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INT J TUBERC LUNG DIS 8(3):286298

2004 IUATLD

REVIEW ARTICLE

The relationship between malnutrition and tuberculosis:


evidence from studies in humans and experimental animals
J. P. Cegielski,* D. N. McMurray
* Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, Department of Epidemiology,
Johns Hopkins University, Baltimore, Maryland, Department of Medical Microbiology and Immunology,
Texas A&M University, College Station, Texas, USA
SUMMARY

The oral traditions of medicine and public health have it


that malnutrition is an important risk factor for the
development of tuberculosis (TB). Malnutrition profoundly affects cell-mediated immunity (CMI), and CMI
is the principle host defense against TB. It makes biological sense. Although most health professionals readily
accept this principle, much of this belief is based on
uncontrolled observations such as disaster situations or
on backwards logic from the cachexia common among
TB patients. In fact, the evidence in humans is surprisingly thin from the perspective of scientific rigor. And
few data, if any, quantify the extent of the relative or
attributable risk of TB due to malnutrition. Moreover,

until recently, data from experimental animals were based


on animal models that were largely not relevant to
human TB infection and disease. This article reviews the
scientific data supporting the contention that malnutrition is an important risk factor for TB concentrating on
observations in humans and on experimental animal
studies based on a highly relevant animal model. If it is
true, malnutrition may account for a greater population
attributable risk of TB than HIV infection, and certainly
a much more correctable one.
K E Y W O R D S : tuberculosis; nutrition; human; guinea
pig

MALNUTRITION has a profound effect on cellular


immune function. Pneumocystis carinii pneumonia,
for example, was first described in malnourished children following the Second World War.1 Many of the
unusual infections seen in patients with human
immunodeficiency virus/acquired immune-deficiency
syndrome (HIV/AIDS), certain leukemias and lymphomas, and other disorders affecting cellular immunity, also characterize malnourished individuals.25
At the same time, malnutrition is an important risk
factor for tuberculosis (TB) because cell-mediated
immunity (CMI) is the key host defense against TB.4,6,7
In malnourished individuals, the likelihood is increased
of primary or latent infection progressing to active
disease.7 In populations with substantial latent TB
infection, the occurrence of malnutrition may be an
important determinant of the incidence of TB. The
potential public health impact of malnutrition on
the global incidence of TB was summarized in the US
Surgeon Generals Report on Nutrition and Health
which emphasized that malnutrition was the leading
cause of acquired, correctable immune system dysfunction throughout the world.8 The United Nations
Food and Agriculture Organization (FAO) estimated

that 841 million people in developing countries or


20% of the 19901992 population were undernourished.9 Modest decreases in resistance affecting such
large numbers of people may result in substantial
changes in TB incidence at a population level. Population groups at highest risk for poor nutrition are
also at high risk for TB, poverty being the common
denominator.
Despite the belief that malnutrition increases the
risk of TB, the depth and quality of the evidence,
especially in humans, is surprisingly thin. Moreover,
it is difficult to say how much the risk of TB increases
relative to specific degrees or types of malnutrition. In
general, there are three streams of evidence relating the
risk of TB to malnutrition: observations in humans,
experimental work in animal models, and inferences
from related work in microbiology and immunology.
In humans, direct evidence for the risk of TB due to
malnutrition is sparse, and the data have not been
reviewed critically in over three decades, especially in
terms of methodological rigor. Until recently, experimental animal studies have not been clearly relevant
to human TB because of immunological differences
between species and because the route and dose of

Correspondence to: Dr Peter Cegielski, TB Department, Centers for Disease Control and Prevention, Mailstop E-10, 1600
Clifton Rd NE, Atlanta, GA 30333, USA. Tel: (1) 404-639-5329. Fax: (1) 404-639-8961. e-mail: gzc2@cdc.gov
Article submitted 11 June 2002. Final version accepted 21 August 2003.

The relationship between malnutrition and tuberculosis

infection have not mimicked human infection. In


vitro studies have generated a substantial body of evidence documenting the negative effects of malnutrition on cell-mediated immune function,4,6,7,1015 and
on the immunology of TB (reviewed by Ellner16). Although one can reason from the in vitro evidence, it
cannot replace in vivo data. The purpose of this paper
is to summarize the evidence 1) from observations in
human populations with special attention to their
methodological validity, and 2) from experimental
animal models with special attention to their relevance to human tuberculosis.
TB risk is of two kinds: the risk of becoming infected
with Mycobacterium tuberculosis and the risk of that
infection progressing to active disease. This paper
focuses on the risk of infection progressing to disease,
because that is where CMI comes into play and the link
with malnutrition is most direct. There is no evidence
for a direct relationship between malnutrition and the
risk of initial infection. Although both TB and malnutrition are linked to poverty, the data reviewed
below suggest no independent association between
malnutrition and primary or latent TB infection.

HUMAN DATA
Early research on the interaction of nutrition and
tuberculosis was reviewed in the classic text by Rich up
to 1950,17 and in the exhaustive treatise by Scrimshaw,
Taylor, and Gordon up to 1968.5 Except for a single,
controlled intervention trial in the 1940s in New York
City,18 studies in humans have been largely either ecological designs or uncontrolled observations.
Chandra and Newberne point out that most of the
published evidence on the interaction of nutrition and
infection in humans consists of only a few types of
data:19
higher point prevalence of infection in undernourished patients or community dwellers;
worse and more frequent complications of infection in children with marasmus and kwashiorkor;
higher mortality in undernourished populations;
and
higher rates of infectious diseases in war, famine,
ghetto, refugee, or natural disaster situations.
These human studies have numerous flaws in sampling, sample size, measurement (or definition) of nutritional deficiency, assessment of infection, unmeasured
confounding variables, and analytic methods. Most
of them, however, are simply ecological or crosssectional studies that cannot confirm causality.
A more formal approach to grading the quality of
evidence from human studies was developed by the
US Preventive Services Task Force to judge evidence
for or against specific clinical and public health interventions.20 This grading scale can be readily adapted
to epidemiological risk factor studies. Grade I evi-

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dence comes from randomized, controlled trials. Grade


II evidence comes from controlled but not randomized studies and is subdivided into three levels: Grade
II-1 evidence comes from well-designed controlled trials
without randomization; Grade II-2 evidence comes
from well-designed cohort or case-control analytic
studies, preferably from more than one center or
research group; Grade II-3 evidence comes from multiple time series with and without the study factor of
interest, but dramatic results of uncontrolled experiments, such as post-exposure vaccination against rabies,
may also be considered in this group. Grade III evidence consists of expert opinion, clinical experience,
descriptive studies, and case reports.
Ecological studies
Studies using the ecological approach are generally
considered to generate hypotheses rather than providing evidence upon which to base conclusions. Thus,
the grading scale described above may not apply. In
the present instance, nutritional deficiency on a broad
scale is inevitably linked to many other adverse circumstances that may be strong, independent risk factors for tuberculosis. Taking this into account, a
wealth of ecological associations link tuberculosis with
malnutrition in populations affected by famine, war,
natural disasters, poverty, mass migration, and confinement in prisons or ghettos. The value of these
observations lies not so much in conclusive contributions to medical knowledge; rather, their value lies in
suggesting causal links that can be investigated fruitfully. At the same time, their value lies precisely in the
difficulty of conducting controlled studies of TB
and malnutrition in human populations. These studies
take advantage of historical circumstances in an attempt to learn about the interaction of nutrition and
tuberculosis.
In general, ecological studies do not attempt to distinguish deficiencies of various macro- or micronutrients. Instead, they can be thought of as addressing
multiple simultaneous nutritional deficiencies, the
most common type of malnutrition in humans. Furthermore, in these complex circumstances, the effects
of malnutrition cannot be disentangled from the effects
of poor housing, overcrowding, lack of medical care,
poor hygiene, massive social disruption, etc. For
example, sharp increases in tuberculosis morbidity
and mortality in Paris21 or in Germany during the two
World Wars5,2224 cannot be ascribed to malnutrition
(which was pervasive) apart from the social upheaval,
collapse of public health programs, mass trauma,
crowding, and psychosocial stresses that were part of
these wars. Similarly, the heroic studies carried out by
Jewish physicians in the Warsaw ghetto during the Second World War do not control for the extreme crowding, psychological stress, and catastrophic social circumstances.2527 We do not wish to devalue these
works, nor the impact of starvation on tuberculosis in

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The International Journal of Tuberculosis and Lung Disease

these situations, but the role of malnutrition independent of other circumstances cannot be isolated
in these studies. Although from the perspective of
methodological rigor much of this evidence is weak,
it constitutes a large body of observation that supports
the contention that inadequate nutrition adversely
influences either the incidence or the severity of
tuberculosis.
In contrast to most of the ecological studies, three
of these studies present fairly convincing evidence
that nutrition, isolated to some extent from other historical circumstances, played a direct role in tuberculosis morbidity and mortality. Thus, the quality of
the evidence from these three studies could be considered to be Grade II-3 evidence. The first is Fabers
report of tuberculosis epidemiology in Denmark during the First World War.28 During most of the war,
neutral Denmark exported the bulk of its meat, fish,
poultry and dairy products to the extent that the local
diet lacked these protein, vitamin, and mineral rich
foods. Tuberculosis rates climbed, as they did in the
warring countries. The German blockade of Denmark
in 1918, however, created a surfeit of these foods, and
tuberculosis rates plummeted. In contrast, tuberculosis rates in the neighboring warring countries continued to climb unabated.
The second study involves the Trondheim, Norway, Naval Training School where the high rate of
tuberculosis among recruits in the early 20th century
was ascribed to crowded, poor housing and unhygienic conditions.29 However, tuberculosis rates
did not decrease after improved housing and hygiene
were implemented. Diet was subsequently fortified
with margarine, cod liver oil, whole wheat bread,
fresh fruits and vegetables, and milk, and tuberculosis
morbidity promptly dropped to the prevailing level
for young adults of that area.
The third important contribution to the early literature was Leytons study of tuberculosis morbidity
among British and Russian prisoners of war held in
German (POW) camps during the Second World War.30
The prisoners shared the same prison diet, but the British received Red Cross food supplements amounting to
30 g protein and 1000 Kcal per day. In a subsequent
radiographic survey, the tuberculosis rate among the
British was only 1.2% and their plasma proteins were
higher than in the Russians, who had a tuberculosis
rate of 1519%. Both groups shared the same living
and working conditions and chance for infection. In
the malnourished prisoners, tuberculosis was more
severe, the onset was more rapid, and patients died
rapidly with large pulmonary cavities and massive tissue breakdown. Granuloma formation was poor in
the malnourished prisoners, supporting the idea that
there was a deficit of CMI in this group.
Lastly, McKeowns seminal work elaborated the
concept that the decline in TB mortality in England
and Wales from 1770 to 1900 was most likely due to

improving standards of living in general and to the


nutritional status of the population in particular.31,32
Through extensive critical reasoning, McKeown excluded the alternative explanations: 1) advances in
medicine and medical effort, or 2) natural selection.
What remained, according to McKeown, was that the
environment, and thereby the resistance of the host,
improved. The death rate from TB at the beginning of
the 19th century was approximately 40/1000 personyears. It declined to 14/1000 by the end of the century,
and accounted for nearly half of the overall decline in
mortality in the 19th century. McKeown concludes,
Having confidently excluded therapy and genetic
selection, with reservations, we are left with changes in
the environment as the most acceptable reason for the
trend of mortality from tuberculosis. Of the features
of the environment to be considered, the evidence in
respect of diet seems . . . highly suggestive.32
Case series
Nutrition, immune function, and infection interact in
complex and dynamic patterns. Protein-energy malnutrition compromises CMI and increases susceptibility to or severity of infections.4,6,7,1012,3337 Conversely, in-fection can rapidly lead to nutritional stress
and weight loss, thereby worsening nutritional status
and immunologic function.2,7,38 Therefore, understanding the temporal relationship between the onset of
malnutrition and the development of the infectious
disease is crucial to correctly assess any possible causeeffect relationship.
Since 1968, several case series of post-surgical
patients undergoing intestinal bypass surgery for
morbid obesity have provided observational data in
which nutritional status and incident cases of tuberculosis were observed in the same individuals in the
correct temporal sequence. These patients experience
rapid weight loss and malabsorption due to their shortcircuited bowel. In several series, the incidence rate of
tuberculosis was 1% to 4% among post-operative
patients during various durations of follow-up. This
range was much higher than expected based on historical or population comparisons.3944 Similarly, partial gastrectomy for ulcer disease was shown to predispose men to tuberculosis, but the association was
14 times more likely for men whose weight was 85%
of ideal than for men whose weight was normal for
their height.45 Although the patients in these series do
not represent persons at risk for TB in general, and
there are no contemporaneous controls, the observations are worth noting due to the sharply increased
incidence of TB following nutritional insult. According to the definitions noted above, these studies might
be considered to provide Grade III evidence.
Cross-sectional and case-control studies
Cross-sectional and case-control studies generally
suffer from the same inherent fatal flaw. Patients with

The relationship between malnutrition and tuberculosis

and without active tuberculosis are compared in terms


of their concurrent nutritional status.4656 However,
tuberculosis itself causes wasting, depression of the
immune system, and other changes resembling malnutrition. Therefore, the intrinsic uncertainty over
the sequence of cause and effect in case-control and
cross-sectional study designs becomes intractable. One
knows that having the outcome of interest (being a
tuberculosis case) alters the primary exposure variables (nutritional status). Such studies do not assess
the role of malnutrition in the development of tuberculosis because there have been no accurate measurements of antecedent nutritional status in comparable
cases and controls. Therefore, these studies cannot be
graded according to the scale noted previously because
of the inadequate study design. There have been
many recent variations on this theme,4654 but they all
founder on the same underlying problem.
In an attempt to circumvent this problem and determine risk of tuberculosis in relation to antecedent
cobalamin deficiency, Chanarin and Stephenson compared the incidence of tuberculosis among Asiatic
Indians who were life-long vegetarians to that of Indians who were omnivores, and found the risk to be
increased nearly three fold.57 These investigators
assumed that cobalamin intake or levels would be
lower in the vegetarians but did not measure them.
Nor did they consider other nutrients that might differ between vegetarian and meat-eating groups.
One study from China, available in English only in
abstract form, measured zinc, copper, and iron in the
hair of patients with active tuberculosis compared to
controls in an attempt to determine past nutritional
status with respect to these minerals.58 The authors
report significantly lower zinc content and zinc/
copper ratios in the hair of tuberculosis patients compared to controls, but no difference in iron content.
Even so, numerous intervening variables prevent us
from assessing the timing of tuberculosis infection
versus growth of the hair segments that were assayed,
and the effects on the mineral content of hair due to
water, soaps, shampoos, lotions, dyes, etc., applied
to the hair.
Although these studies demonstrate substantial
macro- and micronutrient deficits in tuberculosis
patients, one cannot infer a causal role for nutritional
deficiency in the development of disease from these
data because the chronological sequence is unclear
and tuberculosis itself plays a role in the development
of the nutritional deficits.
Two studies on vitamin D metabolism in relation
to TB used a cross-sectional design, but the focus was
on the molecular and cellular mechanisms of the interaction, rather than on the direction of causality.
These two studies examined the dynamics of 1,25(OH)2
vitamin D3 in lymphocytes and macrophages from
patients with tuberculosis compared to patients without tuberculosis.59,60 Investigators in France deter-

289

mined that lymphocytes obtained by bronchoalveolar


lavage from patients with tuberculosis expressed specific receptors for 1,25(OH)2 vitamin D3, but not
25(OH)D3. These were primarily CD4 T-lymphocytes. Peripheral blood lymphocytes did not express
these receptors.59 Furthermore, uncultured cells recovered by bronchoalveolar lavage and blood mononuclear cells from normocalcemic patients with tuberculosis both produced 1,25(OH)2D3. The amount
correlated with the number of CD8 T-lymphocytes
present but not other cell types. Purified T-lymphocytes from all patients with tuberculosis produced
1,25(OH)2D3 which correlated closely with that produced by unseparated lavage cells. Since 1,25(OH)2D3
can improve the capacity of macrophages to kill mycobacteria, these results support the conclusion that cellular interactions mediated in part by 1,25(OH)2D3
may be important in the anti-tuberculosis immune
response.60 These data are consistent with work in
experimental animals noted below, and may provide
the only Grade II-2 evidence from case-control and
cross-sectional studies.
Another study focusing on vitamin D and vitamin
D receptor genetic polymorphism was conducted
among vegetarians of Gujarati, Indian heritage in the
UK.61 They found lower serum levels of 25(OH)cholecalciferol in TB patients than in tuberculinpositive controls. In the context of low serum 25(OH)cholecalciferol, two distinct genotypes of the VDR
gene, TT/Tt and ff, were also associated with active
TB. These authors conclude that vitamin D deficiency
may contribute to the relatively high levels of TB in
that population. This conclusion exemplifies the classic blunder alluded to previously, because the development of clinically active TB may lead to decreased
blood vitamin D levels. Vitamin D metabolism is
linked to granulomatous inflammation both in terms
of the paracrine effects of vitamin D metabolites on
macrophage function and in terms of calcitonin metabolism, osteoclast activity, and the calcification of
granulomas.
Another variation on case-control methodology
that has been applied in this context is based on tracing the contacts of tuberculosis cases, i.e., persons
who have been exposed to an index case with active
tuberculosis. The general approach has been to compare the incidence of tuberculosis in this high risk
group with the incidence of tuberculosis in nonexposed controls in terms of their nutritional status
(or other risk factors). The problem with contact tracing
studies is that they apply only to cases of tuberculosis
that can be linked with a known exposure to an identified active case. In the past, this accounted for only
10% of tuberculosis cases; up to 90% arise sporadically from reactivation of latent infection or progressive primary infection in individuals without identifiable tuberculous contacts.
Technically, malnutrition means bad nutrition,

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The International Journal of Tuberculosis and Lung Disease

which could mean a harmful excess of certain nutrients as well as nutritional deficiencies. In this context,
work in rural Zimbabwe suggested that increased
dietary iron increases the risk of developing tuberculosis, even taking into account that 69% of the TB
patients in the study population had HIV infection.62
However, their measure of iron status was consumption of the traditional beer, which was fermented in
iron pots. Although the authors assessed iron status
from several blood tests, measurement of iron status in
the blood after TB is diagnosed of course bears little
relationship to iron status leading up to the time
when the tuberculous infection began developing into
clinically active TB. Moreover, the analysis does not
control for alcohol consumption, which can be strongly
immunosuppressive and substantially affect nutrition
as well.63
Cohort studies
Very few follow-up studies have been executed with
the explicit purpose of understanding the relationship
between nutrition and the incidence of tuberculosis.
The unique strength of cohort studies is that nutritional status is measured prior to the onset of tuberculosis. In general, well-designed and well-executed
cohort studies provide Grade II-2 evidence, although
in the Finnish and US Navy studies described in this
section, the published interpretations of the results
are debatable.
Only two cohort studies examined the relationship
between micronutrients and TB incidence. Both of
these included vitamin C. In the 1940s, Getz et al. followed 1100 men who were free of TB at baseline, by
clinical and radiographic criteria, for up to 5 years with
serial clinical, radiographic, and laboratory examinations.64 Among 16 men who developed active TB,
blood levels of vitamins A and C were consistently
lower than in those who remained free of TB. Plasma
vitamin A levels were low in 13 of 16 men who developed active TB compared to 30% (318/1058) of
those who did not. Similarly, plasma vitamin C levels
were low in all of the subjects who developed active
TB compared to only 11% (117/1013) of those who
did not. Exposure to TB did not differ between the
men who developed TB and those who did not.
Investigators in Finland randomized 26 975 healthy
male smokers aged 5069 years to supplementation
with tocopherol, beta-carotene, both or neither. The
subjects were followed for a mean 6.7 years for diagnoses of cancer identified through a registry of all
hospital discharges and the associated diagnoses in
the region. Hemil et al. analyzed the dietary data
in this cohort for vitamin C and vitamin C-rich foods
and the discharge registry for diagnoses of TB.65 In
over 173 000 person-years of follow-up, 167 cases of
TB were detected. Higher intake of fruits and vegetables was associated with lower risks of TB. Among
those with increased intakes of vitamin C and fruits

and vegetables, the adjusted relative risk of TB


decreased to 0.4 (95% confidence interval 0.240.69).
This study is noteworthy for its size and quality of data.
However, detecting TB through hospital discharges
selects TB patients who were sick enough to require
hospital admission. Lower intakes of fruits and vegetables and vitamin C may be associated with higher rates
of hospitalization rather than higher rates of TB.
No other studies on individual vitamins or minerals in humans were identified by Scrimshaw et al.5 nor
by exhaustive review of the literature since. Numerous experimental studies from that era carried out in
various animal species support the conclusions noted
previously, i.e., that multifaceted malnutrition, protein deficiency, and deficiencies of vitamins A and C
increase susceptibility to tuberculosis.5
Turning to macro indicators of nutritional status,
as part of the long-term follow-up of participants in
the large scale BCG vaccine trials in Georgia and Alabama, Comstock and Palmer reported that the incidence of tuberculosis was 2.2 times higher in children with 04 mm subcutaneous fat than in those with
10 mm subcutaneous fat.66 Cegielski et al. examined
the relationship between undernutrition and the incidence of TB based on data from the first National
Health and Nutrition Examination (NHANES-1) and
the NHANES-1 Epidemiological Follow-up Study
(NHEFS). NHANES-1 was a cross-sectional survey
of a representative sample of the US population from
1971 to 1975. In the NHEFS, the adult subjects of
NHANES-1, aged 2574 years at baseline, were followed up longitudinally with serial waves of questionnaires and examinations. Follow-up exceeded 95%.
Through 1987, 64 cases of TB were detected. In proportional hazards analysis, having body mass index
(BMI), average skin-fold thickness, or upper arm muscle
area in the lowest decile of the population increased
the adjusted hazard of TB from six to ten fold, controlling for other known risk factors for TB.67
Palmer et al. studied the relationship of TB incidence to naturally acquired delayed-type tuberculin
sensitivity among US Navy recruits.68 Nearly all navy
recruits from 1949 to 1951 were skin tested and followed longitudinally. Of 68 754 subjects with followup data, tuberculin sensitivity was recorded as 0 mm
for 8704 (12.7%). During 4 years of follow-up, 109
developed tuberculosis: 28/100 000 among those with
0 mm skin test reactions, 29/100 000 among those
with 19 mm reactions, and 157/100 000 among those
with 10 mm or greater reactions. Later, these investigators related the risk of tuberculosis to body build
by obtaining height and weight data from the entrance
medical examination on a stratified random sample
of 1138 subjects. A weight-height index was constructed based on deviation of weight from the median
weight for height of the study sample. There were no
significant differences in tuberculin sensitivity by
weight, height, or weight-height index. In contrast,

The relationship between malnutrition and tuberculosis

the weight-height index was strongly associated with


tuberculosis incidence: TB incidence was 75/100 000
for those 15% or more below the median weight for
their height and decreased to 19/100 000 for those at
least 5% overweight for their height (P  0.01 for both
purified protein derivative [PPD] groups). The trends
were the same regardless of the degree of tuberculin sensitivity, although incidence rates were higher among
those with 10 mm PPD reactions. Edwards et al.
extended Palmer et al.s study to over 823 000 navy
recruits, and found that tuberculosis developed three
times more often in young men 10% or more below
their ideal body weight than those 10% or more
above it.69,70
These studies merit special interest because of the
large sample size and consistency of the findings. Yet
several methodological flaws stand out. First, posthoc analyses of data collected for other purposes are
subject to bias and confounding which cannot be controlled because the necessary information was not
measured appropriately. Second, height and weight
had to be gleaned from entrance medical examinations because this aspect of the study was not planned
in advance and the data were not recorded on the
study forms. Thus, the accuracy and precision of the
major predictor variables may be questioned. Third,
of the nearly 100 000 recruits tested, 25 000 were
excluded because their service number was not
recorded on the study forms and could not be linked
to their entrance medical examination. Their characteristics in comparison to the study sample were
unknown, and the representativeness of the study
sample should be questioned. In addition, recruits
who were not white (3.8%) and outside the age range
1721 years (2.7%) were excluded because the initial
sample was nearly homogeneous with respect to age
and race aside from these small percentages. At best
the results apply to young white men, although it is
unclear whether even this narrow slice of the population is represented fairly in the study population.
Fourth, weight as a per cent of the median weight for
height has drawbacks as a weight-height index. It is
not normalized relative to a standard population and,
as a consequence, the interpretation of a given value of
the index differs in different age and height groups.71 It
is impossible to say whether recruits below a certain
percentage of the median weight-for-height were thin
or whether they were just thinner than other recruits.
Curiously, these authors avoid any reference to
inadequate nutrition in the recruits. Instead they conclude that the results demonstrate an association
between body build and tuberculosis disease, that
some unknown factor associated with body build is
an important determinant of host susceptibility to
active disease, but not to primary infection. A small
but consistent body of literature has accumulated on
the relationship of body build to tuberculosis,
reviewed by Snider in 1987.72 One study stands out.

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The country of Norway attempted to screen all persons over the age of 14 years for TB with compulsory
mass miniature radiography from 19631975. This
screening program covered 42% to 85% of the population, the percentage varying by age group. Height
and weight were measured accurately for nearly 80%
of those screened. From these data, Tverdal reported
results from over 1.7 million Norwegians with followup through the national notification system through
1982 (i.e., 819 years follow-up, mean 12.1 years).73
A total of 2531 incident cases of tuberculosis were
identified. The incidence of pulmonary tuberculosis,
both sputum smear-positive and smear-negative,
declined logarithmically with increasing BMI for
both sexes, all age groups, and at all durations of
follow-up: the age-adjusted incidence of new pulmonary tuberculosis was five times higher in the lowest
BMI category than in the highest. Interestingly, this
relationship was not observed for extra-pulmonary
TB. Tverdal argued that the association could not be
explained by pre-existing nutritional status or tuberculosis. As with the US navy studies, this author
argues that this relationship is a function of body
build and, aside from this single mention, does not discuss nutrition. Comstock suggested that body build
may influence susceptibility to tuberculosis because of
differences in pulmonary mechanics,74 but no studies
have attempted to address this hypothesis.
On the other hand, interpreting the findings of
these large studies only in terms of body build rather
than nutritional status disregards the well established
concept that body weight is a function of the balance
over time between caloric intake and energy expenditure. Clearly, increased or decreased intake can transform a thin individual into an overweight one or an
obese person into an underweight one. With physical
training and appropriate intake, a person with either
body type could become muscular and fit. Therefore,
the concept of body build as a fixed phenotype that,
by itself, predisposes to or protects against TB may
be inadequate. Re-interpreting the findings of these
studies in terms of nutritional status may be valid. A
more inclusive view might be that body habitus as a
function of genetic and early environmental influences, and nutritional status as a function of ongoing
nutrient intake and physical activity, each affect the
incidence of TB. Sorting out the mechanisms and relative contribution of each remains a challenge for
future research.
Intervention trial
Micronutrient deficiencies in relation to tuberculosis
are difficult to study in isolation in human beings. In
this respect, a unique study of the effect of micronutrient supplementation on tuberculosis incidence was
reported by Downes in 1949.18 In a controlled trial
among the families of black tuberculosis patients in
Harlem, New York City, 194 of 218 families under

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The International Journal of Tuberculosis and Lung Disease

public health supervision in 1941 were examined and


divided into two groups matched for family size. The
families were allocated alternately to receive vitamin
and mineral supplements versus no supplements along
with the health departments standard health education program. Since the allocation was not randomized, the quality of the evidence from this trial could
be considered to be Grade II-1. The education program included intensive nutrition education. The
two groups were similar in prior attack rates and
mortality from tuberculosis, prevalence of primary
and re-infection tuberculosis at the start of the study,
sputum smear positivity among the index cases, and
relation of the index case to the rest of the family. In
addition, the groups were similar in terms of their
income, the proportion receiving welfare, the degree
of crowding within the home, and their food habits.
After 5 years follow-up, using an intention to treat
analysis, the risk of tuberculosis in the control
group was 2.8 times the risk of tuberculosis in the
vitamin group. However, there was substantial noncompliance with the supplements. The relative risk
of tuberculosis among the controls (1096 personyears of follow-up) compared to those who actually
took the vitamin supplements for the entire followup period (644 person-years of follow-up) was 5.9.
The relative risk compared to those who did not
take the supplements despite being allocated to that
group (27% of the supplement group) or who only
took them for some of the follow-up period (33% of
the supplement group) (total 598 person-years of
follow-up) was only 1.82. Therefore, vitamin supplementation substantially reduced the risk of tuberculosis among family contacts of active tuberculosis
cases.
This study probably underestimates the efficacy of
micronutrient supplements for two reasons related to
an underlying secular trend: the economic status and
food habits of both groups improved substantially
during the period of the study. First, as a consequence of World War II, opportunities for employment increased. The per cent of families whose
income was from welfare alone decreased from 51%
to 18%, and the proportion who depended only on
earnings increased from 37% to 75% over the 5 years
of the study (nearly equal for both groups). Likewise,
the mean family income per person increased from
approximately $524 per year to $967 per year, with
a slightly greater increase in the control group.
Therefore, the overall economic status of both groups
improved. Second, the proportion of families with
marginal or unsatisfactory food habits decreased
from 40.5% in the vitamin group in 1942 to 12.8%
in 1947, and even more in the control group, from
50% to 6.8%. Both these secular trends would
diminish the apparent effect of vitamin and mineral
supplements. A third consideration, unrelated to
secular trends, was that non-compliance with the

supplements by over half of the individuals in the supplemented group would further bias the measure of
effect toward the null. With these three factors working against the experimental intervention, it is
likely that the effect may be greater than the findings
demonstrated.
Nutrition and the immune response
to BCG vaccine in humans
One study design permits prospective evaluation of
the effects of malnutrition on the immune response
to mycobacterial proteins closely related to M.
tuberculosis, namely, delayed-type hypersensitivity
(DTH) responses following bacille Calmette-Gurin
(BCG) vaccination. Satyanarayana et al. showed
that milder grades of malnutrition did not affect the
skin test response to PPD 6 months after immunization with BCG, but that children with kwashiorkor
were skin test negative.75 Chandra and Newberne
demonstrated that the DTH skin test response to
tuberculin and to numerous other antigens is reduced
in protein-energy malnutrition in children and adults.19
Among tuberculosis patients, PPD skin test reactivity
was directly proportional to serum transferrin level, a
sensitive indicator of protein malnutrition.19 Similarly, malnourished individuals do not develop skin
test responses to tuberculin as often or as large after
BCG vaccination as well nourished children. Importantly, this effect has been demonstrated even in modest protein energy malnutrition.36,76
Nutritionimmunitytuberculosis:
limitations of human data
While the Surgeon Generals report summarizes data
on the interaction of nutrition and infection, it cautions that few reliable data have been obtained in
human subjects on the influence of individual essential nutrients or of protein-energy nutrition on specific immune system functions and their interactions.8 Nutrition, immune function, and infection
interact in complex and dynamic patterns. Many
intervening and unknown variables affect the relationship. Protein-energy malnutrition (PEM) impairs
CMI and worsens infections.4,6,7,1012,3337 Conversely,
infection can lead rapidly to weight loss, malnutrition, and immunologic dysfunction.2,6,38 Indeed, PEM
is only partly due to food deprivation. Common
infectious disease such as diarrheal diseases, respiratory and parasitic infections are major contributing
and precipitating factors in PEM.77 However, in patients with TB it is nearly impossible to determine their
nutritional status prior to the onset of TB accurately
and, therefore, determine whether malnutrition led
to TB or whether TB led to malnutrition. This problem naturally leads to the use of experimental animal models to elucidate the causal links between
nutritional deficiencies, immune system function, and
tuberculosis.

The relationship between malnutrition and tuberculosis

EXPERIMENTAL ANIMAL DATA


Experimental animal models in general
In their classical review of the interaction between
nutrient deficiencies and infection, Scrimshaw, Taylor,
and Gordon summarized the results of 40 experimental studies published prior to 1968 which specifically
examined the relationship between diet and tuberculosis.5 These experiments were conducted in several
experimental animal species (mouse, rat, guinea pig,
hamster, chicken), and with at least two species of
mycobacteria (M. avium and M. tuberculosis). The
nutrients examined varied, but included protein, and
vitamins A, C and D. While the details of the experimental protocols varied widely, and the read-outs
were crude by modern immunological standards, the
overwhelming majority of these studies (31/40, or
78%) demonstrated a synergistic relationship, meaning that the nutrient deficiency was accompanied by
an exacerbation of tuberculous disease following
experimental infection. Thus, the weight of the evidence supported a detrimental effect of malnutrition
on the pathogenesis of tuberculosis. However, the
nature of these experimental infection models detracts
from the relevance of these observations. In most
cases, very large numbers (millions) of tubercle bacilli
were injected by a parenteral route (e.g., intravenously), a protocol which in no way approximates the
inhalation of a very small number of bacilli, which
characterizes the initiation of tuberculous infection
in humans. In addition, the field of immunology was in
its infancy when most of these experiments were performed, and thus few inferences can be drawn regarding the nutrient-associated immune defects that led to
the observed loss of disease resistance.
Guinea pig model of pulmonary tuberculosis
In the past 30 years, a modest body of literature has
accumulated regarding the link between diet, antimycobacterial immunity and disease resistance in
tuberculosis. The vast majority of this work has been
conducted in a highly relevant guinea pig model of
low-dose pulmonary tuberculosis.7880 The pathogenesis of tuberculosis in this model mimics essentially all
of the important aspects of tuberculosis in humans.
Following the deposition of a few viable, virulent M.
tuberculosis into the alveolar spaces by means of a
specially-designed aerosol chamber,81 guinea pigs
develop typical pulmonary granulomas, experience
extra-pulmonary dissemination with subsequent reseeding of the lung by the blood stream,82 convert their
tuberculin (PPD) skin tests and lymphocyte proliferation tests to positive, exhibit fever and weight loss,
and eventually succumb to disease.81,83 Vaccination
with BCG protects the guinea pigs, as measured by
reductions in bacillary loads in the lung and spleen
within 35 weeks post-challenge, and significant improvement in long-term outcome.81,84

293

Early studies established that moderate, chronic


deficiencies of protein and other nutrients (e.g., zinc)
could be induced in guinea pigs, and that the resulting
nutritional states had many of the metabolic hallmarks of human dietary deficiencies.85,86 In general,
the design of these experiments called for vaccinating
guinea pigs in different diet treatments with BCG
vaccine and measuring a number of antigen-specific
immune responses in vitro and in vivo several weeks
later. Groups of vaccinated and non-vaccinated animals from each diet group were then challenged with
an aerosol containing a low dose of virulent M. tuberculosis, and the ability of the guinea pigs to control
the infection was assessed quantitatively by culture
of viable mycobacteria from the lungs and spleens.87
Zinc
Chronic dietary zinc deficiency was found to exert a
profound suppressive effect on T-lymphocyte functions in BCG-vaccinated guinea pigs. Thus, there was
significant anergy in response to PPD skin tests in zincdeficient animals, and dramatic loss of PPD-induced
lymphoproliferation in vitro.86 The activity of a cytokine, macrophage migration inhibitory factor (MIF)
was also impaired by zinc deficiency.88 Taken together,
these data implied that zinc deficiency had interfered
with the ability of BCG vaccine to induce protection
against virulent pulmonary challenge. However, no
differences were observed between the bacillary loads
of zinc-deficient and normally nourished guinea pigs
4 weeks following aerosol infection, and BCG exerted
the same protective effect regardless of zinc status in
this model.89
Vitamin D
As mentioned above, 1,25(OH)2 vitamin D3 (calcitriol) is a potent co-activator of macrophages. Several in vitro studies have demonstrated that the addition of calcitriol to cultured human macrophages
enhanced the ability of the cells to control the intracellular replication of virulent M. tuberculosis over
several days in culture.90,91 The role of dietary vitamin
D deficiency was examined in the guinea pig model of
pulmonary tuberculosis. Feeding a diet completely
devoid of vitamin D for several weeks resulted in
marked depletion of serum levels of the calcitriol precursor, 25(OH) vitamin D3, and resulted in significant loss of some T-cell functions in BCG-vaccinated
guinea pigs. However, vitamin D deficiency did not alter
the course of tuberculous disease in non-vaccinated
guinea pigs, nor did it impair the protective efficacy of
BCG vaccination in this model.92
Protein
Most of the work with this model has been carried
out with moderate, chronic protein deficiency. Feeding a 10% ovalbumin-based diet over several weeks
resulted in a dramatic loss of T-cell functions in BCG-

294

The International Journal of Tuberculosis and Lung Disease

vaccinated guinea pigs. Thus, protein-deprived animals


had much smaller PPD skin tests and their lymphocytes
proliferated poorly to mitogenic and antigenic stimuli
in vitro.35,88 PPD-stimulated T-cells from low-protein
animals produced significantly less interleukin (IL)-2,93
and interferons (IFN),94 and macrophage-lymphocyte
co-cultures from malnourished animals produced less
tumor necrosis factor-alpha (TNF-) in response to
infection of the macrophages with virulent M. tuberculosis.94,95 Following virulent, pulmonary challenge,
protein-deficient guinea pigs were unable to form
mature, well-circumscribed granulomas in the lung,96
and expressed significantly less BCG-induced resistance in the lung and spleen.97 Not only was BCGinduced protection diminished by protein deficiency, but
the response to exogenous reinfection was impaired as
well.98 Furthermore, while immune cells from normally nourished guinea pigs adoptively protected
syngeneic, protein-deficient guinea pigs against aerosol infection, the reverse was not true, i.e., immune
lymphocytes from low-protein animals did not protect naive, normally nourished recipients.96
Protein malnutrition altered the absolute and relative numbers of total T-lymphocytes and various subpopulations, including CD2,99 CD4, CD8,100
and Fc receptor-bearing101 T-cell subsets in the circulation and lymphoid organs (e.g., spleen and bronchotracheal lymph nodes draining the infected lung).
Taken together, these results imply that protein deficiency is accompanied by alterations in the ability of
guinea pigs to regulate the normal recirculation and
trafficking of T-lymphocytes which would be required
for the formation of protective granulomas.102 These
phenomena could be explained by diet-induced changes
in the production or function of chemokines, which
have been observed to be altered in tuberculosis,103 or
by perturbations in the expression of adhesion molecules on T-cells or endothelial cells.
Finally, macrophages from tuberculosis patients
are known to produce suppressive factors for T-cells,
including transforming growth factor-beta (TGF).16,104 Alveolar macrophages are particularly effective at down-regulating T-cell proliferation in many
species, including humans.105 While protein deficiency was not associated with loss of some macrophage functions in the guinea pig model,106,107 we did
observe that alveolar macrophages suppressed the
mitogen-induced proliferation of autologous splenic
lymphocytes at macrophage-to-lymphocyte ratios of
1:4 or greater.108 More importantly, the intrinsic suppression by alveolar macrophages was enhanced ten
fold in this system when the cells were derived from
protein-deficient guinea pigs.109 In a separate series of
experiments, we demonstrated that TGF- was produced in higher amounts by cells from protein-deprived
guinea pigs,94 and that recombinant human TGF-
injected daily into guinea pigs infected with virulent M.
tuberculosis suppressed T-cell functions and impaired

bacillary control in the lungs and spleens of treated


animals.110 Thus, macrophages from protein-deprived
guinea pigs appear to be more suppressive for Tlymphocyte functions, and this suppression may be
mediated, in part, by overproduction of TGF-
It should be noted that the profound loss of T-cellmediated resistance that accompanies chronic dietary
protein deprivation in this model is substantially and
rapidly reversible. BCG-vaccinated guinea pigs maintained on a low protein diet during the entire 6-week
period post-vaccination, but given a normal diet beginning on the day of virulent pulmonary challenge, displayed PPD skin test reactivity and vaccine-induced
control of bacillary loads in the lungs and spleens 24
weeks later that were indistinguishable from BCGvaccinated animals which had never been proteindeficient.111 One possible interpretation of these observations is that protein deficiency interferes with the
expression, but not with the development, of T-cellmediated protective mechanisms in tuberculosis.
These basic observations were recently confirmed
and extended by studies performed in protein malnourished mice. Using a high-dose intravenous challenge model, Chan et al. observed many of the same
T-cell defects that have been reported in low-protein
guinea pigs, including loss of control of the virulent
infection and impaired granuloma formation, and
recovery of resistance following refeeding with an adequate diet.112 They concluded that loss of resistance to
tuberculosis in their model was a result of diminished
nitric oxide (NO) production by activated macrophages which occurred secondary to an IFN-gamma
(IFN-) defect in malnourished animals.113 These are
important studies because they confirm the fundamental nature of the effects of protein deprivation in tuberculosis even when such crucial variables as host species
and infection dose and route are altered.
Conclusions from experimental animal studies
Taken together, these published studies confirm that
protein deficiency, in particular, can have devastating
consequences in both innate and vaccine-induced
resistance against tuberculosis in animal models. The
precise mechanisms by which diet exerts these effects
remain to be elucidated. However, the results of the
experiments summarized above point to defects in
T-cell trafficking and antigen-induced proliferation,
inability to form mature granulomas, diminished production of protective cytokines (e.g., IL-2, IFN-,
TNF-) and antimycobacterial effector molecules
(e.g., NO in mice), and increased suppression by
adherent cells, perhaps secondary to increased TGF-
production.

CONCLUSION
This review critiques known studies in human populations and in relevant animal models to cover the in

The relationship between malnutrition and tuberculosis

vivo evidence concerning the risk of tuberculosis due


to malnutrition. Although TB is clearly related to
malnutrition, the risk relative to specific levels and
types of both protein-energy and micronutrient malnutrition remain to be defined. Only the NHANES-1
Epidemiological Follow-up Study provided plausible
relative risk data in a representative nationwide sample of adults. To the extent that the six to ten fold
increase in relative risk reflects mild to moderate as
well as severe undernutrition, these results suggest
that nutritional support of undernourished populations at high risk of TB may reduce the incidence of
TB in such groups.
In this regard, the distinction between relative risk
and attributable risk must be emphasized. Although
the risk of TB in severe malnutrition may be higher
than in mild or moderate malnutrition, severe malnutrition occurs in a small fraction of the population
even in poorer countries except in famine, war, or
disaster-type situations. Mild to moderate malnutrition or micronutrient deficiencies may affect large
fractions of the population at risk for TB so that prevention efforts will not be highly successful if they
target only severely undernourished groups.
The questions we would like answered are not
only how much TB is due to malnutrition, but how is
TB due to malnutrition. As suggested by work in the
aerosol-infected guinea pig model, protein undernutrition in particular impairs host defense against TB,
and the impairment is rapidly reversed with nutritional rehabilitation. Changes in the movement and
proliferation of T-lymphocyte subpopulations in response to specific antigens, and changes in the production of key cytokines, in the formation of organized
granulomas, and in macrophage activation, have been
identified as important components of the process.
Further work is needed to identify the optimal points
for intervention in terms of cost and effectiveness.
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RSUM

Les traditions orales de la mdecine et de la sant publique considrent que la malnutrition est un facteur de
risque important pour le dveloppement de la tuberculose
(TB). La malnutrition atteint profondment limmunit
mdiation cellulaire (IMC), et lIMC est la principale
dfense de lhte contre la TB. Cest donc biologiquement vraisemblable. Bien que la plupart des professionnels de la sant acceptent facilement ce principe, une
grande partie de cette croyance repose sur des observations non contrles comme des situations de dsastre
ou sur une logique rtrospective provenant du caractre
frquent de la cachexie parmi les patients TB. En fait, les
preuves chez lhomme sont tonnamment minces dans
une perspective de rigueur scientifique. Et peu, voire
mme aucune donne, ne quantifie ltendue du risque

relatif ou attribuable de TB d la malnutrition. De


plus, des donnes provenant danimaux dexprience
taient bases jusquil y a peu sur des modles animaux
qui dans lensemble ntaient pas pertinents pour linfection et la maladie TB humaines. Cet article passe en
revue les donnes scientifiques qui soutiennent laffirmation que la malnutrition est un facteur de risque important pour la TB en se concentrant sur des observations
chez lhomme et sur les tudes animales exprimentales
bases sur un modle animal hautement pertinent. Si ceci
savre vrai, la malnutrition pourrait reprsenter un risque attribuable de TB plus important pour la population
que ne lest linfection VIH ; elle serait certainement un
risque beaucoup plus remdiable.

RESUMEN

Segn las tradiciones orales referentes a la medicina y a


la salud pblica, la malnutricin es un factor de riesgo
importante para el desarrollo de la tuberculosis (TB). La
malnutricin afecta profundamente la inmunidad mediada por clulas (IMC) y la IMC es la principal defensa
del husped contra la TB. Desde el punto de vista
biolgico esto tiene sentido. Aunque la mayora de los
profesionales de la salud estn dispuestos a aceptar este
principio, gran parte de esta creencia est basada en
observaciones no controladas como situaciones de
desastre o en una lgica retrospectiva, originada en la
presencia frecuente de caquexia en los pacientes tuberculosos. De hecho, la evidencia en el ser humano es sorprendentemente dbil, desde la perspectiva del rigor
cientfico, y escasos datos, si los hay, cuantifican la

extensin del riesgo relativo o atribuible de TB,


debido a la malnutricin. Adems, los datos provenientes de la experimentacin animal estaban basados,
hasta hace poco, en modelos animales que, en gran
parte, no eran aplicables a la infeccin ni a la enfermedad TB humanas. Este artculo pasa revista de los
datos cientficos que apoyan la afirmacin que la malnutricin es un factor de riesgo importante para la TB, centrndose en observaciones en humanos y en estudios de
experimentacin animal basados en un modelo animal
altamente aplicable. Si esto fuera verdad, la malnutricin podra representar para la poblacin un riesgo atribuible de TB ms importante que la infeccin VIH y, con
certeza, ms fcil de corregir.