.

1. Tuberculosis 126 (2021) 102034
Available online 1 December 2020
1472-9792/© 2020 Elsevier Ltd. All rights reserved.
The association between vitamin D deficiency and extrapulmonary
tuberculosis: Case-control study
Fatma Hammami a,*
, Makram Koubaa a,**
, Yosra Mejdoub b
, Mouna Turki c
, Houda Ben Ayed d
,
Amal Chakroun a
, Khaoula Rekik a
, Fatma Smaoui a
, Mounir Ben Jemaa a
a
Infectious Diseases Department, Extra-pulmonary Tuberculosis Research Unity UR17SP12, Hedi Chaker University Hospital, University of Sfax, Tunisia
b
Community Health and Epidemiology Department, Hedi Chaker University Hospital, University of Sfax, Tunisia
c
Biochemistry Laboratory, Habib Bourguiba University Hospital, University of Sfax, Tunisia
d
Preventive Medicine and Hygiene Department, Hedi Chaker University Hospital, University of Sfax, Tunisia
A R T I C L E I N F O
Keywords:
Extrapulmonary tuberculosis
Vitamin D deficiency
Case-control study
Mycobacterium tuberculosis
A B S T R A C T
Tuberculosis remains a public health issue worldwide. Identifying its risk factors, such as vitamin D deficiency, is
mandatory so as to target the preventive strategies. We aimed to study the association between vitamin D
deficiency and extrapulmonary tuberculosis. We conducted a case-control study including all cases of extrap­
ulmonary tuberculosis hospitalized in the infectious diseases department over a two-year period from April 2017
until April 2019.
We included 45 cases of extrapulmonary tuberculosis and 45 controls matched by gender and age. Vitamin D
deficiency was significantly more frequent among cases (80% vs 37.7%; p < 0.001), with an odds ratio (OR) of
6.5 (IC95% = 2.5–16). The mean levels of vitamin D were significantly lower among cases (11.9 ± 8.8 vs 22.3 ±
11 ng/mL; p < 0.001). In the multivariate analysis, we found that vitamin D deficiency was an independent
predictor of extrapulmonary tuberculosis (OR = 6.13; p < 0.001). The cutoff value of vitamin D predictor of
extrapulmonary tuberculosis was 18.5 ng/mL which was associated with a sensitivity of 80% and a specificity of
62%.
Our study provides strong evidence that vitamin D deficiency was an independent predictor of extrapulmonary
tuberculosis. More studies are needed in order to evaluate the potential preventive role of vitamin D and the
benefit of possible supplementation.
1. Introduction
Tuberculosis (TB) remains a public health issue worldwide. An
estimated 10 million people develop the disease, annually [1]. Accord­
ing to the Sustainable Development Goals, the World Health Organiza­
tion adopted a strategy in order to end TB epidemic by 2030 [1].
Identifying the risk factors for TB is mandatory so as to target the pre­
ventive strategies. Myriad factors were reported including human im­
munodeficiency virus (HIV) infection, younger age, female sex [2],
associated with diabetes mellitus, smoking, alcohol use, under-nutrition
[3], and vitamin D deficiency (VDD) [4]. The debate continues with
discordance between studies. In fact, a literature review reported an
association between VDD and susceptibility to TB in 29 out of 40 studies
[5].
In our intermediate endemicity country for TB, an increase of this
disease was noted in recent years, although a national control program
had been established [6]. In our region, extrapulmonary tuberculosis
(EPT) was predominant over pulmonary TB, due to inadequate pre­
ventive strategies [7]. The aim of this work was to study the association
between VDD and EPT.
Abbreviations: TB, Tuberculosis; HIV, Human immunodeficiency virus; VDD, Vitamin D deficiency; EPT, Extrapulmonary tuberculosis; M. tuberculosis, Myco­
bacterium tuberculosis; 25(OH)D3, 25-dihydoxyvitamin D; CRP, C-reactive protein; ROC, Receiver Operating Characteristic; OR, Odds ratio.
* Corresponding author. Infectious Diseases Department, Hedi Chaker University Hospital, Extra-pulmonary Tuberculosis Research Unity UR17SP12, University of
Sfax, 3029, Tunisia.
** Corresponding author. Infectious Diseases Department, Hedi Chaker University Hospital, Extra-pulmonary Tuberculosis Research Unity UR17SP12, University of
Sfax, 3029, Tunisia.
E-mail addresses: fatma.hammami@medecinesfax.org (F. Hammami), koubaa_makram@medecinesfax.org (M. Koubaa).
Contents lists available at ScienceDirect
Tuberculosis
journal homepage: http://www.elsevier.com/locate/tube
https://doi.org/10.1016/j.tube.2020.102034
Received 18 September 2020; Received in revised form 12 November 2020; Accepted 24 November 2020

2. Tuberculosis 126 (2021) 102034
2
2. Methods
2.1. Study design
We conducted a case-control study including all cases of EPT hos­
pitalized in the infectious diseases department over a two-year period
from April 2017 until April 2019.
2.2. Data collection and definition of cases and controls
We collected data from the patients’ medical records for cases.
Controls were interviewed according to a pre-established questionnaire.
Data including socio-demographic characteristics (age, gender), smok­
ing, alcohol use and previous medical history of patients were reviewed.
For cases, we notified the site of EPT, the diagnostic criteria and the
treatment prescribed. HIV serologic testing was performed for cases.
We included all cases of EPT diagnosed during the study period. The
diagnosis was confirmed with bacteriological proof, based on a positive
microscopy using Ziehl–Neelsen staining for acid-fast bacilli or growth
of Mycobacterium tuberculosis (M. tuberculosis) in culture. Histological
findings including epithelioid cell granulomas with caseous necrosis
confirmed the diagnosis. In default, it was based on strong clinical,
radiological evidence associated with positive tuberculin skin test and
followed by an adequate response to antitubercular treatment.
Controls were healthy non-hospitalized volunteers randomly
selected from the general population. They were matched to case sub­
jects by gender and age (we tolerated a variation of ±5 years).
At enrolment, we excluded from the study patients with previous
condition that may affect vitamin D metabolism such as chronic renal
failure, previous bone disease and recent surgery.
2.3. Measurement of vitamin D levels
We measured serum concentrations of 25-dihydoxyvitamin D (25
(OH)D3) for cases, before starting antitubercular therapy, and for con­
trols. Plasma concentration of 25(OH)D3 was measured by Roche Cobas
E601 electrochemiluminescence immunoassay analyzer. Vitamin D
deficiency was defined as 25(OH)D3 <20 ng/ml.
2.4. Other biological parameters’ measurement
We performed the assay of standard biochemical parameters such as
creatinine, urea and blood glucose, C-reactive protein (CRP) and pro­
tides. Liver function tests included the determination of alanine
aminotransferase, aspartate aminotransferase, total bilirubin, gamma­
glutamyl transferase, alkaline phosphatases, total cholesterol and tri­
glycerides. The parameters of the phosphocalcic balance were measured
such as calcemia, phosphoremia and parathyroid hormone. In addition,
all participants received a blood count to determine hemoglobin level.
2.5. Statistical analysis
We performed statistical analysis using SPSS 20. Categorial variables
were carried out by numbers and percentages. Continuous variables
were driven by means and standard deviations when they were normally
distributed. Otherwise, we used medians and inter quartile range. For
quantitative variables, we checked the normality of the distribution by
the Kolmogorov-Smirnov test and the Shapiro-Wilk test. We used Chi
square and Fisher exact test to compare two frequencies when appli­
cable. For the comparison of two means, we used Student’s T test for
independent samples when they were normally distributed. Otherwise,
we used Mann-Whitney test. The difference between two groups was
considered significant when p < 0.05.
To evaluate the risk factors associated with EPT, we calculated the
unadjusted and adjusted Odds ratio (OR) by using multivariate logistic
regression analysis. The final logistic regression model included
variables that changed the OR by at least 20%.
The analysis of the receiver operating characteristic (ROC) curve was
carried out to determine the area under the curve, the sensitivity and the
specificity at an optimal threshold value of the vitamin D level in order
to predict EPT.
3. Results
During the study period, we included 45 cases of EPT and 45 controls
matched by gender and age.
3.1. Extrapulmonary tuberculosis cases’ characteristics
Lymph nodes TB represented the main site of EPT (29 cases; 64.4%),
followed by urogenital TB (5 cases; 11.1%) and osteoarticular TB (4
cases; 8.9%). Multifocal TB was noted in 8 cases (17.7%). The diagnosis
was confirmed with histopathological proof in 36 cases (80%) and
bacteriological proof in 4 cases (8.9%).
Eight cases were confirmed based on clinical evidence (17.7%):
Clinical and radiological features suggested the diagnosis of TB and
tuberculin skin test was positive. However, no caseous necrosis was
found in specimen taken for histological examination, microscopy using
Ziehl–Neelsen staining for acid-fast bacilli and culture for Mycobacterium
tuberculosis were negative. These cases were at first considered as
probable TB until adequate response was obtained with antitubercular
therapy, confirming therefore, the diagnosis of TB.
Patients received antitubercular therapy, which was based on fixed-
dose combinations in 42 cases (93.3%). All cases were HIV negative.
3.2. Comparison between cases and controls
In the matched groups, no differences were found between cases and
controls regarding the patients’ demographic characteristics, except for
the educational level: a higher educational level was noted among the
control group (95.5% vs 73.3%; p < 0.001) (Table 1).
Comparison of laboratory investigations showed that CRP levels
were significantly higher (8.6 ± 10.2 vs 1.6 ± 1.3 mg/L; p < 0.001) and
hemoglobin levels were significantly lower (12.1 ± 1.7 vs 13.4 ± 1.65 g/
dL; p = 0.002) among cases (Table 2).
We did not find any significant difference between the two groups
Table 1
Comparison of demographic characteristics between extrapulmonary tubercu­
losis cases and controls.
Variables Cases Controls p-value
Total, n (%) 45 (100) 45 (100) –
Gender, n (%) 1
Male 14 (31.1) 14 (31.1)
Female 31 (68.9) 31 (68.9)
Age (years), mean (SD) 40 ± 13 39 ± 13.5 0.87
Male 46 ± 17.7 46 ± 14 0.3
Female 40.9 ± 16.6 39.6 ± 15 0.1
Underlying comorbid disease, n (%)
Diabetes mellitus 3 (6.7) 3 (6.7) 1
High blood pressure 4 (8.9) 4 (8.9) 1
Smoking history 7 (15.6) 7 (15.6) 1
Alcohol use 3 (6.7) 1 (2.2) 0.6
Socioeconomic status, n (%)
Marital status 0.2
Married 29 (64.4) 34 (75.6)
Single 16 (35.6) 11 (24.4)
Educational level <0.001
Primary education 12 (26.7) 2 (4.4)
Secondary or university education 33 (73.3) 43 (95.5)
Employment status 0.4
Employed 21 (46.7) 25 (55.6)
Unemployed 24 (53.3) 20 (44.4)
n: number; %: percentage; SD: standard deviation.
F. Hammami et al.

3. Tuberculosis 126 (2021) 102034
3
when we compared the factors that influence vitamin D metabolism
except for the phosphorus level, which was significantly lower among
controls (1.04 ± 0.1 vs 1.14 ± 0.1 mmol/L; p = 0.01) (Table 2).
3.3. The association between vitamin D and extrapulmonary tuberculosis
Vitamin D deficiency was significantly more frequent among cases
(80% vs 37.7%; p < 0.001), with an odds ratio (OR) of 6.5 (IC95% =
2.5–16). The mean levels of vitamin D were significantly lower among
cases (11.9 ± 8.8 vs 22.3 ± 11 ng/mL; p < 0.001). As to gender, VDD
was significantly more frequent among males in the case group in
comparison with males in the control group (57.1% vs 14.3%; p = 0.04).
Females with EPT were significantly more affected with VDD in com­
parison with females in the control group (90.3% vs 48.4%; p < 0.001).
The mean levels of vitamin D was significantly lower in the case group
among both males (19.4 ± 8.6 vs 27.6 ± 9.8 ng/mL; p = 0.04) and fe­
males (8.5 ± 6.6 vs 19.9 ± 12.1 ng/mL; p < 0.001), in comparison with
males and females in the control group, respectively (Table 3). Females
had significantly lower levels of vitamin D in comparison with males
among the case group (8.5 ± 6.6 vs 19.4 ± 8.6 ng/mL; p < 0.001) and
the control group (19.9 ± 12.1 vs 27.6 ± 9.8 ng/mL; p = 0.029).
3.4. Factors associated with extrapulmonary tuberculosis
In the univariate analysis, we found that patients with EPT had pri­
mary educational level in 85.7% of the cases (OR = 7.81; p = 0.007) and
had VDD in 67.9% of the cases (OR = 6.58; p < 0.001). (Table 4).
In the multivariate analysis, after adjustment for the educational
level, we found that VDD was an independent predictor of EPT (OR =
6.13; p < 0.001) (Table 5).
The cutoff value of vitamin D predictor of EPT was 18.5 ng/mL which
was associated with a sensitivity of 80% and a specificity of 62% (Fig. 1).
4. Discussion
Our study highlighted the link between VDD and EPT. We found that
vitamin D levels were significantly lower among cases in comparison
with controls and VDD was an independent predictor of EPT. In fact,
previous studies found similar results when studying the association
between vitamin D and both EPT and pulmonary TB [8,9]. A recent
meta-analysis reported that VDD was associated with an increased risk
of TB [10]. The level of VDD was correlated with the severity of the
disease. A recent study reported that patients with tubercular meningitis
had significantly lower value of Vitamin D level in comparison with
other forms of TB [9]. Besides, low vitamin D levels were associated with
a five-fold increased risk for progression to TB [11]. That risk was mostly
pronounced among HIV-positive patients with severe deficiency [12].
Vitamin D and TB remain strongly linked. Previous meta-analysis
reported that VDD increased the risk of TB, which is concordant with
our results. However, it reported that TB increased the risk of VDD, as
well, which might be explained by malnutrition and vitamin D receptor
polymorphism [13]. A previous study found a high expression of vitamin
D receptor in macrophage from persons with previous EPT when
compared with macrophages from persons with previous pulmonary TB,
TB contacts with latent M. tuberculosis infection and uninfected contacts,
while vitamin D levels were similarly low in all groups [14]. Vitamin D
can be obtained either from diet and dietary supplements or from
exposure to sunlight [15,16]. In fact, 80% of the vitamin D results from
cutaneous production due to sunlight exposure, that’s why its deficiency
was more prevalent among patients who avoid sun exposure [17]. This
might explain the results found in our study about females who had
significantly lower levels of vitamin D, which is mostly related to their
religious belief and their protective clothing.
The role for vitamin D in the modulation of immune function were
suggested, previously. In fact, vitamin D increases the antimicrobial
activity of the macrophage and monocyte [18], by the activation of
cathelicidin-mediated killing of ingested mycobacteria [19] and the
release of interferon-γ which induce autophagy and phagosomal
maturation leading to degradation of mycobacteria [20]. The exposi­
tion of human monocytes to M. tuberculosis enhances both the cell
ability to produce vitamin D in the site of infection and to respond to
this metabolite [18].
Table 2
Comparison of laboratory investigations between extrapulmonary tuberculosis
cases and controls.
Variables EPT cases
(45 cases)
Controls
(45 cases)
p-value
ASAT (UI/L) 24.4 ± 6.9 17.1 ± 4.4 0.004
ALAT (UI/L) 24.4 ± 13 16.5 ± 7.5 0.01
Total bilirubin (μmol/L) 9.9 ± 4.9 10.1 ± 6.7 0.2
GGT (UI/L) 35.4 ± 40.2 17.6 ± 9.6 <0.001
CRP (mg/L) 8.6 ± 10.2 1.6 ± 1.3 <0.001
Hemoglobin level (g/dL) 12.1 ± 1.7 13.4 ± 1.6 0.002
Protides (g/L) 73.7 ± 5.2 73.2 ± 4 0.06
Blood glucose (mmol/L) 4.3 ± 1.2 5 ± 0.6 0.6
Total cholesterol
(mmol/L)
4.1 ± 1.6 4.9 ± 0.9 0.4
Triglycerides (mmol/L) 1.1 ± 0.5 1.5 ± 1.1 0.1
Creatinine (μmol/L) 61.7 ± 22.5 65.1 ± 13 0.1
Urea (mmol/L) 4.5 ± 1.1 4.4 ± 1.2 0.1
Alkaline phosphatase
(UI/L)
77 ± 42.6 61.6 ± 16.9 0.06
Calcemia (mmol/L) 2.3 ± 0.2 2.2 ± 0.2 0.1
PTH (pg/mL) 37.8 ± 12.2 42.3 ± 9.3 0.5
Phosphorus (mmol/L) 1.14 ± 0.1 1.04 ± 0.1 0.01
EPT: extrapulmonary tuberculosis, ASAT: aspartate aminotransferase, ALAT:
alanine aminotransferase, GGT: gammaglutamyl transferase, CRP: C-reactive
protein, PTH: parathyroid hormone.
Table 3
The distribution of vitamin D deficiency according to gender among extrap­
ulmonary tuberculosis cases and controls.
Cases Controls p-value
Vitamin D deficiency, n (%) 36 (80) 17 (37.7) <0.001
Males 8/14 (57.1) 2/14 (14.3) 0.04
Females 28/31 (90.3) 15/31 (48.4) 0.001
Mean levels of vitamin D (ng/mL) 11.9 ± 8.8 22. ±11 < 0.001
Males 19.4 ± 8.6 27.6 ± 9.8 0.04
Females 8.5 ± 6.6 19.9 ± 12.1 0.001
n: number; %: percentage.
Table 4
Factors associated with extrapulmonary tuberculosis in the univariate logistic
regression.
Variables N (%) OR p-value
Gender Males (N = 28) 14 (50) – 1
Females (N = 62) 31 (50)
Age groups [17–36 years[ (N = 38) 19 (50) – 1
≥36 years (N = 52) 26 (50)
Employment status Employed (N = 46) 21 (45.7) – 0.4
Unemployed (N = 44) 24 (54.5)
Primary educational
level
Yes (N¼14) 12 (85.7) 7.81 0.007
No (N¼76) 33 (43.4)
Marital status Married (N = 63) 29 (46) – 0.2
Single (N = 27) 16 (59.3)
Diabetes mellitus Yes (N = 6) 3 (50) – 1
No (N = 84) 42 (50)
High blood pressure Yes (N = 8) 4 (50) – 1
No (N = 82) 41 (50)
Smoking Yes (N = 14) 7 (50) – 1
No (N = 76) 38 (50)
Alcohol use Yes (N = 4) 3 (75) – 0.6
No (N = 86) 42 (48.8)
Vitamin D deficiency Yes (N¼53) 36 (67.9) 6.58 <0.001
No (N¼37) 9 (24.3)
N: number, %: percentage, OR: odds ratio.
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4. Tuberculosis 126 (2021) 102034
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Although it has no direct antimicrobial activity, vitamin D was used
to treat pulmonary TB, since it modulates host response [21]. Previous
study reported that oral supplementation with a daily vitamin D at a
dose of 5000 IU is optimal for cathelicidin induction and efficient
intracellular killing of M. tuberculosis [22]. In fact, vitamin D supple­
mentation, associated with antitubercular therapy, accelerated sputum
smear conversion [23,24]. Besides, vitamin D has anti-inflammatory
effects and can, therefore, reduce the severity of infection by
decreasing the overall inflammatory state [25].
We believe that VDD was associated with EPT, and Vitamin D sup­
plementation as a preventive therapy and treatment adjunct with anti­
tubercular therapy should be considered. However, our data are limited
and are not really robust enough to propose that. More studies are
required to confirm and propose vitamin D supplementation.
5. Conclusion
Our study provides strong evidence that VDD was an independent
predictor of EPT. More studies are needed in order to evaluate the po­
tential preventive role of vitamin D and the benefit of possible
supplementation.
6. Formatting of funding sources
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Author contributions
Conceptualization: FH, MK, HBA, MBJ. Methodology: FH, MK, YM,
MBJ. Formal analysis: FH, MK, YM, AC, MBJ. Writing - Review &
Editing: FH, MK, MBJ. Visualization: FH, MK, MT, KR, FS, MBJ. Su­
pervision: MK, MT, HBA, KR, MBJ. Final approval of the version to be
submitted: all authors.
Declaration of competing interest
The authors declare no competing interest.
Acknowledgements
None.
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Univariate analysis Multivariate analysis
p-value R2 OR IC95% p-value ORa CI95%
Vitamin D deficiency <0.001 17.4% 6.58 2.55–17 <0.001 6.13 2.29–16.4
Primary educational level 0.01 13% 7.81 1.63–37.3 0.024 6.78 1.29–35.67
Single 0.25 2% 1.7 0.68–4.25 – – –
R2: Nagelkerke R Square = 31%, OR: odds ratio, ORa: adjusted odds ratio, CI: confidence interval.
Fig. 1. Receiver operating characteristic curve determining vitamin D level
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