|Year : 2019 | Volume
| Issue : 2 | Page : 61-67
Vitamin D supplementation for acute bronchiolitis: a double-blind randomized controlled trial
Amr A Sarhan1, Nancy M Saeed2, Ahmed A Mostafa1, Amal M Osman1
1 Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||22-Jul-2019|
|Date of Decision||08-Aug-2019|
|Date of Acceptance||08-Aug-2019|
|Date of Web Publication||6-Feb-2020|
MD Amal M Osman
Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura 35516
Source of Support: None, Conflict of Interest: None
Background Vitamin D deficiency has been declared as a risk factor for acute bronchiolitis.
Objective The aim was to delineate the therapeutic effect of vitamin D supplementation on the clinical course of acute bronchiolitis and to investigate the relationship between vitamin D status and the severity of acute bronchiolitis.
Materials and methods A randomized double-blind controlled trial was conducted including 60 infants who required hospital-based care for acute bronchiolitis. The included infants were randomly assigned to either vitamin D3 treatment (100 IU/kg/day) (vitamin D group) or placebo (placebo group) all through the period of admission. The primary outcome was the length of hospital stay in days, and the secondary outcome measures were as follows: time to resolution of tachypnea, chest retractions, hypoxia, inability to feed/lethargy, and any adverse events. Modified Tal score was used for severity assessment. Basal serum vitamin D level was evaluated in all patients before enrollment in the randomized trial.
Results The vitamin D group had significantly shorter length of hospital stay, rapid resolution of signs of respiratory distress, and shorter need for oxygen therapy. Further, patients with severe disease showed significant low basal serum vitamin D level compared with milder cases. Moreover, patients with exclusive breastfeeding and those with daily outdoor exposure for less than 1 h were found to have significantly lower serum vitamin D.
Conclusion Vitamin D supplementation at a dose of 100 IU/kg/day could have a significant beneficial effect in infants with acute bronchiolitis.
Keywords: acute, bronchiolitis, randomized, therapeutic, vitamin D
|How to cite this article:|
Sarhan AA, Saeed NM, Mostafa AA, Osman AM. Vitamin D supplementation for acute bronchiolitis: a double-blind randomized controlled trial. Alex J Pediatr 2019;32:61-7
|How to cite this URL:|
Sarhan AA, Saeed NM, Mostafa AA, Osman AM. Vitamin D supplementation for acute bronchiolitis: a double-blind randomized controlled trial. Alex J Pediatr [serial online] 2019 [cited 2020 Feb 21];32:61-7. Available from: http://www.ajp.eg.net/text.asp?2019/32/2/61/277834
| Introduction|| |
Acute lower respiratory tract infections (ALRIs) are important causes of child mortality worldwide . Acute bronchiolitis is the most common cause of hospitalization for infants. Further, it is a well-recognized risk for respiratory failure .
The incidence and severity of acute bronchiolitis are affected by diverse factors. Recently, there has been an increasing acknowledgment of the serious extraskeletal roles for vitamin D, with a specific focus on chronic diseases. Vitamin D has an important impact on the immune system, regulating the inflammatory cascade and modulating both adaptive and innate immunity ,.
Previous studies have linked vitamin D deficiency with an increased hazard of ALRIs. Hence, vitamin D status might affect the occurrence or the severity of respiratory syncytial virus bronchiolitis, although there are limited data on the effect of vitamin D status on the course and outcome of the acute bronchiolitis . No consensus exists on the actual need, the timing, and the ideal regimen of vitamin D supplementation in infants with acute bronchiolitis. Moreover, recommendations may differ according to various population characteristics .
The aim of this study was to evaluate the effect of oral vitamin D supplementation on the clinical course of hospitalized infants with acute bronchiolitis, and to investigate the correlation between vitamin D status of those infants and the severity of the acute episode.
| Materials and methods|| |
This was a double-blind randomized controlled trial that was conducted on 60 hospitalized patients with acute bronchiolitis. The study was conducted at Mansoura University Children’s Hospital during the period spanning from October 2016 to March 2017. The diagnosis of acute bronchiolitis was defined as a first episode of respiratory distress with wheezing and/or crackles, preceded by an infection of the upper airways (rhinorrhea, coryza, cough, fever) . Disease severity was evaluated using the modified Tal score .
Infants and toddlers aged 1–24 months of age, diagnosed clinically as suffering from acute bronchiolitis and who presented with any of the following were included in the study:
- Persistent resting oxygen saturation below 92% in room air.
- Marked tachypnea (>70/min) and/or intercostal retractions indicating respiratory distress.
- Difficulty of oral intake.
- Inability of the caregivers to care for the child at home.
Patients were excluded on the basis of the following criteria:
- Infants with a history of prematurity (<37 weeks), chronic cardiopulmonary disease, immunodeficiency, neuromuscular disease, and any other chronic medical condition.
- Patients receiving vitamin D for 4 weeks before the study period.
- Infants with recurrent wheezing or a physician’s diagnosis of asthma.
- Patients with acute bronchiolitis having a very severe clinical score.
Our hospital data have shown that the mean length of hospital stay (LOS) for cases admitted with acute bronchiolitis was 3±2 days . Assuming a reduction in LOS by 50% and a study power of 80% to detect a clinical significance (type-I error rate) of 0.05 between interventional groups, we calculated a sample size of 30 patients in each treatment group.
Randomization and enrollment
Eighty patients were initially recruited for the study. Twenty patients were secondarily excluded, and 60 were eventually enrolled for the trial. Patients were randomized to receive vitamin D3 treatment (100 IU/kg/day) (vitamin D group) or placebo (placebo group) all through the period of admission, as a previous cohort observational study has postulated that vitamin D daily dose close to 100 IU/kg body weight is favorable for infants up to the age of 12 months . The assignments were kept in sealed envelopes until data analysis. The randomization and allocation process was carried out by a higher nursing staff blinded to the study. The medical staff and parents were blind to assignments during the study period.
The treatment of hospitalized infants consisted of intravenous fluids, oxygenation, nebulized hypertonic saline and antipyretics if needed. The clinical severity score for acute bronchiolitis was taken after a period of adjustment with the child quiet, not crying, without fever, and breathing room air. Respiratory rate was counted over a full minute. The degree of intercostal or subcostal retraction was assessed. Physical examination and clinical severity score were recorded for each case at admission and every 12 h, and at discharge. On discharge, all caregivers of breastfed, partially breastfed and bottlefed infants were advised vitamin D supplementation at a dose of 400 IU/day .
Primary outcome measure was the LOS in days. Secondary outcome measures were as follows: time to resolution of tachypnea, chest retractions, hypoxia, inability to feed/lethargy and any adverse events.
All patients were submitted to careful history taking, complete clinical examination and assay of basal serum vitamin D3 (the 25-hydroxy vitamin D) level, which was carried out before enrollment of patients in the randomized trial. Serum vitamin D3 level was considered deficient if less than 20 ng/ml, insufficient if ranging from 20 to 30 ng/ml, and sufficient if more than 30 ng/ml .
Two ml of blood was delivered into a plain tube and centrifuged to obtain a clear nonhemolyzed serum, which was used for performing 25 (OH) vitamin D assays. The specimens were stored at– 20°C until the time of the analysis. The serum 25 (OH) D levels were measured using the enzyme-linked immunosorbent assay method.
The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1964, as revised in 2000. Informed consents were obtained from all caregivers. The study protocol and the informed consents were approved by the Institutional Research Board of our University.
The collected data were coded, processed and analyzed using the Statistical Package for the Social Sciences (SPSS) (SPSS, Inc., Chicago, IL, USA) program for Windows (standard version 22). The normality of data was first tested with one-sample Kolmogorov–Smirnov test. Qualitative data were described using number and percent. Association between categorical variables was tested using χ2-test. Fisher’s exact test or Monte Carlo test was used when more than 20% of the cells had an expected count less than 5. Continuous variables were presented as mean±SD for parametric data and median (range) for nonparametric data. Student’s t-test was used to compare two means. Binary logistic regression was used for the detection of predictors of binary outcome with calculation of adjusted odds ratio. The results were considered significant when the probability of error was less than 5% (P<0.05).
| Results|| |
This double-blind randomized controlled trial comprised 60 hospitalized infants with acute bronchiolitis. They were enrolled and randomized to either arm of treatment (vitamin D vs placebo group) ([Figure 1]).
The vitamin D group included 30 infants (15 male babies and 15 female babies) with median (range) for age in months of 3.5 (1–11). The placebo group included 30 infants (20 male babies and 10 female babies) with median (range) for age in months of 4.5 (1–14). No significant differences were found between the two groups as regards the baseline demographic data, clinical characteristics, and laboratory data ([Table 1] and [Table 2]). However, most of the patients had a deficiency (46.7%) or insufficiency (31.7%) of serum vitamin D.
|Table 2 Baseline modified Tal score and vitamin D status of the studied groups|
Click here to view
As regards the outcome parameters of the randomized trial, the vitamin D group was significantly better compared with the placebo group. It had a significantly shorter LOS (P<0.001), rapid resolution of tachypnea, chest retractions, inability to feed (P<0.001), and shorter need for oxygen therapy (P<0.001) ([Table 3]).
Patients with severe disease according to the modified Tal score showed significantly lower basal serum vitamin D level compared with milder cases (P=0.005) ([Figure 2]). Further, patients with exclusive breastfeeding and those with daily outdoor exposure for less than one hour were found to have significantly lower serum vitamin D ([Table 4]).
|Figure 2 Serum vitamin D level in patients with different disease severity.|
Click here to view
|Table 4 Serum 25(OH) vitamin D in patients with various demographic and clinical characteristics|
Click here to view
After logistic regression analysis and adjusting for confounding factors, the following were independent predictors for severe modified Tal score on admission: duration of daily outdoor exposure less than 1 h (odds ratio=17.5) and low serum vitamin D level (odds ratio=0.809) ([Table 5]).
|Table 5 Logistic regression analysis of independent predictors for severe modified Tal score on admission|
Click here to view
| Discussion|| |
Vitamin D was found to have a significant role in modulating innate immune responses toward various pathogens, increasing the phagocytic ability of immune cells, and reinforcing the physical barrier function of epithelial cells. In addition, the overall effect of vitamin D on Th-cell differentiation may be mediated by its effect on dendritic cells . These results could point to the valuable effect of vitamin D supplementation in decreasing the risk and adverse outcomes of inflammatory diseases .
This study was conducted to investigate the role of oral vitamin D supplementation in the clinical outcome of hospitalized infants with acute bronchiolitis and to correlate basal serum vitamin D levels in those infants with severity of acute episodes.
In this study, no significant differences were found between the vitamin D group and placebo group as regards baseline demographic data, clinical characteristics, laboratory data, and modified Tal score on admission. However, most of the included patients were vitamin D deficient and/or insufficient. This fact is worrying, as there were previous proposals that vitamin D levels more than 40 ng/ml might be fundamental for favorable immune function and overall health . In our country, this could be due to the absence of compliance on vitamin D supplementation for full or partial breastfeeding infants, staying indoors for a long time, excessive skin coverage, no food fortification with vitamin D and decrease in vitamin D photosynthesis in response to UVB due to high melanin content. In agreement with these findings, previous studies had confirmed the greater prevalence of vitamin D deficiency among infants with ALRTI or bronchiolitis compared with healthy controls ,.
In this study, patients with severe disease according to modified Tal score had lower basal vitamin D levels, as compared with milder cases, and, after logistic regression analysis, serum vitamin D was reported to be an independent predictor for severity of modified Tal score. These findings are in accordance with previous studies, which found that serum level of 25 (OH) D is inversely proportional to the disease severity ,,,. This could suggest that vitamin D deficiency is not only an etiologic factor in the disease pathogenesis, but its deficiency can also aggravate the disease severity, and thus vitamin D supplementation might be helpful in the treatment of acute bronchiolitis. Yet, one study has found that vitamin D status was not associated with the clinical severity of acute bronchiolitis .
This study has found a significant decrease in serum vitamin D among infants with daily outdoor exposure for less than 1 h and among infants with exclusive breastfeeding who represented the majority of those with severe disease. Further, after logistic regression analysis, the duration of daily outdoor exposure was found to be an independent predictor of severity of modified Tal score. Similarly, a previous study reported significant decrease in mean 25(OH) D concentrations in breastfed children with ALRI compared with those with ALRI who were bottlefed/weaned or on a regular diet . In contrast to our results, a previous study has found that the shorter the duration of breastfeeding, the more the risk for severe outcome of infants with acute bronchiolitis . Further, it was found that infants weaned before one month of life had a significantly higher risk of being hospitalized for bronchiolitis . Thus, although breastfeeding was previously postulated to be protective against RTI, vitamin D content of breast milk must be taken into account. Exclusive breastfeeding without appropriate sun exposure or vitamin D supplementation is believed to be a significant risk factor for vitamin D deficiency .
Interestingly, as regards the outcome parameters of our study, we observed that vitamin D3 administered in a single oral dose of 100 IU/kg/day to hospitalized infants with acute bronchiolitis decreased significantly the LOS and the need for oxygen therapy and hastened the resolution of the signs of respiratory distress.To the best of our knowledge, only one previous similar trial was conducted on infants with acute bronchiolitis. However, it did not explore serum vitamin D level and its correlation with the disease severity or the patient’s clinical characteristics. They found that daily vitamin D supplementation with a similar dose has led to a significant reduction in the duration of hospitalization .
On another aspect, a double-blind randomized, placebo-controlled trial reported that vitamin D supplementation to school children in winter has decreased significantly the number of ARIs during the study period . Further, a meta-analysis of 11 placebo-controlled studies has proved that vitamin D supplementation is preventive against respiratory tract infections .
Eventually, our results point out the high prevalence of vitamin D deficiency and or insufficiency among infants with acute bronchiolitis and its correlation with disease severity. They also suggest that vitamin D supplementation at a dose of 100 IU/kg/day could have a significant beneficial effect on the clinical course of those infants.
Our study had some limitations that have to be pointed out. The study included a relatively small number of cases. Moreover, our study lacked documentation of post-therapeutic vitamin D level in order to correlate the clinical improvement with serum vitamin D level. However, vitamin D adjunctive therapy for acute bronchiolitis is still not adequately explored.
Future large-scale studies are recommended to confirm the therapeutic benefit of short-term vitamin D supplementation in the clinical course of infants with acute bronchiolitis, including those with normal serum levels, and to adjust the proper needed supplementary dose.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Esposito S, Lelii M. Vitamin D and respiratory tract infections in childhood. BMC Infect Dis 2015; 15:487.
Lin JA, Madikians A. From bronchiolitis guideline to practice: a critical care perspective. World J Crit Care Med 2015;4:152–158.
Foong RE, Zosky GR. Vitamin D deficiency and the lung: disease initiator or disease modifier? Nutrients 2013;5:2880–2900.
Vo P, Koppel C, Espinola JA, Mansbach JM, Celedón JC, Hasegawa K et al.
Vitamin D status at the time of hospitalization for bronchiolitis and its association with disease severity. J Pediatr 2018; 203:416–422.e1.
Beigelman A, Castro M, Schweiger TL, Wilson BS, Zheng J, Yin-DeClue H et al.
Vitamin D levels are unrelated to the severity of respiratory syncytial virus bronchiolitis among hospitalized infants. J Pediatric Infect Dis Soc 2015; 4:182–188.
Florin TA, Plint AC, Zorc JJ. Viral bronchiolitis. Lancet 2017;389:211–224.
Golan-Tripto I, Goldbart A, Akel K, Dizitzer Y, Novack V, Tal A. Modified Tal score: validated score for prediction of bronchiolitis severity. Pediatr Pulmonol 2018;53:796–801.
Zedan M, Gamil N, El-Assmy M, Fayez E, Nasef N, Fouda A et al.
Montelukast as an episodic modifier for acute viral bronchiolitis: a randomized trial. Allergy Asthma Proc 2010; 31:147–153.
Pludowski P, Socha P, Karczmarewicz E, Zagorecka E, Lukaszkiewicz J, Stolarczyk A et al.
Vitamin D supplementation and status in infants: a prospective cohort observational study. J Pediatr Gastroenterol Nutr 2011; 53:93–99.
Umaretiya PJ, Oberhelman SS, Cozine EW, Maxson JA, Quigg SM, Thacher TD. Maternal preferences for vitamin D supplementation in breastfed infants. Ann Fam Med 2017;15:68–70.
Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 2009;19:73–78.
Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr 2008; 87:1087S–1091SS.
Sassi F, Tamone C, D’Amelio P. Vitamin D: nutrient, hormone, and immunomodulator. Nutrients 2018; 10(11).
Yin K, Agrawal DK. Vitamin D and inflammatory diseases. J Inflamm Res 2014;7:69–87.
Hollis BW, Wagner CL, Drezner MK, Binkley NC. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status. J Steroid BiochemMol Biol 2007;103:631–634.
Roth DE, Shah R, Black RE, Baqui AH. Vitamin D status and acute lower respiratory infection in early childhood in Sylhet. Bangladesh Acta Paediatr 2010;99:389–393.
Moreno-Solís G, Fernández-Gutiérrez F, Torres-Borrego J, Torcello-Gáspar R, Gómez-Chaparro Moreno JL, Pérez-Navero JL. Low serum 25-hydroxyvitamin D levels and bronchiolitis severity in Spanish infants. Eur J Pediatr 2015; 174:365–372.
Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5y. Eur J Clin Nutr 2004; 58:563–567.
McNally JD, Leis K, Matheson LA, Karuananyake C, Sankaran K, Rosenberg AM. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol 2009;44:981–988.
Inamo Y, Hasegawa M, Saito K, Hayashi R, Ishikawa T, Yoshino Y et al.
Serum vitamin D concentrations and associated severity of acute lower respiratory tract infections in Japanese hospitalized children. Pediatr Int 2011; 53:199–201.
Chatzimichael A, Tsalkidis A, Cassimos D, Gardikis S, Tripsianis G, Deftereos S et al.
The role of breastfeeding and passive smoking on the development of severe bronchiolitis in infants. Minerva Pediatr 2007; 59:199–206.
Dornelles CT, Piva JP, Marostica PJ. Nutritional status, breastfeeding, and evolution of Infants with acute viral bronchiolitis. J Health Popul Nutr 2007;25:336–343.
Saad K, Hassan N, El-Houfey A, El-Asheer O, Mohamed S, Ahmed A et al.
Trial of vitamin D supplementation in infants with bronchiolitis: a randomized, double-blind, placebo-controlled study. Pediatr Allergy Immunol Pulmonol 2015; 28:102–106.
Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K et al.
Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics 2012; 130:e561–e567.
Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2013;8:e65835.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]