Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 793–798

Review

Vitamin D in the treatment of pulmonary tuberculosis

Adrian R. Martineau a,b,c,∗ , Friedemann U. Honecker d ,
Robert J. Wilkinson b,c , Christopher J. Griffiths a
a Centre for Health Sciences, Institute of Health Sciences Education, Barts and The London School of Medicine and Dentistry,
London E1 2AT, United Kingdom
b Wellcome Trust Centre for Research in Clinical Tropical Medicine, Division of Medicine, Wright Fleming Institute,

Imperial College London, W2 1PG, United Kingdom

c Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences,

University of Cape Town, Observatory 7925, South Africa

d Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany

Abstract

Vitamin D was used to treat tuberculosis in the pre-antibiotic era. New insights into the immunomodulatory properties of 1␣,25-dihydroxy-
vitamin D have rekindled interest in vitamin D as an adjunct to antituberculous therapy. We describe the historical use of vitamin D in
tuberculosis treatment; discuss the mechanisms by which it may modulate host response to infection with Mycobacterium tuberculosis; and
review three clinical trials and ten case series in which vitamin D has been used in the treatment of pulmonary tuberculosis.
© 2006 Elsevier Ltd. All rights reserved.

Keywords: Vitamin D; Tuberculosis; Paradoxical reaction; Hypercalcemia

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
2. Historical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
3. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
4. Clinical studies describing the use of vitamin D in pulmonary tuberculosis treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
4.1. Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
4.2. Patient characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
4.3. Dosing regime . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
4.4. Evidence that vitamin D modulated host response to infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
4.5. Evidence of vitamin D-induced toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797

1. Introduction

∗
The resurgence of tuberculosis (TB) is a global emer-
Corresponding author at: Centre for Health Sciences, Barts and The
London School of Medicine and Dentistry, 2 Newark Street, London E1
gency: in 2003 the disease caused an estimated 8.8 million
2AT, United Kingdom. Tel.: +44 207 882 2503; fax: +44 207 882 2552. new cases and 1.7 million deaths [1]. The development of
E-mail address: a.martineau@qmul.ac.uk (A.R. Martineau). new drugs to shorten treatment time and treat multi-drug

0960-0760/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jsbmb.2006.12.052
794 A.R. Martineau et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 793–798

resistant disease is a priority in controlling this epidemic

[2]. Pharmacologic doses of vitamin D were used to treat
TB in the pre-antibiotic era, but this practice fell out of
widespread use with the introduction of effective anti-
tuberculous chemotherapy. Interest in this area has recently
been rekindled due to emerging evidence regarding the
immunomodulatory properties of 1␣,25-dihydroxyvitamin D
(1␣,25(OH)2 D) in vitro.

2. Historical aspects

The use of vitamin D in TB treatment has a long history:

in 1849 Williams reported results of administering fish liver
oil to 234 TB cases, noting that ‘even in a few days. . .the
appetite, flesh and strength were gradually improved’ and
concluding that ‘the pure fresh oil from the liver of the cod
is more beneficial in the treatment of pulmonary consump-
tion than any agent, medicinal, dietetic, or regiminal, that has
yet been employed’ [3]. Vitamin D3 was subsequently iso-
lated from cod liver oil and vitamin D2 was synthesised by
exposure of ergosterol to ultraviolet light in 1931, after which
Charpy pioneered the use of pharmacologic doses of vitamin
D2 to treat cutaneous TB [4].
Charpy’s initial regime consisted of oral doses of 600,000
IU vitamin D2 (taken with calcium gluconate or 1–2 l of milk)
administered weekly for the first 3 months, fortnightly for
the next 3 months, and then monthly pending clinical res-
olution. He subsequently adopted a more intensive regime:
600,000 IU vitamin D2 three times per week for the first
week, twice a week for the next 3 weeks, then weekly for the
next 4 months. No toxic symptoms were reported with either
regime [5]. Two phases of clinical response were described:
in the initial 2–3 weeks cutaneous lesions became inflamed;
patients with co-existing tuberculous cervical adenitis some-
times developed exacerbation of lymphadenopathy during
this period. In the second phase, beginning at 5–6 weeks,
cutaneous lesions began to fibrose [6]. Vitamin D2 was also
used to treat pulmonary TB (PTB), both as a single agent
and, following the introduction of effective anti-tuberculous
chemotherapy, as an adjunct to antibiotic treatment. Stud-
ies reporting this practice are reviewed below, following
a consideration of the mechanisms by which vitamin D
modulates the immune response to Mycobacterium tuber-
culosis, the gram positive acid-fast bacillus that causes TB
disease.
3. Mechanism of action
Vitamin D has no direct antimycobacterial action, but its
active metabolite 1␣,25(OH)2 D modulates host response to
M. tuberculosis infection. In active disease the organism is
contained within a central core of macrophages surrounded
by T cells: the granuloma (Fig. 1). Expression of macrophage
25-hydroxy-vitamin D 1␣-hydroxylase (1␣-hydroxylase) is
Fig. 1. Upregulation of macrophage 1␣,25(OH)2 D synthesis following
administration of pharmacologic doses of vitamin D in active Mycobac-
terium tuberculosis infection. In the granuloma both IFN␥ and ligation of
macrophage TLR2/1 by M. tuberculosis induces macrophage expression
of 25(OH)D-1␣-hydroxylase. Administration of pharmacologic doses of
vitamin D results in increased circulating concentrations of free 25(OH)D,
which is metabolised by upregulated 1␣-hydroxylase to 1␣,25(OH)2 D. This
may either act in a paracrine manner to modulate immune responses in the
granuloma, or, if produced at high concentration, may enter the systemic
circulation and induce hypercalcemia.
upregulated by ligation of macrophage toll-like receptors
by M. tuberculosis antigens [7]. This enzyme metabolises
25-hydroxy-vitamin D (25(OH)D) to 1␣,25(OH)2 D. Inter-
feron gamma (IFN␥) secreted by armed TH 1 cells potentiates
this effect by upregulating 1␣-hydroxylase [8] and inhibiting
induction of 25(OH)D 24-hydroxylase [9], a key enzyme in
1␣,25(OH)2 D inactivation.
1␣,25(OH)2 D induces anti-mycobacterial activity in vitro
in both monocytes [10] and macrophages [11]. Several
mechanisms of action have been described. Exogenous
1␣,25(OH)2 D induces a superoxide burst [12] and enhances
phagolysosome fusion [13] in M. tuberculosis-infected
macrophages; both phenomena are mediated by phos-
phatidylinositol 3-kinase, suggesting that this response is
initiated by ligation of membrane vitamin D receptor (VDR)
[14]. 1␣,25(OH)2 D also modulates immune responses by
binding nuclear VDR, where it upregulates protective innate
host responses (including induction of nitric oxide synthase
[15] and cathelicidin [7]) and down-regulates IFN␥ gene
expression (by down-regulating activity of the IFN␥ pro-
moter) [16].
 A.R. Martineau et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 793–798
In addition to this paracrine action, sufficient concentra-
tions of 1␣,25(OH)2 D may be generated to enter the systemic
circulation to induce hypercalcemia via action on the kidney,
gut and bone [17]. This phenomenon has been observed in
patients with active TB who may present with established
hypercalcemia or develop hypercalcemia in the early phases
of treatment [18].
Administration of pharmacologic doses of vitamin D may
elevate serum 25(OH)D concentrations to levels at which
the ability of vitamin D binding protein (DBP) to bind
vitamin D metabolites becomes saturated. A greater propor-
tion of 1␣,25(OH)2 D synthesised as a result of upregulated
macrophage 1␣-hydroxylase activity in active TB may there-
fore be unbound by DBP, resulting in an increase in its
biological activity. 25(OH)D may also act as a VDR agonist
at high concentrations [19]. Systemically, this has the poten-
tial to induce hypercalcemia and ultimately lead to vitamin
D toxicity, in which deposition of calcium phosphate crys-
tals in the kidney and vasculature leads to renal failure and
hypertension [20].
4. Clinical studies describing the use of vitamin D in
pulmonary tuberculosis treatment
4.1. Literature search
We identified 14 prospective clinical studies in which
vitamin D had been administered to patients with PTB by
searches of Medline, Oldmedline and reference lists from
relevant articles. Search terms were “tuberculosis”, “vita-
min D”, “calciferol”, “ergocalciferol” and “cholecalciferol”.
Papers in all languages were considered. We obtained all
papers but one [21]. Three studies were randomized con-
trolled trials (RCT), and 10 were case series (four including
patients administered concurrent antibiotic therapy) (see
Table 1).
4.2. Patient characteristics
One study specified that it recruited children only [22],
and two studies specified that they recruited adults only
[6,23]. All studies included patients with PTB (as per lit-
erature search criteria); some also included patients with
co-existing extra-pulmonary disease [22,24,25]. One study
also included patients without TB (healthy controls and
patients with chronic obstructive pulmonary disease) [23].
4.3. Dosing regime
Where specified, vitamin D was given as vitamin D2 ; this
was taken orally in all but one [6] of the studies, where it
was administered intramuscularly. A wide range of doses
was administered: daily doses ranged from 400 to 100,000 IU
daily, while intermittent doses ranged from 400,000 IU every
10 days to 600,000 IU three times per week. Where specified,
795
total dose ranged from 60,000 IU to 7.2 M IU. Adjunc-
tive antibiotics administered included rifampicin, isoniazid,
streptomycin, para-aminosalycilic acid (PAS) and the ben-
zaldehyde thiosemicarbazone derivative TB.I 698; adjunctive
vitamin B1 was administered in one study [26].
4.4. Evidence that vitamin D modulated host response to
infection
Only one out three RCT commented on the effects of vita-
min D supplementation on disease course [22]. This study
recruited 24 children with pulmonary and/or extra-pulmonary
disease and randomized them to receive isoniazid, rifampicin
and streptomycin therapy either alone or with a daily oral
dose of 1000 IU vitamin D for 2 months. Intervention and
control groups were poorly matched for disease site at base-
line. Mean weight increased after treatment in both groups
(mean weight gain 2.63 kg versus 1.89 kg for control and
intervention groups, respectively); degree of weight gain was
not compared between groups with statistical tests. No statis-
tically significant differences in clinical response to treatment
were reported between groups. The other two RCT reviewed
did not report effects of vitamin D on course of disease.
All 10 of the case series reviewed commented on the
effects of vitamin D on the course of disease. The most
consistent clinical observation reported was of an inflam-
matory reaction (reported in four case series) [24,26–28].
This was documented in 4–21% of patients, and occurred at
1–4 weeks after initiation of vitamin D treatment. It mani-
fested as a worsening of pulmonary symptoms, accompanied
by pyrexia, weight loss, raised erythrocyte sedimentation
rate (ESR) and the appearance of inflammatory infiltrates on
chest radiograph. Gastric washings were negative for acid-
fast bacilli when tested [24]. In one case series [24] patients
with coexisting pulmonary and cutaneous disease experi-
enced simultaneous inflammatory reactions at both disease
sites. These reactions were seen more often in patients tak-
ing higher doses of vitamin D (≥100,000 IU/day). Symptoms
of this inflammatory response resolved on discontinuation of
vitamin D, which was then reintroduced at lower dose without
complication.
4.5. Evidence of vitamin D-induced toxicity
Administration of vitamin D was reported to induce a sta-
tistically significant rise in mean serum calcium in only one
of three RCT reviewed [23]. Nineteen of thirty patients with
smear or culture positive PTB developed hypercalcemia at
doses of 400–3800 IU daily, of whom two were symptomatic.
Mean serum calcium levels rose after 15 days of vitamin D
administration: the degree of rise in serum calcium was not
dose-dependent. Calcium levels returned to normal after 6
months despite continuation of vitamin D treatment, with fall
in serum calcium level coinciding with conversion of sputum
from positive to negative (whether by smear or culture is not
stated). No patient developed renal impairment as evidenced
 796
Table 1
Prospective studies of administration of vitamin D to patients with pulmonary tuberculosis
Reference; language; Patients Dose of vitamin D Adjunctive treatment Therapeutic response Adverse events
study design
Morcos, Boll Chim Farm 24 children with 1000 IU po daily for 2 months Isoniazid, rifampicin and None attaining statistical significance None reported
1998; English; RCT pulmonary and/or streptomycin
extrapulmonary TB
Narang, JAPI 1984; 60 adult patients with 400, 800, 1200, 2400 and 3600 IU Antibiotic treatment—not None reported Mean serum calcium elevated in

A.R. Martineau et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 793–798
English; RCT pulmonary TB + 90 po daily for up to 6 months specified all smear/culture positive PTB
controls patients participants and in
controls taking ≥2400 IU/day
Gwinup, Acta Endocrinol 23 patients with 5000 IU D2 po daily for up to 10 Isoniazid, rifampicin and None reported None reported
1981; English; RCT pulmonary TB weeks streptomycin
Brincourt Poum Coeur >100 patients with PTB 600,000 IU D2 every 10 days for up Antibiotic treatment—not Rapid liquefaction of caseating One patient developed
1967; French; Case to 4 months (maximum dose 7.2 M specified necrosis; decreased fibrotic sequalae hypercalcemia after 7.2 M IU
series IU) total dose; nephrocalcinosis did
not ensue
Trautwein, BKTST 1952; 35 patients with PTB and 200,000 IU D2 3 times per week PAS or TB.I 19/35 made ‘good/very good response’, 4/35 developed hypercalcemia
German; Case series cutaneous TB 10/35 ‘some/temporary’ response (>3 mmol/l)
Fielding, Lancet 1951; 7 adult patients with PTB 600,000 IU D2 IM weekly for three Streptomycin and PAS ‘Cavitation reduced’ in 6/7; 1/7 (with No toxic effects attributed to
English; Case series doses, fortnightly for 4 weeks, streptomycin-resistant disease) calciferol; anorexia and vomiting
monthly for 4 months (total dose deteriorated ‘in some cases’ attributed to PAS
5.4 M IU)
Gerecke, Z Tuberk 1950; 81 patients with PTB 40,000 IU daily With or without TB.I Four cases with combination showed Not reported
German; Case series response; none taking vitamin D alone
showed a response
Sude, Med Klin 1950; 9 patients with PTB 600,000 IU D2 3 times per week for No None improved; five deteriorated Two patients developed
German; Case series first week, 2 times per week in 2nd hypertension; one patient
to 4th weeks, then weekly discontinued vitamin D due to
symptomatic hypercalcemia
Jongmans, Ned Tij Gen 123 patients with PTB 90,000 IU D2 po daily for up to 12 No Not reported Five patients experienced
1950; Dutch; Case months exacerbation of symptoms
series
Ianovskaya, Prob Tub 78 patients with PTB and 50,000–100,000 IU D2 po daily No 42/78 improved; 28/78 unchanged; 16 of the 42 patients who
1950; Russian; Case cutaneous TB 8/78 deteriorated improved experienced
series exacerbation of symptoms
Seeber, Z Tuberk 1950; 28 patients with PTB 20,000 IU daily, increasing to No 12/28 improved; 13/28 unchanged; Not reported
German; Case series 40,000 IU daily; total dose 6 M IU 3/28 deteriorated
Winterberg, Z Tuberk 52 patients with PTB 400,000 IU every 5–10 days Not reported 44/52 improved Not reported
1950; German; Case
series
Feeny, Lancet 1947; 21 patients with PTB 25,000 IU D2 daily po, increasing 3 mg vitamin B1 daily po ESR up in 12/21, down in 5/21. 16/21 Headache in 7/21; Nausea in
English; Case series to 100,000 IU/day sputum positive before and after 16/21; vomiting in 4/21
treatment; 2 converted positive to
negative; 2 remained negative; 1
produced no sputum
 A.R. Martineau et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 793–798
by urinary potassium excretion. No change in serum calcium
was observed with vitamin D administration in the other trials
reviewed here.
Hypercalcemia was documented in three of the ten case
series reviewed [25,28,29]. Between 1% and 11% of patients
were affected, all of whom were receiving at least 600,000 IU
vitamin D per week. Nephrocalcinosis did not ensue in one
case series [28], and no comment on development of nephro-
calcinosis was made in the other two case series reporting
hypercalcemia [29,25]. Hypertension was documented in one
case series, affecting two of nine patients receiving an ini-
tial dose of 600,000 IU vitamin D three times per week. In
one series, 16/21 patients receiving 20,000–100,000 IU/day
developed nausea, and 4/21 developed vomiting; this usually
occurred among patients who had been receiving treatment
for ‘some weeks’ following increases in dose; serum calcium
levels in these patients were not reported [26].
5. Discussion
We reviewed 3 RCT and 10 prospective cases series in
which vitamin D was administered to patients with PTB. The
only RCT to investigate effects of vitamin D on course of
TB was of poor quality. In the absence of a control group
of patients not receiving vitamin D, clinical observations
reported in case series cannot reliably be attributed to vita-
min D treatment. Four case series describe features consistent
with paradoxical upgrading reaction. These reactions are
defined as the worsening of pre-existing tuberculous lesions
or the development of new TB lesions on the basis of clinical
or radiological findings in patients receiving TB treatment
[30]. The authors imply that they observed this phenomenon
more often in patients administered vitamin D than in those
who did not receive vitamin D. The frequency of these reac-
tions reported in the case series reviewed here (4–21%) is
comparable to that seen in HIV-negative patients receiving
modern standard anti-microbial therapy [31].
Narang’s report of the effect of 2400 IU vitamin D on
serum calcium in control patients has caused much contro-
versy and forms the basis of the USA National Academy
of Sciences lowest observed adverse effect level [32]. The
observation that a daily oral dose of 2400 IU vitamin D ele-
vates mean serum calcium in healthy controls is in contrast
to other studies which demonstrate that identical [33] or
considerably higher [34] doses of vitamin D do not induce
hypercalcemia in healthy people; it may be that actual doses
of vitamin D administered in this study were higher than
reported. Narang’s observations of the effect of vitamin D
in PTB are also in contrast to those of the other two trials
reviewed here. Hypercalcemia in TB patients receiving vita-
min D supplements has also been reported in a retrospective
case series, in which 22/79 patients with active TB devel-
oped hypercalcemia during the course of their disease; all
except one had received supplemental vitamin D at a daily
dose of 400–3800 units daily, and degree and duration of
797
hypercalcemia correlated positively with dose of vitamin D
administered. The onset of hypercalcemia occurred at 4–16
weeks post-admission, and resolved in all patients in 1–7
months; 4/22 discontinued vitamin D [35].
In contrast, the frequency of hypercalcemia reported in the
case series reviewed here is surprisingly low. Daily doses of
40,000 IU and higher produce serum concentrations in excess
of 200 nmol/l and are widely documented to induce toxicity
in individuals without vitamin D hypersensitivity [32]; rates
of toxicity in patients with active TB might be expected to
be even higher. Anti-tuberculous therapy has been reported
to reduce circulating levels of 25(OH)D and 1␣,25(OH)2 D
in healthy subjects [36], but this does not explain the low
incidence of hypercalcemia reported in patients not receiv-
ing antibiotic therapy. No study reported whether doses of
vitamin D administered were verified, patients were compli-
ant or serum 25(OH)D levels were elevated after vitamin D
treatment. No study explicitly stated a protocol for checking
serum calcium, and it may be that toxicity was not detected
because it was not often looked for.
In summary, there is growing evidence to suggest that
1␣,25(OH)2 D modulates antimycobacterial immunity in
vitro. Existing studies investigating the effects of vitamin D in
TB treatment are methodologically flawed. There is a need for
double-blind randomized placebo-controlled trials in patients
with active TB, powered to detect the effect of adjunctive vita-
min D on an outcome measure which has been validated to
correlate with risk of relapse.
Acknowledgements
We thank John Nyman of St. Mary’s Medical School
library for obtaining copies of the papers for review. Adrian
Martineau is supported by the British Lung Foundation.
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