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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 41  |  Issue : 3  |  Page : 129-133

Vitamin D supplementation in the prevention of recurrent acute respiratory tract infections in children aged <5 years


1 Department of Pharmacology, Krishna Institute of Medical Sciences (Deemed-to-be University), Karad, Maharashtra, India
2 Department of Pediatrics, Krishna Institute of Medical Sciences (Deemed-to-be University), Karad, Maharashtra, India

Date of Submission22-Apr-2020
Date of Decision18-Jul-2020
Date of Acceptance11-Aug-2020
Date of Web Publication06-Oct-2020

Correspondence Address:
Dr. Sujata Jadhav
Department of Pharmacology, Krishna Institute of Medical Sciences (Deemed-to-be University), Karad, Maharashtra - 415 110
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_101_20

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  Abstract 


Background: Children with Vitamin D deficiency are at an increased risk for acute respiratory tract infections (ARTIs). Till now, few studies have been conducted on the use of Vitamin D against ARTIs, but the findings are conflicting and not conclusive. Aim: The aim was to study the effect of Vitamin D supplementation in the prevention of recurrent ARTIs in under-five children. Methods: In this prospective study, a total of 310 children aged between 1 and 5 years diagnosed with ARTI were included. They were randomized into two groups: Group A (oral Vitamin D 120,000 IU with standard treatment; n = 155) and Group B (placebo with standard treatment only; n = 155). Follow-up of the patient was done every month for a period of 6 months to document the recurrence of acute attacks of ARTI. R version 3.6.0 software was employed to analyze the data. Results: Twelve children (3.9%) in Group B were unable to follow-up, and hence, 143 were considered for statistical analyses in that group. Among the 298 children, 63.7% were males and majority (25.5%) of them were in the age group of 11–20 months. Cough (96%), fever (93%), and rhinitis (85.2%) were the commonly encountered symptoms. On day 4th (after Vitamin D supplementation), majority in Group A (40%) had recovered completely compared to Group B (5.6%). Within 5 days, Group A patients were 7 times (odds ratio: 6.97, Confidence interval: 3.5–13.8; P < 0.0001) more likely to have a high recovery rate compared to Group B patients. The proportion of patients with minimal attacks (three or four) of ARTI was significantly less in Group A (7.7%) compared to Group B (32.4%; P < 0.001). Conclusions: Children with Vitamin D supplementation had better and rapid recovery from ARTIs and reduced frequency of ARTI attacks.

Keywords: Respiratory tract infections, Vitamin D, pediatrics


How to cite this article:
Jadhav S, Khanwelkar C, Jadhav A, Seshla S. Vitamin D supplementation in the prevention of recurrent acute respiratory tract infections in children aged <5 years. J Med Sci 2021;41:129-33

How to cite this URL:
Jadhav S, Khanwelkar C, Jadhav A, Seshla S. Vitamin D supplementation in the prevention of recurrent acute respiratory tract infections in children aged <5 years. J Med Sci [serial online] 2021 [cited 2021 Jun 22];41:129-33. Available from: https://www.jmedscindmc.com/text.asp?2021/41/3/129/297426




  Introduction Top


Globally, acute respiratory tract infections (ARTIs) are more common in children, leading to frequent visits to pediatricians and accounting for 20%–30% of deaths. Despite advances in the treatment of RTIs, pneumonia is the leading cause of death in 13%–16% of hospitalized pediatric patients in India.[1],[2] Hence, there is a need for effective and novel treatment modalities.[3] In addition to antibacterials, micronutrients and vitamin supplementations (especially A and C) play a significant role in the clinical resolution of RTIs.[4]

Researchers indicate that probably Vitamin D has a potential role in the prevention of ARTIs by increasing the production of natural antibodies in the body.[5] A study reported Vitamin D deficiency in children as a predisposing factor to RTIs and concluded that Vitamin D-deficient children were 2.5 times more prone to RTIs, especially pneumonia, than children with adequate Vitamin D levels.[6] Vitamin D supplementation coupled with standard treatment might be useful in the treatment of antimicrobial-resistant and opportunistic infections.[7] The active form of Vitamin D (cholecalciferol) has anti-inflammatory effects on the acquired immune system by shifting CD4+ T-cells pool from a T-helper cell 1/T-helper cell 17 response to a regulatory T-cell/T-helper cell 2-dominated response.[8],[9] Cholecalciferol also suppresses the T-helper cell 2 response in allergic bronchopulmonary aspergillosis. Hence, cholecalciferol modulates both the acquired and innate immune systems.[10]

To date, various clinical trials and observational studies have been established in all groups to emphasize the role of Vitamin D in the treatment of ARTIs.[6],[11],[12],[13],[14] A randomized controlled trial reported that a single high dose of Vitamin D in children with severe pneumonia reduced its recurrence.[13] In contrast, a recent case-controlled study in adults reported no significant association between Vitamin D supplementation and pneumonia. Furthermore, the study stated that Vitamin D supplementation without the administration of drugs increased the risk of pneumonia.[15] Thus, this study was designed to test the hypothesis that a single dose of Vitamin D (cholecalciferol) in patients with frequent ARTIs could prevent or reduce the frequent attacks of infections.


  Methods Top


After obtaining ethical clearance (KIMSDU/IEC-307/06/12/2018), this was carried out for a period of 1 year (Apr 2018 to Mar 2019) in the Department of Pediatrics (OPD) of a tertiary care teaching hospital in Karad, Maharashtra, India. This study was complied with the Declaration of Helsinki guidelines and adhered to the applicable CONSORT guideline [Figure 1]. A minimum sample size of 114 was required in each group for an effect size (Cohen's d; w = 0.2) at a significance level of 95% and power of 90% to detect a difference of 20% in the number of acute attacks of RTIs between the study groups with/without Vitamin D supplementation.
Figure 1: A consort flow diagram of the study

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A total of 298 patients aged 1–5 years, with the primary diagnosis of ARTI, who had not received any antimicrobial therapy for the same or any other indication in the past 1 week were included after taking written informed consent from the parents or guardians. Patients with Vitamin D deficiency, rickets, tuberculosis, or any other chronic RTI, and congenital anomalies (viz., scoliosis, kyphosis, cleft lip, and cleft palate) were excluded from the study. Furthermore, children who were under Vitamin D supplementation continuously in the last 1 year were exempted from the study.

The patients were randomized into two groups (Groups A and B) using a computer-generated sequence: Group A (Vitamin D 120,000 IU with standard treatment; n = 155) and Group B (placebo with standard treatment; n = 155). The pharmacologist, who was not involved in the study, dispensed the identical containers (Abbott Healthcare Pvt. Ltd., India) containing Vitamin D and placebo to assigned random groups. Data regarding demographics, clinical history of patients, socioeconomic status of parents, clinical presentations, and medication details were recorded in a predesigned pro forma. All the children were evaluated clinically, followed by systemic and respiratory examination. Sputum or throat swab samples were collected aseptically and immediately sent to the microbiology laboratory for culture and sensitivity tests. After collecting blood samples, Group A children received standard treatment for their respective infection along with oral Vitamin D3 (cholecalciferol) at a dose of 1, 20, 000 IU only once. Later, each child was followed for 5 successive days by regular telephonic contact to assess improvement. The day the fever subsided and the child became playful and started eating normally was considered as a complete cure. Thereafter, follow-up of the patient was done every month for a period of 6 months, and the recurrence of acute attack of ARTI was noted. Treatment compliance was also monitored through regular telephonic contact.

Statistical analysis was done using R version 3.6.0 software (Revolution Analytics, Mountain View, CA, United States). Normality of the data was determined using the Shapiro–Wilk test. The continuous variables with normal distribution were presented as mean ± standard deviation and compared using paired t-test, whereas the Chi-square test was employed for dichotomous data. The Mann–Whitney U-test was performed for variables without a normal distribution. The categorical variables were presented as frequencies and percentages. P < 0.05 was considered statistically significant at 95% confidence interval (CI).


  Results Top


Twelve children (3.9%) in Group B were unable to be followed up, and hence, 143 were considered for statistical analyses in Group B [Figure 1]. Out of 298 (155 in Group A and 143 in Group B) patients, 190 (63.7%) were males and 108 (36.2%) were females with mean age and mean weight of 35 ± 16.8 versus 36.3 ± 15.5 months and 12.1 ± 3.4 versus 11.5 ± 3.2 kg, respectively, and no significant difference was found (P > 0.05) between them. Majority (76; 25.5%) of the patients were in the age group of 11–20 months. Furthermore, a trend of gradual decrease in the number of ARTI patients was observed with the progression of age till 40 months of age. Later, it increased in the 51–60 (66; 22.1%)-month age group. Statistically, no significant association was found between the different age groups with respect to ARTI [P = 0.394; [Table 1]].
Table 1: Age- and gender-wise distribution of acute respiratory tract infection patients

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Most (205; 68.8%) of the children presented with three symptoms (viz., cough, fever, and rhinitis), followed by two symptoms (56; 18.8%) and four symptoms (37; 12.4%). Cough (286, 96%), fever (277, 93%), and rhinitis (254, 85.2%) were the commonly encountered symptoms, followed by sore throat (31, 10.4%), breathlessness (19, 6.4%), and earache (6, 2%). Antipyretics (293; 98.3%) and antimicrobials (272; 91.2%) were the commonly prescribed drugs. Among antibiotics, cephalosporins (161; 54%) were most commonly prescribed, followed by penicillins (86; 28.7%). Totally, 33 (11.1%) patients had positive bacterial cultures.

Before Vitamin D supplementation, the frequency of ARTI ranged from 3 to 12 per year. Only one patient in each group experienced three attacks of RTIs, while one patient in Group A experienced 12 attacks of ARTI in the previous year. In both the groups, majority of the patients experienced five or six attacks per year [Table 2]. Before Vitamin D supplementation, the mean ARTI episodes during the last 1 year in Groups A and B were 5.66 ± 1.24 and 5.55 ± 0.94, respectively, with no significant difference (P = 0.829).
Table 2: Frequency of acute respiratory tract infection in the last 1 year before Vitamin D supplementation

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None of the patients in either group recovered from ARTI within 3 days after Vitamin D supplementation. On the 4th day, majority of the patients in Group A (40%) had recovered completely compared to Group B [5.6%; [Table 3]]. Group A patients were 7 times (odds ratio [OR]: 6.97, CI: 3.5–13.8; P < 0.0001) more likely to have a high recovery rate compared to Group B patients.
Table 3: Recovery speed in the groups before Vitamin D supplementation

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In both the groups, the frequencies of ARTI reduced from 3 to 12 (during the last 1 year before treatment) to 1–4 (during treatment post 6 months). ARTI frequencies were found to be decreased in both the groups during treatment post 6 months [Table 4]. The proportion of three or four episodes of ARTI was significantly less in Group A (7.7%) compared to Group B (32.4%; P < 0.00001).
Table 4: Frequency of acute respiratory tract infection during 6 months after Vitamin D supplementation

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  Discussion Top


In this study, the active form of Vitamin D, i.e., cholecalciferol (Vitamin D3), was used against ARTIs as it modulates both the acquired and innate immune systems.[10] The effect of Vitamin D supplementation in ARTI in under-five children was studied at a bolus dose of 120,000 IU only once as previously established studies reported little benefit at smaller doses (10,000 IU).[13] Kearns et al. reported that quarterly doses of Vitamin D (up to 300,000 IU) are more safe and effective and not associated with any Vitamin D-related toxicity.[16] Accordingly, none of the patients in this study experienced any signs of Vitamin D toxicity. In the current study, majority of the patients in Group A (40%) recovered completely within 4 days compared to Group B (5.6%), indicating that the speed of recovery was better in patients who received Vitamin D along with standard treatment of ARTI.

Wayse et al. conducted a study in under-five children with lower RTI and reported that low levels of Vitamin D3 were one of the risk factors for severe acute lower RTIs.[17] Ginde et al. performed the secondary analysis of the third National Health and Nutrition Examination Survey regarding the association between serum Vitamin D3 level and upper RTI.[18] They concluded that serum Vitamin D3 levels are inversely associated with ARTI. However, they had included all age groups in their study and not studied the recovery rate of ARTI after correction of Vitamin D deficiency.[18]

In our study, a significant reduction in the recurrence of ARTI was observed in patients who received Vitamin D with seven times better recovery rate (OR: 6.97, CI: 3.5–13.8; P < 0.0001) compared to controls, indicating that Vitamin D is effective in the prevention of ARTI in children. Laaksi et al. found a preventative effect of daily doses of 400 IU Vitamin D3 supplementation for 6 months on RTIs in young adults.[19] Urashima et al. reported a similar effect against influenza A (but not influenza B) with Vitamin D 1200 IU for 3 months in children.[20] In this study, we performed a bacterial culture and sensitivity test only, and 33 (11.1%) patients showed a positive bacterial culture. Thus, most of the patients had a nonbacterial infection and most probably viral. Probably, we can say that Vitamin D supplementation has a preventive effect on viral ARTI as well as it hastens the recovery.

Although the findings are encouraging in demonstrating Vitamin D's role in the prevention of ARTI in under-five children, the results are not conclusive, probably due to single-dose administration of Vitamin D. In addition, this study has a major limitation that therapeutic drug monitoring (TDM) of Vitamin D was not performed to assess the optimal therapeutic dose of Vitamin D and its frequency of administration for resolution of RTIs. Further studies should be encouraged on TDM of Vitamin D and to determine the predisposing factors such as nutritional and socioeconomic status in RTIs.


  Conclusions Top


Children with Vitamin D supplementation had better and rapid recovery from ARTIs and reduced frequency of ARTI attacks.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S. Vitamin D status is not associated with the risk of hospitalization for acute bronchiolitis in early childhood. Eur J Clin Nutr 2009;63:297-9.  Back to cited text no. 11
    
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Karatekin G, Kaya A, Salihoğlu O, Balci H, Nuhoğlu A. Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr 2009;63:473-7.  Back to cited text no. 12
    
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Manaseki-Holland S, Maroof Z, Bruce J, Mughal MZ, Masher MI, Bhutta ZA, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: A randomised controlled superiority trial. Lancet 2012;379:1419-27.  Back to cited text no. 13
    
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