Table 1.
Results of the 19 studies selected for this review with regard to the effect of vitamin D on various ARTIs.
| Study | Study Design | Pico Framework | Results of the Study | Conclusion | VIT. D Supplementation |
|---|---|---|---|---|---|
| Zhou et al. [47] | RCT | Participants: In total, 169 children were included in the low-dose vitamin D group and 164 in the high-dose group (aged 3–12 months old) Intervention: Infants were randomly assigned to low-dose or high-dose vitamin D3 (VD3) groups, with children in each group receiving drops orally for 4 months (one drop containing 400 IU of vitamin D) Comparison: The two groups were compared for the suitability of administering vitamin D to prevent the development of seasonal influenza. Outcome: To assess vitamin D’s safety and clinical effectiveness in preventing influenza A. |
In total, 78 (46%) and 43 (26%) influenza A infections occurred in the groups receiving low and high vitamin D doses, respectively. When comparing the two sets of children, there was a significant difference when it comes to the median durations of fever (22.18 ∓ 36.77 vs. 35.20 ∓ 47.53), cough (1.42∓2.57 vs. 3.43 ∓ 4.38), and wheeze (0.99 ∓ 1.82 vs. 2.83 ∓ 3.69) in the high dose and the low dose group, respectively. | A dose of 1200 IU 25(OH)D is suitable for lowering the risk of Influenza A. This conclusion is backed up by the rapid rate of disease improvement, lower viremia, and fast recovery. In addition, an increased dose of VD is probably safe for patients in this age group. | YES |
| Chowdhury et al. [48] | RCT | Participants: In total, 97 vs. 100 children included in the experimental and the placebo group, respectively (2–59 months old with severe pneumonia). Intervention: Depending on the group, children received either 20,000 IU per mL of vitamin D3 (a high dose or miglyol oil 812. Children could not tell the difference between these two substances, as they looked and tasted the same. Comparison: Children received a vitamin D3 doze according to their age, as follows: 20,000 IU for those under 6 months, 50,000 IU for children 6 to 12 months, 100,000 IU for the remaining ones 13 to 59 months old, and those in the placebo group received miglyol oil. Upon receiving the mega dose, all children included in the study received 10,000 IU doses for 4 days or until discharge from the hospital.Outcome: To evaluate the necessity of 25(OH)D3 supplementation in children admitted to the hospital with severe cases of pneumonia. |
On admission to the hospital, the serum VD level was measured, and around half of the children from each group were VDD (52% the intervention group and 49% in the placebo group). Children with severe pneumonia from the 1st group seemed to recover faster (72 h pneumonia resolution time) when compared with the control group (88 h resolution time). The same trend was also noticed regarding hypoxemia, as children in the VD group were hypoxic around 24 h, while those in the 2nd group were hypoxic 48 h. A small difference was also noticed in the period needed for the full recovery of children. The VD group needed around 4 days, while the placebo group needed 5 days. | Even though there were some differences between the two groups, the authors concluded that the time needed for improving tachypnea, chest in-drawing, or the overall resolution of severe pneumonia, irrespective of VD status, were not that great. Also, not-so-great differences were registered regarding the number of days until hospital discharge of children from the two groups. A maintenance dosage of VD after an age-specific megadose was shown to not statistically vary from the other two intervention groups. | NO |
| Labib et al. [49] | RCT | Participants: In total, 191 children (1 month to 12 years old) were put into two groups, 93 in the experimental group and 98 in the control group. All children were either with VDI or VDD and were diagnosed with pneumonia. Intervention: A dose of 100,000 IU of VD3 (intravenous), or placebo. Comparison: To ensure that every participant was evaluated before being discharged, children were assessed for seven days following vitamin D treatment, especially on the day when vitamin D concentration in the blood reached their peak. Outcome: To evaluate the development and recovery time of the children. |
Seven days after the injection with the high dose of VD3, the experimental group showed higher serum concentration levels. In this group, the percentage of patients who were VDI or VDD on the 1st day had significantly reduced by the last day (with 11.8% on the 1st day and 52.7% on the 7th day). Also, most of the children in the intervention group (93.5%) of the supplementation group registered normal PaO2/FiO2 values, from 300 to 360 (day 1 and day 7), compared with 340 to 345 (day 1 and day 7) in the intervention group and placebo group, respectively. | It was shown that a high dose of VD administration is indeed related to a decreased risk of mortality, shortened recovery time, better PaO2/FiO2, and lower qSOFA scores in pneumonic children with high VDD. Seven days following the intervention, most of the vitamin D group’s PaO2/FiO2 readings returned to normal, showing a reduction in the severity of lung damage in the children receiving mechanical ventilation (MV). | YES |
| Alpcan et al. [50] | RCT | Participants: In total, 155 pediatric patients (75 in the intervention group and 80 in the control group) with mild or moderate COVID-19 disease (1 month to 17 years old). Intervention: To determine vitamin D serum level and other biological analyses. Comparison: To compare the blood results between the groups. Outcome: To compare the VD levels of pediatric patients identified with COVID-19. |
The average blood level of 25(OH)D concentration was lower in the 1st group than the control group (21.5 vs. 28.0), and the percentage of VDD patients was higher in the COVID-19 group than 2nd group (44% vs. 17.5%). The mean C-reactive protein (CRP) level was higher in the vitamin D-deficient children (9.6 vs. 4.5). Still the hospitalization days were similar for both groups, with a statistical difference of only r = 0.724. | Parallel examination of different blood results showed an essential relation between VD level and leukocyte, lymphocyte, and thrombocyte count and no negative association with age and duration of hospitalization. The regression analysis suggests an inverse relation between low vitamin D concentration and the risk of developing respiratory infections. | YES |
| Loeb et al. [51] | Participants: Two groups totaling 1300 healthy children (3 to 17 years of age) were divided between two groups, each with 650 children (vitamin D and placebo). Intervention: Those included in the study were randomized, half of them receiving 7 drops of vitamin D (0.028 mL per drop—14,000 U/week) every week for 8 months, while those arbitrarily receiving were administered 7 placebo drops (0.028 mL per drop) for the same period. Comparison: Children in the two groups were compared for signs and symptoms of influenza two times every week over a period of one year. Outcome: To analyze RT-PCR-confirmed infection with influenza and PCR-confirmed non-influenza respiratory viruses. |
In total, 7.7% (50) of children in the intervention group were confirmed by RT-PCR with influenza A or B, while only 1% less (6.6%, or 43 children) were RT-PCR confirmed with the same virus. Additionally, regarding other viruses, 146 patients (22.5%) from the VD group acquired non-influenza infections, compared with 185 patients (28.5%) in the placebo group. Thus, 25 hydroxyvitamin D’s had some effect in reducing all respiratory infections, 177 of the total 650 (27.2%) in the VD group compared with 209 in the 2nd group (32.2%). | The conclusions of this study suggest that 25 hydroxy cholecalciferol supplementations did not reduce the incidence of influenza A or B virus but reduced in a small percentage the other respiratory infections. Therefore, it can be presumed that VD supplements can have some influence in reducing viral respiratory infections. Still the authors conclude that it is not enough to recommend the routine administration of it to the general pediatric population. | NO | |
| Zhang et al. [52] |
RCT | Participants: In total, 422 youngsters were included in the intervention group and 100 in the control group were observed for recurrent respiratory infections (RRIs). Intervention: Serum levels of 25 (OH) D2, and vitamin A, and E were analyzed. Comparison: The study group was further separated into two subgroups, with an active group of 222 children, and a stable group of 200, along with other 100 healthy children and they were all compared for their risk of developing RRIs. Outcome: To analyze if there is any connection between the different vitamins (A, D and E) and RRIs among the pediatric population. |
The study found that the relationship between vitamins A and D was positive in children with RRIs (r = 0.945 for vit. A and r = 0.988 for vit. D). The relationship between vitamin E and vitamin D was also positive in those children, with r = 0.959 for vitamin E (vitamin D having an r = 0.988). | Deficiency in the three vitamins relates to RRIs in children. Thus, supplementing vitamins A, D, and E via dietary changes is advantageous for the faster recovery of the patients. | YES |
| Kuang et al. [53] | RCT | Participants: In total, 948 children aged 0 to 16 years, divided as follows: 295 with ARTIs, 17 with co-infection and 636 healthy children. Intervention: PCR or (RT)-PCR was used to examine oropharyngeal samples from patients, detecting the existence of viruses or unusual infections. Comparison: The study compared the results of the PCR and RT-PCR of the intervention group and the healthy group. Outcome: To determine if there is a connection between the vitamin D status in children with ARTI due to viruses or other unusual pathogens. |
Of the total 295 children infected with a single virus, more than half (58.98%) were VDD (>50.0 nmol/L), together with a large percentage of the 17 children infected with more than one virus (76.47%). However, regarding the ARTIs and the co-infected sub-groups, the differences in the VD levels were not great. |
The study showed that VDD is associated with developing ARTIs with typical or atypical pathogens. Thus, the recovery of ARTIs may be correlated with serum 25(OH)D concentrations. | YES |
| Golan-Tripto et al. [54] | RCT | Participants: In total, 127 patients less than 24 months were divided into an acute bronchiolitis group (80 children) and a group of 47 children with other non-respiratory illnesses. Intervention: Blood samples were collected to determine if the children were either VDD (<50 nmol/L), VDI (≥50 and <75 nmol/L), or sufficient (≥75 nmol/L). Comparison: The vitamin D status of the children was compared against the severity of bronchiolitis and length of hospital stay. Outcome: To analyze if there is a connection between the 25(OH)D concentration in very young patients diagnosed with acute bronchiolitis compared to other infections not related to respiratory tract. |
In this study, more than half of the children from each group received vitamin D supplementation (66% and 60% in the bronchiolitis group and control groups, respectively). In the bronchiolitis group, blood 25(OH)D concentration was considerably lower when compared with the control group. The statistics showed a median of 28 vs. 50 nmol/L, respectively. VDI happened more likely in the bronchiolitis group, according to the regression model used by the authors. |
Even though the authors did not observe any association between 25(OH)D concentrations and bronchiolitis severity, they noticed that children in acute bronchiolitis group displayed lower vitamin D levels than children from the 2nd group. Also, they required a longer recovery period, measured in the length of days spent in the hospital. | YES |
| Alakaş et al. [55] |
RCT | Participants: In total, 182 children with acute bronchiolitis between 1 month and 2 years of age were divided into a group of 73 children (40%) with severe cases of disease admitted in the ICU department, and 109 children (60%) in the typical patient ward. Intervention: An amount of 2 mL of blood was collected for vitamin D examination. This was done on the same day as admission to the hospital, along with other regular blood analyses. Comparison: The vitamin D concentration of those admitted in the ICU department as opposed to those that did not need intensive care. Outcome: To assess if VD is linked to the symptoms and outcome of acute bronchiolitis in very young patients. |
When comparing the progress to the ICU department, the study shows that 25 (34.2%) of children whose VD levels were normal (73), 29 (39.7%) who were VDD, and 19 (26%) who were VDI needed intensive care. The trend is similar with the 109 patients admitted to the normal patient ward. Therefore, 70 (64.2%) children had sufficient VD concentration, 25 (22.9%) and 14 (12.8%) were VDD and VDI, respectively. |
A significantly higher likelihood of VDD or VDI was found in patients diagnosed with bronchiolitis that needed intensive care compared to those in normal patient wards. Hence, vitamin D deficiency is indeed correlated with severe bronchiolitis. | YES |
| Vo et al. [56] | Prospective cohort study | Participants: In total, 1016 infants under 12 months hospitalized with bronchiolitis were divided into 3 groups, depending on blood 25(OH)D levels: 298 children (<20 ng/mL), 352 with vit. D values of 20–29.9 ng/mL, and 366 children having serum concentrations of ≥30 ng/mL. Intervention: Blood was collected within 24 h of patients being admitted to the hospital. Using a standardized approach, RT-PCR was also performed, as well as a nasopharyngeal aspirate. Comparison: The number of patients needing ICU department, as well as longer hospital length of stay (LOS) was compared between the two groups. Outcome: To evaluate if there is a connection between the circulating VD status at the start of the illness and the severity among infants diagnosed with bronchiolitis. |
Compared to those with VD values of ≥30 ng/mL, children with <20 ng/mL had a greater probability of needing ICU and a longer LOS. Patients at the lowest end of circulating 25(OH)D concentration had longer LOS than those with the highest tertile, but neither unadjusted nor adjusted models found a relationship between the free 25-OHD concentration and the clinical outcome of bronchiolitis. | This research concluded that values of <20 ng/mL put infants at risk of needing intensive care and longer hospital days; thus, this vitamin plays an essential role in the outcome of bronchiolitis. The observed correlation between total 25(OH)D concentration and bronchiolitis severity, rather than bioavailable or free 25(OH)D, shows that total concentration may be a more accurate indicator of ARTI. |
YES |
| Toivonen et al. [57] |
Multicenter prospective cohort study | Participants: In total, 1005 infants under 12 months hospitalized with bronchiolitis were distributed into two groups. The lower serum concentration of 25OHD included 498 patients, and the higher serum concentration had 507 patients. Intervention: In the first 24 h of hospital admission, staff collected blood and nasopharyngeal airway samples. Comparison: The lower vitamin D level group (<26.5 ng/mL) and the higher one (≥26.5 ng/mL) were compared against the days of ICU stay. Outcome: To analyze the possible 25(OH)D—ICU admission relation and use of mechanical ventilation (such as CPAP or intubation) during hospitalization. |
25(OH)D and nasopharyngeal microbiota profiles appear to be related to the risk of needing intensive care, as patients at the lower spectrum of 25(OH)D levels had a higher risk of ICU (24.5%) when it comes to Hemophilus when compared with the higher-level group (16.2%). In contrast, there were no significant associations among those with higher 25(OH)D concentrations. | The study concludes that circulating 25OHD concentrations are associated with certain nasopharyngeal metabolomic signatures, like increased pro-inflammatory lipids, which may function as mediators in the microbiome-host interactions in the airways. | YES |
| Hueniken et al. [58] | RCT | Participants: In total, 703 children between 1 and 5 years of age with upper respiratory tract infections (URTIs) were divided into a group that received a high-dose supplementation of vitamin D (349 children) and a group that received the standard dose (354 children). Intervention: Oral VD doses of 2000 IU/day or 400 IU/day were randomly administered to children in the study for one winter season. Comparison: The two groups were compared for the risk of developing URTIs. Outcome: To analyze the effects of vitamin D concentration of 2000 IU/day on outpatient or emergency department (ED) visits correlated with antibiotic prescriptions for URTI. |
The incidence rate ratio of the high supplementation group did not reduce the severity of the URTIs symptoms (IRR = 0.97), together with the frequency of ED and outpatients’ visits (IRR = 1.17 and IRR = 1.16, respectively). The IRR of antibiotic prescriptions for the two groups had similar results, of only 1.02. | This research concluded that high doses of VD in wintertime did not lessen the severity of the symptoms in URTI compared to the normal dosage for children, as the American Academy of Pediatrics (AAP) advised. High-dose vitamin D supplementation also did not reduce the incidence of ED visits, outpatient doctor visits, or antibiotic prescriptions. | NO |
| Kun et al. [59] | Prospective cohort study | Participants: In total, 175 children with Mycoplasma pneumoniae (MPP) were divided into two groups according to the existence of bronchial mucus plugs (BMP). Thus, 73 children were included in a BMP group and 102 in a non-mucus group. Intervention: Fiberoptic bronchoscopy of the mucus secretions was performed on patients where it was blocking the respiratory tract, and for the rest of the children where they could not be easily removed, doctors used a cell brush or biopsy forceps. Comparison: The two groups of patients were compared by looking at 25(OH)D concentrations, IL8, and other inflammatory markers. Outcome: To evaluate any associations between these specific blood tests and clinical characteristics in the pediatric population with mycoplasma pneumonia (MPP). |
25(OH)D, IL8, neutrophils and other inflammatory cells were lower in the non-BMP group when compared with the BMP group. On the other hand, the relation between the blood VD and the other inflammatory markers tested here appeared to be inversely related. | According to this research, vitamin D could be used as a marker in diagnosing children with MPP. Young patients with MPP often have vitamin D insufficiency, and its levels are strongly correlated with the presence of inflammatory cells and the severity of the illness. Children with MPP and BMPs had serum 25(OH)D concentrations lower than those without MPP and BMPs. | YES |
| Oktaria et al. [60] | Prospective cohort study | Participants: In total, 422 pregnant women and their subsequent babies were observed for ARTI episodes for a period of 12 months following delivery. Intervention: At birth, newborns were tested for their VD levels, and a follow-up occurred 6 months later. Comparison: Blood results of children’s vitamin D taken 6 months apart were analyzed against the incidence of ARTIs. Outcome: To observe the incidence of pneumonia concerning VDD for the 1st year of life. |
Within the selected sample of patients, 1601 ARTIs incidents were found to have occurred over 1 year. In total, 96 and 7 pneumonia cases matched the WHO criteria for pneumonia and severe pneumonia, respectively (8.7% of the total). Nearly all newborns (96%) had at least one instance of ARI that was not pneumonia. The 9 to 12 months age group had the greatest pneumonia frequency, whereas newborns under 3 months had the lowest. For non-pneumonia and pneumonia illnesses, the median length of full symptom resolution was 7 days and 15 days. Between those with VDD and non-VDD at birth, there was no difference in the prevalence of the 1st episode of pneumonia when compared with the 2nd one within 6 months, as well as other incidences of pneumonia from 6 to 12 months. It appears as if these events were unrelated to vitamin D status at 6 months of age. | VD status of newborns, influenced by the mother’s exposure to the sun, influenced very little the occurrence rate of pneumonia in the first 6 months of life. Still, the overall frequency rate was not considerably changed by the status of vitamin D (whether at birth of after 6 months). Reducing VDD at birth by giving supplements to mothers or increased sun exposure during pregnancy has very little potential to reduce ARTIs. |
NO |
| Oktaria et al. [61] |
Cross-sectional study | Participants: In total, 127 hospitalized patients diagnosed with pneumonia (2 to 59 months old) whose vitamin D concentrations were measured. The study sample was divided between those who had VDI or VDD (25 children), and those whose levels were normal (102 children). Intervention: Doctors measured the total VD2 and VD3 using liquid chromatography [tandem mass spectrometry. Comparison: The two groups were analyzed, comparing the vitamin D concentration and their risk of developing pneumonia. Outcome: To observe if there is any correlation linking vitamin D and symptom severity in these patients. |
Infants younger than 6 months needed longer LOS in the hospital (more than 5 days). However, this seemed to be more related to the low birth weight and poor nutritional status on admission, which were also risk factors for hypoxemia. |
1/5 children in this study group were VDD. Still, the authors concluded that this status was not associated with the severity of pneumonia, and with the presence of other danger signs, such as hypoxemia or the quantity of oxygen required. Also, the 25(OH)D concentration was unrelated to the hospitalization duration. | NO |
| Akeredolu et al. [62] | Cross-sectional study | Participants: In total, 270 children were put into a group for those with pneumonia (135), and another one with 135 apparently healthy children. The children were aged 1 to 59 months. Intervention: Vitamin D serum levels were measured for both groups. Comparison: The two groups were compared for their vitamin D concentration. Outcome: To assess the suitable intervention of vitamin D supplementation in preventing acute pneumonia in children younger than 5 years of age. |
Statistics in this study showed a difference between the means of the serum concentration (52.14 vs. 60.91) for the 1st group when compared to the control group. Also, most children in the pneumonia group (91.1%) were VDI (with VD concentration of less than 75.0 nmol/L) when compared to the healthy children, that were almost 20% less (71.9%). | This study supports the link between vitamin D and acute pneumonia in pediatric population. To lower children’s risk of pneumonia, the authors advise that techniques and treatments, including supplementation of VD, better nutrition (food that includes vitamin D), and additional measures regarding increasing children’s vitamin D status should be seriously examined. | YES |
| Bayramoğlu et al. [63] | RCT | Participants: In total, 103 COVID-19-positive children between 1 and 18 years of age were put into 3 groups: asymptomatic patients (29); patients with mild infections (40); and those with severe infections (34). Patients in the last group had pneumonia confirmed by physical examination and X-ray/CT Intervention: The infection with the virus was confirmed by PCR, with sample collected through a nasopharyngeal swab. Comparison: The 3 groups (asymptomatic, mild, and severe) were compared against their vitamin D concentration. Outcome: To assess the symptoms severity and inflammatory markers in the pediatric population during COVID-19 concerning the VD status. |
Compared to the mild and asymptomatic groups, the 3rd group showed lower lymphocyte counts and significantly C reactive protein, lymphocyte count, pro-calcitonin, fibrinogen, and D-dimers, which are signs of inflammation. Some children were also VDI, and the ratio was 70.6% in the severe group. The VD level had a positive relation with the lymphocyte count (r = 0.375), and an inverse association with age (r = −0.496), CRP (r = −0.309), and fibrinogen levels (r = −0.381). | This study revealed an association between insufficient concentrations of 25(OH)D and the evolution of the COVID-19 infection. The 3rd group had worse vitamin D levels and higher inflammatory cells. Although vitamin D’s effects on the immune system are important as the evidence suggests that appropriate 25OH vitamin D concentration assists the body’s ability to fight off viral and bacterial infections and minimize inflammation. |
YES |
| Doğan et al. [64] |
Prospective cohort study | Participants: In total, 176 children aged 1–18 years divided into two groups: one with 88 children with COVID-19 disease and the other with 88 healthy children. Intervention: Electrochemiluminescence immunoassay was used to measure the serum VD. Comparison: The 25(OH)D concentrations of the groups were compared in relation to the severity of the infection. Outcome: To evaluate if there is a connection between the severity of the COVID-19 infection and this vitamin. |
When looking at the two sets of children, COVID-19-positive patients’ mean blood 25 hydroxy cholecalciferol levels were lower (11.73) than those of the other group (18.14). Also, the study shows a significant link between VD and Zn values in the two groups (r = 0.245). | Since the two assessment markers (vitamin D and Zn) showed a connection with the infection, being higher in healthy children, the authors recommend supplementing of the two as a supportive treatment for COVID-19 infection. | YES |
| Jaybhaye et al. [65] | RCT | Participants: In total, 108 children with RRIs (both inpatients or outpatients) aged from six months to 15 years in one group and 55 healthy children of the same age group who visited the hospital throughout the research period for immunizations and regular checkups, as the control group. Intervention: The serum 25-hydroxyvitamin D collected from venous blood from patients and controls was analyzed. Comparison: The intervention group was compared with the control one Outcome: To evaluate whether the RRIs and 25 hydroxyvitamin D are connected. |
Essentially, all children with RRIs had less than normal vitamin D levels. Around 75% of these patients had VDI, and the rest had VDD. With a p-value of less than 0.001, these variations in 25(OH)D status of the two groups were statistically significant. | Comparatively, to controls, children with recurrent respiratory infections had a significantly high rate of vitamin D insufficiency. Children with recurrent respiratory infections should be managed with an evaluation of their vitamin D level. | YES |