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Published by Oxford University Press on behalf of the International Epidemiological Association International Journal of Epidemiology 2008;37:113119

The Author 2008; all rights reserved. doi:10.1093/ije/dym247

Low serum vitamin D levels and tuberculosis:


a systematic review and meta-analysis
Kelechi E Nnoaham1* and Aileen Clarke2

Accepted 13 November 2007


Objective To explore the association between low serum vitamin D and risk
of active tuberculosis in humans.
Design Systematic review and meta-analysis.
Data sources Observational studies published between 1980 and July 2006
(identified through Medline) that examined the association
between low serum vitamin D and risk of active tuberculosis.
Results For the review, seven papers were eligible from 151 identified in
the search. The pooled effect size in random effects meta-analysis
was 0.68 with 95% CI 0.430.93. This medium to large effect
represents a probability of 70% that a healthy individual would
have higher serum vitamin D level than an individual with
tuberculosis if both were chosen at random from a population.
There was little heterogeneity between the studies.
Conclusions Low serum vitamin D levels are associated with higher risk of
active tuberculosis. Although more prospectively designed studies
are needed to firmly establish the direction of this association, it is
more likely that low body vitamin D levels increase the risk of
active tuberculosis. In view of this, the potential role of vitamin D
supplementation in people with tuberculosis and hypovitaminosis
D-associated conditions like chronic kidney disease should be
evaluated.
Keywords Vitamin D, tuberculosis, systematic review, meta-analysis, vitamin
D deficiency

Introduction in pathogenesis. Vitamin D acts by binding to nuclei


receptors on target cells. Therefore both low levels of
Vitamin D modulates monocyte-macrophage activity the vitamin and abnormalities in receptor structure
in the body and plays a role in human innate and function may result in impairments in host
immunity to certain infectious agents. This role may immunity to the tubercle bacillus.1 The contribu-
be important in the bodys defence against tubercu- tion of vitamin D receptor abnormalities has been
losis, in which attack of macrophages is a key step examined in a systematic review,2 which was incon-
clusive, but no similar review of low body vitamin D
1
Department of Public Health, Oxfordshire Primary Care Trust,
levels has been undertaken. This is in spite of a
Richard Building, Old Road Campus, Headington, Oxford OX3 number of studies reaching varying conclusions about
7LG, UK. the risk of tuberculosis associated with vitamin D
2
Public Health Resource Unit (PHRU), 4150 Chancellor Court, deficiency.
Oxford Business Park South, Oxford, OX4 2GX, UK. In this review, appropriate communityor hospital-
* Corresponding author. Department of Public Health,
based studies comparing serum vitamin D levels in
Oxfordshire Primary Care Trust, Richard Building, Old Road tuberculosis patients and healthy controls were
Campus, Headington, Oxford OX3 7LG, UK. systematically identified, examined and pooled in a
E-mail: kcnnoaham@yahoo.com meta-analysis.

113

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114 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

Methods 103 articles excluded: 28 dealt with vegetarian diets or with vitamin D
151 articles but not its deficiency; 36 dealt with other medical conditions; 39 were
Identification and selection of papers laboratory studies or studies on vitamin D deficiency and ethnicity.

This review was restricted to published research


articles and abstracts that compared the serum 39 articles were excluded at this stage
levels of vitamin D in tuberculosis patients (not yet 48 articles because they were reviews, letters,
comments, case reports or news articles.
commenced on treatment) with those of an appro-
priate control group of healthy people. These studies
were identified in three ways: 2 articles were excluded
9 articles because they had no
(i) Medline was searched through PubMed for appropriate control arm.
studies published between January 1980 and July
2006. The search was limited to English language 7 articles
papers on research in humans. The key words used
included tuberculosis, vitamin D, vitamin D defi-
ciency and cholecalciferol; (ii) the reference lists of Figure 1 Selection of studies for review
identified publications were searched; (iii) the
International Journal of Tuberculosis and Lung 2 test, and estimated the amount of variation due
Disease was identified as the key journal for hand to heterogeneity by calculating the I2.
searching, and editions of this journal from 1980 to
June 2006 were searched.
The following inclusion criteria were applied to
each publication: (i) studies had to be community
Results
or hospital-based, (ii) examined the association of Figure 1 schematically presents the study selection
vitamin D deficiency and tuberculosis, (iii) studied process. One hundred and fifty-one studies were
untreated adult tuberculosis patients, (iv) used a identified from the initial PubMed search. No additional
control group comparable to the cases, and (v) dealt references were identified from other databases. A total
with Mycobacterium tuberculosis (studies dealing with of seven studies involving 531 participants met the
other Mycobacteria were excluded). Important details inclusion and exclusion criteria. They were all published
regarding the methods and results were extracted between 1985 and 2002 and compared vitamin D levels
from appropriate papers and summarized. in tuberculosis patients and controls (Table 1).
Of five studies based on Asian populations, four were
based on indigenous populations6,1113 and one was a
Defining parameters study of UK-resident Asians.1 One study7 was based on
Serum vitamin D was defined in each paper as serum a predominantly White UK population and one8 on an
levels of 25-(OH)D3 (25 hydroxycholecalciferol). It is indigenous East African population. Migrants repre-
generally accepted that its assay may be a better sented one-third of the study population.
indicator of vitamin D status than 1,25(OH)2D3 (1,25 We evaluated the quality of primary studies using
dihydroxycholecalciferol).3 The study population of the NewcastleOttawa Scale,14 a validated technique
cases was estimated as the number of culture positive for assessing the quality of observational and non-
tuberculosis patients yet to commence treatment. randomized studies. The instrument uses a star
Controls were healthy people and had to be represen- system to evaluate observational studies based on
tative of the population from which cases were drawn. three criteria: participant selection, comparability of
study groups and assessment of outcome or exposure.
As shown in Table 2, higher quality studies rigorously
Statistical analysis controlled for potential confounders13 and did better
All results were expressed in terms of a bias corrected with respect to selection of cases and controls.1,8
effect size of the difference between serum vitamin All studies investigated untreated culture-positive
D levels in patients and controls.4 For continuous tuberculosis patients recruited either as inpatients or
measures, an EffectSizeCalculator worksheet was outpatients. Controls were mostly healthy contacts of
used to derive effect sizes from means and pooled tuberculosis cases but one study12 selected controls
standard deviations.5 For three studies68 that from blood donors attending a hospital blood bank.
expressed outcomes in medians and ranges, the Another study11 recruited controls who were inpati-
medians and ranges were converted to means and ents and outpatients at the same hospital as the
standard deviations using Hozos approach.9 These cases, but who did not have any condition known to
were then used in the worksheet to derive effect sizes. affect calcium or vitamin D deficiency. Information
The odds ratio in one study1 was converted directly to about potential confounders of a relationship between
an effect size using the approach described by serum vitamin D deficiency and tuberculosis, such as
Chinn.10 Effect sizes were used in a random effects chronic co-morbidity and malnutrition, was variably
meta-analysis (Review Manager Version 4.2). We provided across the studies. Authors in one study13
assessed heterogeneity between studies using the excluded TB patients who had risk factors for

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Table 1 Summary of included studies

Author,
date, Study Parameter Results (serum Vitamin D
place population Design Cases Controls measured levels)
Davies UK Whites (84%); Prospective 40 untreated inpatients and 40 controls were either Serum Median (range) in: Cases
PD et al., Indiana (8%); study outpatients with mainly members of patients vitamin D 16.0 nmol/L (2.2574.25
1985, UK7 othersb (8%) culture-positive pulmonary families or age and levels nmol/l) Controls27.25
TB. Mean age 43.1 years sex-matched healthy nmol/l (9.0132.5 nmol/l)
volunteers. Mean age P < 0.005
42.2 years
Grange Indigenous Casecontrol 40 untreated patients with 38 apparently healthy age- Serum Median (range) in: Cases
et al., 1985, Indonesian study smear-positive pulmonary matched controls (mean or vitamin D 65.75 nmol/l (43.75130.5
Indonesia6 population TB (source of recruitment range of ages not stated) levels nmol/l) Controls69.5
unclear). Age range 1850 nmol/l (48.5125 nmol/l)
years. P40.25
Davies Indigenous Prospective 15 untreated culture-positive 15 age and sex-matched Serum Median (range) in: Cases
et al., 1987, African study pulmonary TB patients healthy controls selected vitamin D 39.75 nmol/l (16.7589.25
Kenya8 population presenting to hospital. from patients families. levels nmol/l) Controls65.5
(Kenyans) Mean age 33 years Mean age 35 years nmol/l (26.25114.75 nmol/
l) P < 0.05
Davies Indigenous Thai Prospective 51 untreated smear-positive 51 age and sex-matched Serum Mean (SD) in: Cases69.5

LOW SERUM VITAMIN D LEVELS AND TUBERCULOSIS


et al., 1988, population study pulmonary TB patients healthy controls selected vitamin D nmol/l (24.5 nmol/l)
Thailand12 presenting to a chest clinic. from blood donors levels Controls95.5 nmol/l
Mean age 30.5 years attending a hospital blood (29.25 nmol/l) P < 0.001
bank. Mean age 30.4 years
Chan Indigenous Case-control 22 untreated hospital 23 in-patients and out- Serum Mean (SD) in: Cases46.5
et al., 1994, Chinese study in-patients with culture- patients receiving care at vitamin D nmol/l (18.5 nmol/l)
Hong population positive pulmonary TB. same time as cases levels Controls52.25 nmol/l
Kong11 Mean age 56.3 years (15.75 nmol/l)
Wilkinson Gujarati Hindus Case-control 103 untreated patients with 42 household multiple Serum Odds ratio (CI) for vitamin D
et al., resident in study localizedc- and severed TB, contacts of TB patients Vitamin D deficiency in cases
2000, UK1 London recruited from a hospital. attending TB contact clinics deficiency compared to controls2.9
Mean age 45.5 years of same hospital. Mean age (1.36.5) P 0.008
42.7 years
Sasidharan Indigenous Indian Case-control 35 untreated hospital 16 healthy age- and sex- Serum Mean (range) in: Cases
et al., 2002, population study in-patients with pulmonary matched controls (source of vitamin D 26.75 nmol/l (2.575
India13 (15) and extra-pulmonary recruitment not stated). levels (in nmol/l) Controls48.5
(20) TB. Mean age Mean age 34.1 years fasting blood nmol/l (22.5145 nmol/l)
37.5 years samples) P < 0.005
a
Indianrefers to those whose ethnic origin is in the Indian subcontinent (Indian, Pakistani or Bangladeshi).
b
Includes one person each of West Indian, African, Malaysian and Chinese ethnic origin.
c
Localized disease defined by author as TB confined to one anatomical site.
d
Severe disease defined by author as pulmonary or miliary tuberculosis.

115
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116 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

Table 2 Assessing the quality of included studies using the tuberculosis compared to controls (Table 4). The
NewcastleOttawa Scale average member of the control group has a serum
Author Selection Comparability Exposure Score
vitamin D level that is 0.68 SD above the average
Davies7 6 level of serum vitamin D for tuberculosis patients,
Grange6 5 representing a medium to large association of
Davies8 7 vitamin D deficiency with tuberculosis risk.15 Using
Davies13 5 the Common Language Effect Size approach of
Chan11 6
McGraw and Wong, the probability is about 70%
Wilkinson1 7
that an individual without tuberculosis would have a
Sasidharan13 7
higher serum vitamin D level than an individual with
tuberculosis if both individuals were chosen at
Table 3 Effect size estimates from studies on low serum random from a population.16
vitamin D and tuberculosis Heterogeneity between studies was low, although
only five of seven studies showed a clear difference
Estimated between serum vitamin D levels in tuberculosis
effect 95%
size (bias confidence patients and controls.
Study and place Total n corrected) interval
Davies, UK 80 0.86 0.401.32
Grange, Indonesia 78 0.18 0.260.63 Discussion
Davies, Kenya 30 1.04 0.281.80 Our review finds that patients with tuberculosis have,
Davies, Thailand 102 0.96 0.551.37 on average, lower serum levels of vitamin D than
Chan, Hong Kong 45 0.33 0.260.92
healthy controls matched on sex, age, ethnicity, diet
and geographical location (Table 4). As antitubercu-
Wilkinson, UK 145 0.59a 0.141.04 lous chemotherapy can lower serum vitamin D levels,
Sasidharan, India 51 0.94 0.321.56 we reviewed only studies of tuberculosis patients
a
This effect size was derived directly from the odd ratio in the who were yet to commence treatment at the time of
study. their study. Five of the primary studies included in
the review found lower levels of serum vitamin D in
tuberculosis patients compared to controls.1,7,8,12,13
hypovitaminosis D (such as malnutrition, liver disease,
In one study that found no such difference in
renal disease, gastric or bowel resection, malabsorption
indigenous Indonesians,6 there was insufficient infor-
states, intake of drugs antagonistic to Vitamin D). In
mation about controls to establish that they were
other studies, risk factors for hypovitaminosis D were
completely free of any conditions associated with low
generally adequately controlled for but in one study,1 serum vitamin D levels. In another study with similar
women comprised 65% of the cases and 45% of the conclusion, 50% of the controls had either hyperten-
controls and in another,11 the mean weight of patients sion or diabetes, conditions which may be associated
was lower than that of controls. In all studies except with vitamin D metabolism.17
two,1,6 the collection of blood samples was done at Although there is good evidence to suggest that a
about the same period in cases and controls, and fall in serum vitamin D levels compromises cell-
investigators in all studies used either radioimmunoas- mediated immunity and leads to the activation of
say68,12,13 or competitive protein binding assay1,11 to latent tuberculosis,18 it is also possible that low serum
measure serum vitamin D levels. vitamin D levels result from tuberculosis itself.
Two studies reported means of serum vitamin D The design of the primary studies in this review
levels and standard deviations;11,12 one study reported only permits the medium to large association of TB
means and ranges of serum vitamin D levels13 (with and low serum vitamin D to be established in the
standard deviations estimated from the ranges9); populations investigated in those studies. Determining
three studies reported medians of serum vitamin D the direction of the association will need larger
levels and ranges,68 and one study reported odds prospectively designed studies.
ratios for vitamin D deficiency in tuberculosis cases Two facts from other research lend plausibility to
compared to controls.1 the direction of the relationship being from low serum
All effect sizes were positive, ranging from 0.18 to vitamin D to tuberculosis, rather than the reverse.
1.04 (Table 3). Positive effect sizes suggest that First, the active form of vitamin D enhances the
tuberculosis patients have lower vitamin D levels ability of macrophages to suppress the intracellular
than controls. In five of the studies, the lower limits growth of Mycobacterium tuberculosis. Secondly, on
of the effect size confidence intervals were greater triggering of toll-like receptors by molecules of the
than zero.1,7,8,12,13 In two studies, the lower limits of tubercle bacillus, the production of microbe-killing
the confidence intervals were negative.6,11 cathelicidin is impaired in the absence of adequate
A summary effect size of 0.68 suggested that serum serum vitamin D.19 One limitation of the primary
vitamin D levels are 0.68 SD lower in people with studies included in our review however raise the

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LOW SERUM VITAMIN D LEVELS AND TUBERCULOSIS 117

Table 4 Effect sizes of low serum vitamin D in tuberculosis patients and controls

possibility of confounding. Smoking is a risk factor for contributory factor as far as migrants are concerned.22
tuberculosis disease but, although vitamin D is impor- Our review however finds an association between low
tant for calcium absorption (which is impaired by serum vitamin D and active tuberculosis in predomi-
smoking), there is no evidence to suggest that vitamin nantly indigenous populations, most of whom have
D absorption is impaired directly by smoking. However, adequate year-round sunshine, suggesting that other
women who smoke also tend to ingest less vitamin D factors in addition to sunlight exposure may influence
than non-smoking women.20 Therefore, if reduced the association, at least in such populations.
intake of vitamin D caused vitamin D deficiency, In one of the primary studies demonstrating lower
smoking would not only be associated with vitamin D serum vitamin D levels in TB patients than in controls,
deficiency but also be an independent risk factor for 84% of the patients were of White ethnicity.7 Concerns
tuberculosis, making it an important confounder of the about vitamin D deficiency and the risk of tuberculosis
low vitamin D-tuberculosis association. Since only one may therefore not be limited to Afro-Asian indigenous
primary study controlled for this effect, more smokers and migrant communities. Indeed, half of people in
amongst the TB cases than amongst controls could have Europe over 60 years of age are vitamin D deficient23
accounted for the lower vitamin D levels in cases and recently, concerns have been expressed in the UK
compared to controls. about increasing malnutrition in the elderly.24 More
Much remains to be known of the relative contribu- attention needs to be paid to the nutritional and
tions of sunlight and diet to body vitamin D levels. vitamin D needs of older vulnerable people who may
A study of indigenous Indonesians suggested that in be prone to hypovitaminosis D.
populations with good year-round sunshine, people The significance of an association between vitamin
could maintain adequate serum levels of vitamin D in D deficiency and tuberculosis is 2-fold. First, already
spite of poor dietary intake.6 A similar study in India low vitamin D levels in tuberculosis patients may fall
however found low vitamin D levels in the study further on commencement of treatment.16 Further
population despite adequate sun exposure, concluding drops can predispose to other vitamin D deficient
that diet was the more important factor.13 The latter states. Although the potential role of vitamin D
study did not take into account the actual time spent supplementation in contacts of tuberculosis cases
outdoors, extent of body exposed to the sun or level of has been the subject of recent investigations,25 there
cutaneous pigmentation. On migration away from is a case for more evaluations of vitamin D
home, Hindu Asians largely maintain socio-religiously supplementation in tuberculosis patients on treat-
determined adherence to vegetarian diets but expo- ment. Second, the prevalence of diabetes mellitus
sure to sunshine is reduced. The observation that (DM) is increasing globally26 and people with DM are
Asian migrants have lower serum vitamin D than 45 times more likely than those without DM to have
matched controls in their home countries21 have led clinically significant chronic kidney disease (CKD).27
some authors to conclude that the fall in vitamin D In addition, patients with CKD or those who are
levels associated with migration from sunshine-rich to dialysis-dependent are more likely to have low levels
sunshine-poor areas is probably the most important of vitamin D in comparison to those without kidney

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118 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

disease.28 The incidence of tuberculosis is high in been because of the non-normality of the distributions.
CKD partly as a result of impaired cell-mediated In addition, Chinns approach involving the use of the
immunity29 but if low serum vitamin D levels also factor of 1.81 for converting log odds ratio to effect size
predisposed to tuberculosis, the growing population of is an approximation, although it is believed to be a
people with CKD from underlying causes like DM good one over the likely range of use.
may need early attention to their body vitamin D It seems from knowledge of the causal factors of
levels to mitigate the risk of active tuberculosis. vitamin D deficiency that exposure to sunlight and
In renal failure, vitamin D supplementation normalizes adequate dietary intakes are key ways to ensuring
bone metabolism by correcting elevated parathyroid enough levels of vitamin D in the body. However, the
hormone. However, the hydroxylase systems that wisdom in espousing the message of sunlight
convert vitamin D to its biologically active form exposure to people who avoid it for cultural and
become substrate dependent in renal failure religious reasons is dubious. Addressing dietary
(i.e. higher doses of vitamin D increase the rate of intake of vitamin D seems a more desirable option.
production of its active form). There is therefore the Engineering changes in dietary habits may however
possibility that vitamin D supplementation can impact be fraught with difficulties if these habits are rooted
other clinical outcomes in renal failure, such as in cultural and religious persuasions. Therefore, while
prevention of active tuberculosis. This application public health education should stress the need for
would need to be explored by appropriate studies. adequate dietary intake of vitamin D in all vulnerable
A limitation of this review regards the methodology. groups, there is need to explore a potential role for
A meta-analysis of odds ratios is equivalent to a meta- vitamin D supplementation in treatment of TB and
analysis of effect sizes when there is an underlying hypovitaminosis D-associated conditions like CKD.
continuous distribution, albeit with loss of power.10 Large and well-designed prospective studies examin-
The method of meta-analysis using effect sizes assumes ing the vitamin D-TB association, in which possible
an underlying normal distribution and common confounders are exhaustively controlled for, will
variance. These assumptions are however not entirely provide a foundation for such evaluations.
correct in our population, as the use of medians and
ranges in some of the studies would have presumably Conflict of interest: None declared.

KEY MESSAGES
What this paper adds
 There is a medium to large association between low serum vitamin D and tuberculosis in the
populations from which the samples in the primary studies were drawn.
 As the observational primary studies in this review are unable to conclusively establish the direction of
the association between low serum vitamin D and tuberculosis, this review highlights the need for
larger, well-designed prospective studies clarifying the association.

Policy and research implications


 Public health education stressing the need for adequate dietary intake of vitamin D in all vulnerable
groups is necessary.
 Prospective studies to firmly establish the direction of the relationship between vitamin D and
tuberculosis as well as evaluations of vitamin D supplementation in tuberculosis and renal failure
patients are needed.

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