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Abstract

Objectives:

To compare the serum vitamin D and serum cathelicidin antimicrobial peptide (CAMP) levels among tuberculosis patients and healthy subjects and to determine the association between serum vitamin D and cathelicidin in tuberculosis.

Materials and Methods:

This is a case-control study carried out at the pulmonary medicine and pediatrics departments of a tertiary care hospital in Chengalpattu. The study included 180 tuberculosis cases and 90 control subjects of both sexes between the age group of 1 to 80 years. Serum was used to estimate vitamin D and CAMP. The study was analyzed using SPSS version 21 (IBM Corp. Armonk, New York). The results were evaluated using the chi-square test at a 95% confidence interval, and P value <.05 was considered highly significant.

Results:

This study observed vitamin D deficiency, vitamin D insufficiency, and optimum vitamin D among 55%, 41%, and 3.89% tuberculosis cases, respectively. Similarly, vitamin D deficiency, vitamin D insufficiency, and optimum vitamin D were seen in 40%, 50%, and 10% healthy controls, respectively.

Conclusion:

This study found no association between serum vitamin D and serum CAMP levels in tuberculosis patients and healthy controls.

Keywords

Immunomodulatory LL-37 Sunshine vitamin The white plague Antimicrobial peptide Tuberculosis

Introduction

Tuberculosis (TB) is the world’s deadliest chronic granulomatous disease and the second most important infectious killer disease. It mostly affects the lungs and can affect organs, such as the abdomen, urogenital system, glands, lymph nodes, bones, blood, and the central nervous system. The incidence of TB cases in India was 2.59 million cases, according to the WHO report 2021.¹ In 2020, India is first among eight high-burden TB countries, which account for two-thirds of the new TB cases.² Vitamin D is a sunshine vitamin, and its main role is associated with bone homeostasis. Recent research studies have reported the role of vitamin D in the prevention and treatment of a variety of disorders, like cancer, cardiovascular diseases, autoimmune diseases, infectious diseases, and diabetes mellitus.³ Vitamin D is an immunomodulator that exerts innate and adaptive immunity and helps to combat TB.^4–6 It produces cathelicidin antimicrobial peptides (CAMP) or LL-37, which are the first-line defensins against invading microorganisms, thereby protecting the body against TB.^{4, 7} They are expressed in epithelial cells of the testis, skin, the gastrointestinal tract, the respiratory tract, and in leukocytes, such as monocytes, neutrophils, T cells, NK cells, and B cells.⁸ Increased CAMP expression is seen in macrophages by optimum levels of vitamin D, which causes damage to the tubercle bacilli and eventually results in autophagy.^9–11 The antimicrobial and immunomodulatory properties of human LL-37 are dependent on vitamin D status. A decreased growth rate of Mtb was seen in the macrophages treated with vitamin D, proving that vitamin D has immunity against TB, which was proved way back in 1836.¹² In vitro studies have also shown that vitamin D deficiency acts as a risk factor for the development of TB by modifying immunomodulatory effects of vitamin D.^{4, 12–15} A study demonstrated that vitamin D insufficiency inhibits the induction of the CAMP gene, which subsequently leads to decreased LL-37 expression.¹⁶ However, other studies have failed to demonstrate the association between vitamin D status and LL-37 in TB. In India, the association between serum vitamin D and serum CAMP levels among TB patients and control subjects has not been carried out till date. Thus, the objective of the present study is to compare serum vitamin D and CAMP levels among TB patients and controls and to determine the association between serum vitamin D and LL-37 among the two study groups.

Materials and Methods

Study Population

The present study screened 410 study subjects and after considering inclusion and exclusion criteria, the study included 180 TB cases and 90 control subjects of both sexes between the age group of 1 to 80 years. Patients from the Departments of Paediatrics and Pulmonology, SRM Medical College Hospital and Research Centre were enrolled as a case group, and adults working within SRM university campus were enrolled as an adult control group in the present study. Pediatric control subjects were chosen from in and around the Potheri and Kattankulathur areas. For each subject, all demographic and anthropometric details, sunlight exposure, monthly income, skin color, diet pattern, and living condition were collected using a preformed proforma. Acid fast staining for sputum, Mantoux test, chest X-ray, and other blood investigations were carried out to confirm the cause of TB.

Study participants were informed about the nature and purpose of the present study and written informed consent was obtained. The Scientific Committee and Institutional Ethical Committee clearance (913A/IEC/2015) was obtained before starting the study.

Inclusion Criteria

Patients of both genders aged between 1 and 80 yr and registered under DOTS at SRM MCH & RC were included. Subjects who were not having TB acted as control.

Exclusion Criteria

TB patients infected with HIV or with a history of seizures or taking drugs phenobarbitone, phenytoin, orlistat, corticosteroids, cholestyramine, statins, and thiazide diuretics were not included in the study. Pregnant patients were also excluded.

Study Design

The present study was a case-control study carried out at a tertiary care teaching hospital in Chengalpattu from January 2016 for a period of 15 months. About 3 mL of venous blood was collected from each subject, and serum was separated to estimate vitamin D and cathelicidin.

Estimation of Serum Vitamin D

It was done using the chemiluminescent microparticle immunoassay with an Architect 25-OH vitamin D assay kit.

Estimation of Serum CAMP Level

It was estimated using quantitative sandwich enzyme immunoassay technique with a Blue gene kit.

Sample Size Calculation

Sample size was calculated using PS power and sample size calculation software version 3.1. Keeping α = 0.05, power = 0.8, the probability of exposure in controls = 0.82, m = the ratio of control to cases 0.5, and β = 3.1 showed a sample size of 183 cases and 91 controls obtained from a pilot study.

Statistical Analysis

In the present study, serum vitamin D and serum cathelicidin anti-microbial levels were expressed in numbers and percentage. Serum vitamin D levels and serum CAMP levels were compared among TB patients and controls using the chi-square test at a 95% confidence interval, and a P value <.05 was considered statistically significant. SPSS version 21 was used for the statistical analysis.

Results

In this study, mean vitamin D levels in TB cases and healthy controls were 16.56 ng/mL and 21.59 ng/mL, respectively. In the present study, vitamin D deficiency, vitamin D insufficiency, and optimum vitamin D levels were seen in 55%, 41%, and 3.89% of cases, respectively. Among healthy controls, 40%, 50%, and 10% had vitamin D deficiency, vitamin D insufficiency, and normal levels of vitamin D in the serum, respectively. Among TB cases, 96% had below optimum vitamin D levels compared to 90% in healthy controls. Both mean vitamin D levels and optimum serum vitamin D levels were lower in TB cases compared to controls.

Among vitamin-D-deficient TB patients, 18.88% had below-normal serum cathelicidin levels and 36.11% had normal serum levels of cathelicidin. Among vitamin-D-insufficient cases, 15.55% and 25.55% had below-normal and optimum levels of cathelicidin in the serum, respectively. Among vitamin D optimum cases, 0.55%, 1.11%, and 2.22% had above-normal, below-normal, and optimum levels of cathelicidin in the serum, respectively. Among vitamin-D-deficient controls, 25.55% had below-normal serum cathelicidin levels and 14.44% had normal serum levels of cathelicidin. Among vitamin-D-insufficient controls, 16.66% and 33.33% had below-normal and optimum levels of cathelicidin in the serum, respectively. Among vitamin D optimum controls, 1.11% and 8.88% had below-normal and optimum levels of cathelicidin in the serum, respectively. The present study showed that 96% of TB patients and 90% of controls had serum vitamin levels below the optimum levels, showing that vitamin D deficiency is very common among the general population irrespective of whether the population is infected with TB or not (Table 1).

Table 1.

Comparison of Vitamin D Status and Serum CAMP Among Study Population.

Vitamin D Status—Cases	CAMP Status	Case (180)	Vitamin D Status—Controls	CAMP Status	Control (90)
VDD 99 (55%)	Hyper	0	VDD 36 (40%)	Hyper	0
	Hypo	34 (18.88%)		Hypo	23 (25.55%)
	Normal	65 (36.11%)		Normal	13 (14.44%)
VIS 74 (41%)	Hyper	0	VIS 45 (50%)	Hyper	0
	Hypo	28 (15.55%)		Hypo	15 (16.66%)
	Normal	46 (25.55%)		Normal	30 (33.33%)
VO 7 (3.89%)	Hyper	1 (0.55%)	VO 9 (10%)	Hyper	0
	Hypo	2 (1.11%)		Hypo	1 (1.11%)
	Normal	4 (2.22%)		Normal	8 (8.88%)

Note:Normal serum CAMP level - 0.6 ng/ml to 5.8 ng/ml. Serum vitamin D status according to USA endocrine society classification. Vitamin D deficiency <20 ng/mL, Vitamin D insufficiency 21 ng/mL to 29 ng/mL, Vitamin D optimum >30 ng/mL, and toxicity >150 ng/mL

Abbreviations: CAMP, cathelicidin antimicrobial peptide; VDD, Vitamin D deficiency; VIS, Vitamin D insufficiency; VO, Vitamin D optimum

Among 55% vitamin-D-deficient cases, 36.11% had optimum cathelicidin levels when compared to 40% vitamin-D-deficient controls, who had 14.44% normal cathelicidin levels. Among 41% vitamin-D-insufficient cases, 25.55% had normal cathelicidin levels compared to 50% vitamin-D-insufficient controls, who had 33.33% normal cathelicidin levels. Among 3.89% optimum vitamin D cases, 2.22% had normal cathelicidin levels, and among 10% optimum vitamin D controls, 8.88% had normal vitamin D levels. This study showed that even though there was vitamin D deficiency and insufficiency among cases and controls, normal cathelicidin levels were observed.

In the present study, among all the study subjects, below-normal levels of vitamin D were seen in 254 subjects. Among these, 100 had cathelicidin levels in the normal range and 154 had abnormal cathelicidin levels. Among optimum vitamin D study subjects, 12 had cathelicidin levels in the normal range and 4 had abnormal serum cathelicidin levels. Among 270 study subjects, 166 had normal serum cathelicidin levels irrespective of their vitamin D status. The present study was not able to find a statistically significant association between serum vitamin D levels and serum cathelicidin antimicrobial levels (Table 2). Among 180 TB cases, 115 had cathelicidin levels in the normal range and 65 had abnormal cathelicidin levels. Among healthy controls, 51 had normal serum cathelicidin and 39 had abnormal cathelicidin levels. The present study could not find a statistically significant association between TB cases and serum cathelicidin levels. Among the vitamin-D-deficient population, below-normal levels of CAMP were observed in 18.88% of cases compared to 25.55% of controls. In the study population that exhibited vitamin D insufficiency, below-normal levels of CAMP were observed in 15.55% of cases compared to 16.66% of controls. Among the vitamin D optimum study population, both cases and controls had 1.11% and 2.22% below-normal and normal levels of CAMP, respectively (Table 3).

Table 2.

Association Between Serum Vitamin D Status and Serum CAMP Levels

Vitamin D Status	CAMP		Total	Chi-Square Value	P Value	Odds Ratio	95% CI
	Abnormal	Normal	–	1.31 (d _f = 1)	.25	1.19	0.6, 6.2
Deficient	100	154	254
Normal	4	12	16
Total	104	166	270

Note: Normal serum CAMP level—0.6 ng/mL to 5.8 ng/mL. *P < .05—statistically significant.

Abbreviation: CAMP, cathelicidin antimicrobial peptide.

Table 3.

Association Between Serum CAMP Levels and Tuberculosis.

Tuberculosis Status	CAMP		Total	Chi-Square Value	P Value
Tuberculosis Status	Abnormal	Normal	–	1.3215 (d _f = 1)	.25
TB	65	115	180
Control	39	51	90
Total	100	164	270

Note: *P < .05—statistically significant.

Abbreviation: CAMP, cathelicidin antimicrobial peptide.

Discussion

Vitamin D is a fat-soluble vitamin that acts as an immune modulator against infectious diseases. Vitamin D inhibits the growth of microorganisms, like Staphylococcus aureus, Streptococcus pyogenes, Klebsiella pneumonia, and E. coli, as reported in some of the in vitro studies.¹⁷ Cod liver oil has a large amount of vitamin D and was used as a treatment for TB before antibiotic usage.¹⁸ It is evident from previous studies that there is a definite link between vitamin D and TB disease. Literature review says that vitamin D deficiency poses a risk for the development of TB infection and disease. The present study showed lower levels of mean serum vitamin D among TB cases compared to controls. It also showed that hypovitaminosis D was observed in 96% of TB cases and 90% of healthy controls. A study conducted in Australia among African immigrants also showed that mean vitamin D levels were lower in latent TB patients compared to the control group.¹⁹ A meta-analysis of vitamin D in TB also revealed that vitamin D levels were low in TB patients compared to controls.¹⁰ A cross-sectional study on TB also showed that hypovitaminosis is more among TB cases compared to controls, and it adds to a greater rate of sputum smear positivity, severe clinical symptoms, and larger lesions in the chest X-ray among cases.^{20, 21} A cohort follow-up study conducted in Pakistan among healthy household contacts reported an association of vitamin D deficiency with TB.²² A study conducted in Vietnam stressed that hypovitaminosis could be a possible cause of TB.²³ In the present study, vitamin D deficiency was not only predominant among cases, but it was also common in control subjects. Recently, vitamin D deficiency has become very common worldwide. Tropical areas, like Chennai, where there is scorching sun throughout the year, make it very surprising to observe the vitamin D deficiency in this part of the country. Because of an ultramodern lifestyle, indoor stay during the daytime, using sunscreen lotions, lack of vitamin D supplementation, and fortification of food items could be the reasons for vitamin D deficiency. Vitamin D is an immune modulator. It combats Mtb by the production of LL-37, which causes the formation of phagolysosomes. It is clear that vitamin D levels are proportional to CAMP to protect the body against infections. In our study, vitamin-D-deficient and vitamin-insufficient study subjects showed normal serum cathelicidin levels. When study subjects had serum vitamin D levels within the normal range, there was a deficiency of CAMP levels in the serum. It shows that the present study could not find a statistically significant association between serum vitamin D levels and serum CAMP levels among study subjects (Table 3). A study conducted among HIV-positive patients showed a positive correlation between vitamin D and LL-37.²⁴ A study conducted among healthy subjects showed that serum vitamin D levels ≤ 32 ng/mL had a positive correlation with serum cathelicidin, and when serum vitamin D levels exceeded 32 ng/mL, there was a fall in serum cathelicidin levels.²⁵ A study conducted among the elderly showed a decreased serum vitamin D and an associated fall in serum cathelicidin levels.²⁶ A study on neonates and mothers could not find an association between serum vitamin D and LL-37 in the cord blood, which supports the present study.²⁷ Among critically ill patients with sepsis, there was a positive correlation between serum levels of vitamin D and LL-37 compared to healthy subjects.²⁸ Some studies have shown that vitamin D considerably increases serum cathelicidin levels and helps to improve the clinical outcomes of TB, which is contradictory to the present study.^{29, 30} The present study found no association between serum CAMP levels and TB (Table 3). Our study could not find an association between serum vitamin D levels and serum cathelicidin or between serum cathelicidin and TB. There was no association between serum vitamin D levels, serum cathelicidin levels, and TB. A meta-analysis and systematic review reported hypovitaminosis D in TB cases with raised circulatory cathelicidin levels.³¹ A prospective Canadian study found an association between serum concentrations of 25 hydroxyvitamin D levels (25(OH)D) and LL-37, and the study also revealed that there was a decrease in LL-37 concentrations following vitamin D supplementation. Also, this study could not find any association between serum 25(OH)D and LL-37, which is in agreement with our study results in TB patients.³² A meta-analysis reported that serum vitamin D levels ≤25 nmol/L are associated with a high risk for TB disease.³³ In a cross-sectional study conducted in Pondicherry, there was an inverse relation between serum vitamin D levels and bacterial load among active pulmonary TB cases.³⁴ A systematic review and meta-analysis reported that hypovitaminosis D is a risk factor for developing TB.³⁵ A South Korean study showed vitamin-D3-induced colocalization of mycobacterial phagosomes with autophagosomes of macrophages mediated through cathelicidin and observed the direct antimycobacterial activity of cathelicidin in TB.³⁶ A case-control study conducted among pediatric TB patients could not find a correlation between LL-37 and 25(OH)D levels, which is in accordance with the present study.⁵ Our findings are in line with a USA study conducted in 95 TB patients, which failed to find an association between vitamin D and serum LL-37 concentrations, similar to the present study results.³⁷

Strength of the Study

The present study confirms a high percentage of vitamin D deficiency among the study population. It stresses the protective role of vitamin D in various diseases. It is the first study to confirm no association between serum vitamin D levels and serum cathelicidin levels among TB patients in comparison to healthy controls.

Limitations of the Study

In the present study, we evaluated vitamin D status after the diagnosis of active TB disease and were unable to find out the effect of prior vitamin D levels on the probability of TB disease. TB can cause severe metabolic defects, and it is ambiguous whether vitamin D deficiency (VDD) increases the TB disease risk or whether underlying TB infection or disease leads to decreased serum 25(OH)D levels. Hence, it was challenging to come to a conclusion about whether individuals with vitamin D deficiency are at a high risk of TB disease. The smaller sample size of 180 cases and 90 controls was one more limitation in the present study. Future studies designed to be randomized controlled trials with a larger sample size and vitamin D supplementation following will be very much helpful in finding out the association between vitamin D and TB via cathelicidins.

Conclusion

Our findings reveal that there is no association between serum CAMP levels and serum vitamin D levels or TB infection. It has been reported in the literature that cathelicidin is an integral part of innate immunity during infection and the entry of the pathogen into the body causes the synthesis of cathelicidin as a first-line defense mechanism.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Fact sheet: TB statistics India [Internet]. TB facts.org [updated 2022 Apr]. [about 1 screen]. Available from: https://tbfacts.org/tb-statistics

Fact sheet: Tuberculosis [Internet]. World Health organisation (Switzerland); 2021 Oct 14. [about 3 screens]. Available from: https://www.who.int/news-room/fact-sheets/detail/tuberculosis.

Holick

. Vitamin D deficiency. N Engl J Med July 19, 2007; 357(3): 266–281. DOI: 10.1056/NEJMra070553.

Liu

, Stenger

, Tang

, . Cutting edge: Vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol August 15, 2007; 179(4): 2060–2063. DOI: 10.4049/jimmunol.179.4.2060, PMID 17675463.

Cakir

, Torun

, Gedik

, . Cathelicidin and human β-defensin 2 in bronchoalveolar lavage fluid of children with pulmonary tuberculosis. Int J Tuberc Lung Dis June 1, 2014; 18(6): 671–675. DOI: 10.5588/ijtld.13.0831, PMID 24903937.

Dixon

, Barker

, McKinnon

, . Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18/LL-37) and 25-hydroxyvitamin D levels in healthy adults. BMC Res Notes December 2012; 5(1): 575. DOI: 10.1186/1756-0500-5-575, PMID 23095332.

Campbell

and Spector

. Autophagy induction by vitamin D inhibits both Mycobacterium tuberculosis and human immunodeficiency virus type 1. Autophagy October 16, 2012; 8(10): 1523–1525. DOI: 10.4161/auto.21154, PMID 22892387.

Dürr

, Sudheendra

and Ramamoorthy

. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta September 1, 2006; 1758(9): 1408–1425. DOI: 10.1016/j.bbamem.2006.03.030, PMID 16716248.

Aibana

, Huang

, Aboud

, . Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis. PLOS Med September 11, 2019; 16(9): e1002907. DOI: 10.1371/journal.pmed.1002907, PMID 31509529.

10.

Mehta

, Mugusi

, Bosch

, . Vitamin D status and TB treatment outcomes in adult patients in Tanzania: A cohort study. BMJ Open November 1, 2013; 3(11): e003703. DOI: 10.1136/bmjopen-2013-003703, PMID 24247327.

11.

Hong

, Kim

, Lee

, . Levels of vitamin D-associated cytokines distinguish between active and latent tuberculosis following a tuberculosis outbreak. BMC Infect Dis December 2019; 19(1): 151. DOI: 10.1186/s12879-019-3798-5, PMID 30760247.

12.

Rook

, Steele

, Fraher

, . Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology January 1986; 57(1): 159–163. PMID 3002968.

13.

Fabri

, Stenger

, Shin

, . Vitamin D is required for IFN-γ–mediated antimicrobial activity of human macrophages. Sci Transl Med October 12, 2011; 3(104): 104ra102. DOI: 10.1126/scitranslmed.3003045, PMID 21998409.

14.

Sly

, Lopez

, Nauseef

, . 1α, 25-dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J Biol Chem September 21, 2001; 276(38): 35482–35493. DOI: HYPERLINK “https://doi.org/10.1074/jbc.M102876200”10.1074/jbc.M102876200, PMID HYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/11461902”11461902.

15.

Hmama

, Sendide

, Talal

, . Quantitative analysis of phagolysosome fusion in intact cells: Inhibition by mycobacterial lipoarabinomannan and rescue by an 1α, 25-dihydroxyvitamin D3–phosphoinositide 3-kinase pathway. J Cell Sci April 15, 2004; 117(10): 2131–2140. DOI: 10.1242/jcs.01072, PMID 15090599.

16.

Gombart

. The vitamin D–antimicrobial peptide pathway and its role in protection against infection. Future Microbiol November 2009; 4(9): 1151–1165. DOI: 10.2217/fmb.09.87, PMID 19895218.

17.

Martineau

, Jolliffe

, Hooper

, . Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ February 15, 2017; 356: i6583. DOI: 10.1136/bmj.i6583, PMID 28202713.

18.

Green

. Cod liver oil and tuberculosis. BMJ December 20, 2011; 343: d7505. DOI: 10.1136/bmj.d7505, PMID 22187324.

19.

Gibney

, MacGregor

, Leder

, . Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa. Clin Infect Dis February 1, 2008; 46(3): 443–446. DOI: 10.1086/525268, PMID 18173355.

20.

Afzal

, Rathore

, Butt

, . Efficacy of vitamin D supplementation in achieving an early sputum conversion in smear positive pulmonary tuberculosis. Pak J Med Sci July 2018; 34(4): 849–854. DOI: 10.12669/pjms.344.14397, PMID 30190740.

21.

Jaimni

, Shasty

, Madhyastha

, . Association of vitamin D deficiency and newly diagnosed pulmonary tuberculosis. Pulm Med January 15, 2021; 2021: 5285841. DOI: 10.1155/2021/5285841, PMID 33510909.

22.

Talat

, Perry

, Parsonnet

, . Vitamin D deficiency and tuberculosis progression. Emerg Infect Dis May 2010; 16(5): 853–855. DOI: 10.3201/eid1605.091693, PMID 20409383.

23.

Ho-Pham

, Nguyen

, . Association between vitamin D insufficiency and tuberculosis in a Vietnamese population. BMC Infect Dis 2010; 10: 306. DOI: 10.1186/1471-2334-10-306, PMID 20973965.

24.

Tangpricha

, Judd

, Ziegler

, . LL-37 concentrations and the relationship to vitamin D, immune status, and inflammation in HIV-infected children and young adults. AIDS Res Hum Retroviruses July 1, 2014; 30(7): 670–676. DOI: 10.1089/AID.2013.0279, PMID 24798231.

25.

Bhan

, Camargo

, Wenger

, . Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J Allergy Clin Immunol May 1, 2011; 127(5): 1302–1304.e1. DOI: 10.1016/j.jaci.2010.12.1097, PMID 21310475.

26.

Alvarez-Rodriguez

, Lopez-Hoyos

, Garcia-Unzueta

, . Age and low levels of circulating vitamin D are associated with impaired innate immune function. J Leukoc Biol May 2012; 91(5): 829–838. DOI: 10.1189/jlb.1011523, PMID 22345707.

27.

Mandic Havelka

, Yektaei-Karin

, Hultenby

, . Maternal plasma level of antimicrobial peptide LL37 is a major determinant factor of neonatal plasma LL37 level. Acta Paediatr June 2010; 99(6): 836–841. DOI: 10.1111/j.1651-2227.2010.01726.x, PMID 20178514.

28.

Jeng

, Yamshchikov

, Judd

, . Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med December 2009; 7(1): 28. DOI: 10.1186/1479-5876-7-28, PMID 19389235.

29.

Bartley

, Garrett

, Camargo Jr

, . Vitamin D3 supplementation in adults with bronchiectasis: A pilot study. Chron Respir Dis November 2018; 15(4): 384–392. DOI: 10.1177/1479972318761646, PMID 29490469.

30.

Mily

, Rekha

, Kamal

, . Oral intake of phenylbutyrate with or without vitamin D 3 upregulates the cathelicidin LL-37 in human macrophages: A dose finding study for treatment of tuberculosis. BMC Pulm Med December 2013; 13(1): 23. DOI: 10.1186/1471-2466-13-23, PMID 23590701.

31.

Acen

, Biraro

, Worodria

, . Impact of vitamin D status and cathelicidin antimicrobial peptide on adults with active pulmonary TB globally: A systematic review and meta-analysis. PLOS One June 11, 2021; 16(6): e0252762. DOI: 10.1371/journal.pone.0252762, PMID 34115790.

32.

Larcombe

, Mookherjee

, Slater

, . Vitamin D, serum 25 (OH) D, LL-37 and polymorphisms in a Canadian First Nation population with endemic tuberculosis. Int J Circumpolar Health January 31, 2015; 74(1): 28952. DOI: 10.3402/ijch.v74.28952.

33.

Zeng

, Wu

, Yang

, . A serum vitamin D level <25nmol/L pose high tuberculosis risk: A meta-analysis. PLOS One May 4, 2015; 10(5): e0126014. DOI: 10.1371/journal.pone.0126014, PMID 25938683.

34.

Yuvaraj

, Sridhar

, Kumar

, . Association of serum vitamin D levels with bacterial load in pulmonary tuberculosis patients. Tuberc Respir Dis (Seoul) July 1, 2016; 79(3): 153–157. DOI: 10.4046/trd.2016.79.3.153, PMID 27433175.

35.

Nnoaham

, Clarke

. Low serum vitamin D levels and tuberculosis: A systematic review and meta-analysis. Int J Epidemiol February 1, 2008; 37(1): 113–119. DOI: 10.1093/ije/dym247, PMID 18245055.

36.

Koo