellular and
extracellular spaces (11
). It is still unclear why this
derived indicator from BIA is such a strong predictor of survival
during HIV infection. During semistarvation, the ECW does not change
much (21
); thus, phase angle appears to be superior to
reactance or ICW alone. In healthy adults, the phase angle at 50 kHz is
usually in the range of 8–15° (22
). Among
HIV-infected adults on triple antiretroviral therapy, the phase
angle was 6.2° (23
), compared with the phase angle of
4.8–5.8° described in the present study.
Wasting is a cardinal sign of tuberculosis in both HIV-positive and
HIV-negative patients, and the etiology of the wasting is unclear.
Pulmonary tuberculosis appears to worsen wasting when compared with HIV
infection alone in sub-Saharan Africa (18
). Although
the cause of wasting is likely to be multifactorial, the overexpression
of tumor necrosis factor- (TNF-) may be involved. During
tuberculosis, antigen-specific major histocompatability–restricted
interaction between T-lymphocytes and macrophages induces the
release of T-helper type-1–like cytokines and proinflammatory
cytokines such as TNF- (4
). TNF- activates
macrophage clearance of the organism and is essential for granuloma
formation. Increased concentrations of TNF- are found in the serum
and pleural fluid of patients with tuberculosis (24
).
Higher plasma TNF- concentrations have been reported in
HIV-positive compared with HIV-negative adults with
tuberculosis (25
, 26
). The relationship between TNF- and
wasting in tuberculosis and HIV/AIDS needs elucidation.
Further investigation is needed to determine whether ICW:ECW and phase
angle are useful predictors of clinical outcome among
HIV-infected adults with pulmonary tuberculosis. The most commonly
used indicator of nutritional status during tuberculosis chemotherapy
has been weight gain (4
). It is unclear whether successful
tuberculosis chemotherapy in HIV-infected adults is associated with
improvement in BMI, BCM, ICW:ICW or phase angle . Future studies
should determine whether BIA will be useful in monitoring nutritional
status during tuberculosis chemotherapy.
ACKNOWLEDGMENTS
We thank the study team nurse Grace Tumesiimi; the members of the Case Western Reserve University/Makerere University collaboration staff, Jessica Milman, Michael Odi, and Duncan Smith; and the physicians and staff of the Tuberculosis Research Unit for their assistance. We thank Barbara Laughon, National Institute for Allergy and Infectious Diseases, and Ken Bridbord, Fogarty International Center, for continued encouragement and support.
FOOTNOTES
1 Financial support for this study was provided by
The National Institute of Allergy and Infectious Diseases (AI32414,
AI41956), the National Institute of Child Health and Human Development
(HD32247, HD30042), and the Fogarty International Center, the National
Institutes of Health and the United States Agency for International
Development (Cooperative Agreement HRN A-0097-00015-00). 
3 Abbreviations used: BCM, body cell mass; BIA,
bioelectrical impedance analysis; ECW, extracellular water; FFM,
fat-free mass; HIV, human immunodeficiency; ICW, intracellular
water; MHC, major histocompatibility complex; TBW, total body water;
TNF-, tumor necrosis factor-.
Manuscript received 19 March 2001. Initial review completed 7 June 2001. Revision accepted 9 August 2001.
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