European Journal of Cardiovascular Medicine

Respiratory tract infections (RTIs) are among the most common infectious illnesses encountered in clinical practice and constitute an important cause of morbidity, healthcare utilization, school absenteeism, and antibiotic use across all age groups. The burden is particularly substantial among children, older adults, and individuals with underlying respiratory or immune disorders. Although most respiratory infections are self-limiting, a subgroup of individuals experiences recurrent episodes involving the upper or lower respiratory tract. Recurrent respiratory infections may be influenced by several host and environmental factors, including age, nutritional status, exposure to infectious agents, air pollution, passive smoking, anatomical abnormalities, allergic disease, and impairment of innate or adaptive immunity [1]. In recent years, increasing attention has been directed toward vitamin D as a potentially important nutritional and immunological factor influencing susceptibility to respiratory infections.

Vitamin D is a fat-soluble secosteroid traditionally recognized for its essential role in calcium and phosphate homeostasis and maintenance of skeletal health. However, the discovery of vitamin D receptors in a wide range of immune cells has considerably expanded the understanding of its biological functions [2]. Serum 25-hydroxyvitamin D [25(OH)D] is generally regarded as the most useful circulating marker for assessing vitamin D status because it reflects vitamin D derived from both cutaneous synthesis and dietary intake [2]. Vitamin D deficiency or insufficiency is common worldwide and may occur as a consequence of inadequate sunlight exposure, increased skin pigmentation, limited dietary intake, malabsorption, obesity, cultural clothing practices, or geographical and seasonal factors [2]. These determinants may be especially relevant in populations in which recurrent infections coexist with a high prevalence of hypovitaminosis D.

The relationship between vitamin D and host defence provides a strong biological rationale for investigating its association with recurrent RTIs. The active metabolite, 1,25-dihydroxyvitamin D, influences both innate and adaptive immune responses. Activation of Toll-like receptors on macrophages has been shown to increase expression of the vitamin D receptor and vitamin D-activating enzyme, thereby promoting production of antimicrobial peptides such as cathelicidin [3]. Cathelicidin possesses broad antimicrobial activity and contributes to mucosal defence against bacterial and viral pathogens. Vitamin D also participates in regulation of inflammatory cytokine production and may help balance antimicrobial defence with excessive inflammatory responses. Consequently, deficient vitamin D status could theoretically compromise respiratory mucosal immunity and increase susceptibility to repeated infections.

Epidemiological observations have provided support for this hypothesis. In a large analysis of 18,883 participants from the Third National Health and Nutrition Examination Survey, Ginde et al. demonstrated an inverse association between serum 25(OH)D concentrations and recent upper respiratory tract infection, with a higher prevalence of infection among participants with lower vitamin D concentrations [4]. Similar observations have been reported in paediatric populations. Wayse et al., in a case-control study among Indian children younger than five years, found that subclinical vitamin D deficiency was significantly associated with severe acute lower respiratory tract infection [5]. This finding is particularly relevant in settings where both childhood respiratory infections and vitamin D deficiency are common.

Evidence from younger populations has further supported a potential relationship between inadequate vitamin D and respiratory morbidity. Karatekin et al. reported an association between low vitamin D status in newborns and acute lower respiratory tract infection, together with evidence of lower maternal vitamin D concentrations [6]. McNally et al. examined young children with bronchiolitis or pneumonia and found that although average vitamin D concentrations did not differ substantially between all infected children and controls, markedly lower concentrations were observed among children requiring admission to intensive care [7]. These findings suggest that vitamin D status might be associated not only with susceptibility but potentially with the clinical severity of respiratory disease in selected populations.

Interventional studies conducted before 2015 produced encouraging but heterogeneous findings. In a randomized double-blind trial among schoolchildren, Urashima et al. reported a lower incidence of influenza A among children receiving vitamin D3 compared with placebo [8]. Laaksi et al. subsequently investigated vitamin D supplementation among young Finnish men and observed findings suggestive of a possible protective effect against acute respiratory infection, although the overall evidence was not definitive [9]. In Mongolian schoolchildren with low baseline vitamin D status, Camargo et al. reported that vitamin D supplementation significantly reduced the risk of acute respiratory infections during winter [10].

The potential relevance of vitamin D may be even greater in patients experiencing frequent or recurrent infections. Bergman et al. conducted a randomized, double-blind trial involving individuals with frequent respiratory tract infections or antibody deficiency and found that daily vitamin D3 supplementation reduced infectious symptoms and antibiotic consumption compared with placebo [11]. Nevertheless, supplementation studies have not produced uniformly positive findings, and considerable differences in study populations, baseline vitamin D concentrations, dose, dosing interval, duration of supplementation, and definitions of respiratory infection make direct comparison difficult. A systematic review by Jolliffe et al. found that observational studies predominantly demonstrated an association between lower vitamin D status and increased susceptibility to acute respiratory infections, whereas randomized trials showed inconsistent outcomes [12]. Similarly, a meta-analysis of randomized controlled trials by Bergman et al. suggested an overall protective effect of vitamin D supplementation against respiratory tract infections but highlighted substantial heterogeneity among available studies [13].

Thus, available evidence before 2015 indicates a biologically plausible and clinically important relationship between vitamin D status and susceptibility to respiratory infections, but the precise role of vitamin D in recurrent respiratory infections remains incompletely defined. Much of the earlier literature focused on individual acute episodes, severe lower respiratory infections, or seasonal viral illness rather than the frequency of repeated respiratory infections in the same individuals. Furthermore, uncertainty remains regarding whether low vitamin D is an independent risk factor for recurrent infection or a marker associated with other nutritional, environmental, or health-related determinants. Assessment of serum 25(OH)D concentrations in individuals with recurrent respiratory infections and comparison with appropriate controls may therefore provide valuable information. The present study is undertaken to evaluate vitamin D status and its association with recurrent respiratory infections, with the aim of determining whether reduced serum vitamin D concentrations are associated with increased frequency or susceptibility to recurrent respiratory morbidity.

Study Design and Setting

This hospital-based, analytical case-control study was conducted at the Department of Paediatrics, Andhra Medical College, King George Hospital, Visakhapatnam, Andhra Pradesh, India. over a period of six months, from September 2015 to February 2016. The study was designed to evaluate serum vitamin D status among individuals with recurrent respiratory tract infections (RTIs) and to determine whether reduced serum 25-hydroxyvitamin D [25(OH)D] concentrations were associated with an increased occurrence of recurrent respiratory infections.

Study Population and Sample Size

A total of 90 participants were enrolled during the study period. Participants were divided into two groups:

• Case group: 45 patients presenting with a clinical history of recurrent respiratory tract infections.

• Control group: 45 apparently healthy individuals without a history of recurrent respiratory tract infections, selected from individuals attending the hospital for routine evaluation or minor non-respiratory complaints.

Controls were frequency-matched with cases as far as possible for age and sex to minimize the influence of major demographic confounders on vitamin D status.

The sample size of 90 participants was considered feasible within the defined study period and was sufficient for detecting clinically meaningful differences in serum 25(OH)D levels between participants with and without recurrent respiratory infections.

Definition of Recurrent Respiratory Tract Infection

Recurrent respiratory tract infection was defined on the basis of repeated, clinically documented episodes of infection involving the upper and/or lower respiratory tract within the preceding 12 months. Recurrent infection included repeated episodes of rhinitis, pharyngitis, tonsillitis, sinusitis, otitis-associated upper respiratory infection, bronchitis, bronchiolitis, or pneumonia, as clinically applicable.

A participant was categorized as having recurrent respiratory infection when there was a clear history of multiple discrete respiratory infectious episodes separated by periods of clinical recovery and requiring repeated medical consultation or treatment. Whenever available, previous prescriptions, hospital records, laboratory investigations, and radiological findings were reviewed to confirm the history and reduce recall bias.

Inclusion Criteria

Patients of either sex presenting with recurrent respiratory tract infections during the study period and willing to participate were eligible for inclusion. Participants were required to have a documented or reliably reported history of recurrent respiratory infections during the preceding year. Controls were individuals without recurrent respiratory infections or other active infective illnesses at the time of recruitment.

Exclusion Criteria

Participants were excluded if they had conditions likely to independently influence vitamin D metabolism or predispose to recurrent infections. These included known primary or secondary immunodeficiency, chronic kidney disease, chronic liver disease, malabsorption syndromes, active tuberculosis, malignancy, severe protein-energy malnutrition, metabolic bone disease, or other major chronic systemic illness.Individuals receiving vitamin D or calcium supplementation in therapeutic doses during the preceding three months were excluded. Patients receiving long-term corticosteroids, anticonvulsants, immunosuppressive agents, or other medications known to alter vitamin D metabolism were also excluded. Participants with incomplete clinical information or those who declined blood sampling were not included.

Clinical Assessment

All recruited participants underwent detailed clinical assessment using a predesigned study proforma. Demographic information including age, sex, place of residence, and relevant socioeconomic characteristics was recorded. A detailed history was obtained regarding the number of respiratory infections during the previous 12 months, predominant type of respiratory infection, duration of symptoms, previous hospital admissions, antibiotic use, and family history of recurrent respiratory disease.

Potential determinants of vitamin D status were also recorded, including approximate sunlight exposure, dietary sources of vitamin D, nutritional status, and previous vitamin supplementation. Relevant history of allergic respiratory disease, passive or active tobacco-smoke exposure, recurrent wheezing, and other comorbid illnesses was documented.

A complete physical examination was performed with particular attention to anthropometric measurements, nutritional status, respiratory system findings, and signs potentially suggestive of vitamin D deficiency.

Assessment of Vitamin D Status

Venous blood samples were collected from all cases and controls under aseptic precautions. Approximately 3–5 mL of venous blood was obtained and allowed to clot. Serum was separated by centrifugation and analyzed for 25-hydroxyvitamin D [25(OH)D], the preferred biochemical marker of vitamin D status because it represents vitamin D derived from both endogenous synthesis and dietary sources.

Serum 25(OH)D concentration was measured using a standardized chemiluminescent immunoassay available in the institutional laboratory. Internal quality-control procedures were performed according to the manufacturer's instructions and institutional laboratory standards.

For analysis, vitamin D status was classified according to serum 25(OH)D concentration as:

• Vitamin D deficiency:<20 ng/mL

• Vitamin D insufficiency: 20–29 ng/mL

• Vitamin D sufficiency: ≥30 ng/mL

Serum 25(OH)D was also retained as a continuous variable for comparison between cases and controls and for assessment of its relationship with respiratory infection frequency.

Laboratory Investigations

In addition to serum 25(OH)D measurement, routine laboratory investigations were performed where clinically indicated. These included complete blood count, serum calcium, serum phosphorus, and alkaline phosphatase. Additional investigations, such as C-reactive protein, chest radiography, throat swab, sputum examination, or other microbiological tests, were performed according to the clinical presentation rather than uniformly in all participants.

Outcome Measures

The primary outcome was the difference in mean serum 25(OH)D concentration between participants with recurrent respiratory tract infections and controls.

Secondary outcomes included:

1. prevalence of vitamin D deficiency and insufficiency in the recurrent-RTI and control groups;

2. association between vitamin D deficiency and recurrent respiratory tract infection;

3. relationship between serum 25(OH)D concentration and the number of respiratory infection episodes during the preceding year;

4. association between vitamin D status and the anatomical pattern of respiratory infection; and

5. identification of demographic and clinical factors associated with recurrent RTIs and low vitamin D concentrations.

Control of Potential Confounding Factors

Because vitamin D status may be influenced by several environmental and clinical factors, information regarding age, sex, sunlight exposure, nutritional status, season of recruitment, dietary practices, and relevant comorbidities was collected. These variables were considered during statistical analysis to minimize confounding. Cases and controls were recruited during the same six-month period to reduce seasonal differences in vitamin D exposure.

Statistical Analysis

Data were entered into a computerized database and analyzed using IBM SPSS Statistics 24.0. Continuous variables were assessed for distribution and expressed as mean ± standard deviation for normally distributed data or median with interquartile range for non-normally distributed variables. Categorical variables were presented as frequencies and percentages.

Differences between cases and controls were assessed using the independent-samples Student's t-test for normally distributed continuous variables and the Mann-Whitney U test for non-normally distributed variables. Categorical variables, including the prevalence of vitamin D deficiency, were compared using the chi-square test or Fisher's exact test, where appropriate.

Correlation between serum 25(OH)D concentration and the frequency of respiratory infection episodes was evaluated using Pearson's or Spearman's correlation coefficient according to data distribution. The association between vitamin D deficiency and recurrent respiratory tract infection was quantified using odds ratios (ORs) with 95% confidence intervals (CIs).

Binary logistic regression analysis was performed to examine whether vitamin D deficiency was independently associated with recurrent respiratory infection after adjustment for relevant confounding variables such as age, sex, nutritional status, sunlight exposure, and other clinically relevant factors. Variables with a P value <0.20 on univariate analysis and variables considered clinically important were considered for the multivariable model. Multicollinearity and model fit were assessed before final interpretation. A two-sided P value <0.05 was considered statistically significant.

A total of 90 participants were included in the study, comprising 45 patients with recurrent respiratory tract infections (RTIs)and45 controls without recurrent RTIs. All enrolled participants completed the clinical evaluation and serum 25-hydroxyvitamin D [25(OH)D] assessment and were included in the final analysis.

The mean age of participants with recurrent RTIs was 24.8 ± 12.4 years, compared with 25.6 ± 11.9 years among controls, with no statistically significant difference between the groups (P=0.756). Males constituted 57.8% of the case group and 53.3% of the control group (P=0.671). The distribution according to place of residence and nutritional status was also comparable.

A significantly greater proportion of patients with recurrent RTIs reported low habitual sunlight exposure compared with controls (60.0% vs. 37.8%, P=0.035). Passive exposure to tobacco smoke was more frequent among cases, although the difference did not reach conventional statistical significance (P=0.069).

Table 1. Baseline demographic and clinical characteristics of cases and controls

Serum 25(OH)D concentrations were significantly lower among patients with recurrent RTIs than among controls. The mean serum 25(OH)D concentration was 17.9 ± 7.8 ng/mL in cases compared with 27.6 ± 9.4 ng/mL in controls (P<0.001).

Vitamin D deficiency, defined as serum 25(OH)D <20 ng/mL, was identified in 29 of 45 cases (64.4%), compared with 12 of 45 controls (26.7%). Conversely, vitamin D sufficiency was present in only 13.3% of cases, compared with 35.6% of controls. The overall distribution of vitamin D categories differed significantly between the two groups (P=0.001).

Table 2. Comparison of vitamin D status between recurrent RTI cases and controls

These findings demonstrated a clear shift toward lower vitamin D concentrations among patients experiencing recurrent respiratory infections.

Among the 45 patients with recurrent RTIs, the median number of documented or reliably reported respiratory infection episodes during the preceding 12 months was 5 episodes (interquartile range: 4–6). Upper respiratory tract infections constituted the predominant pattern in 25 patients (55.6%), while 8 patients (17.8%) had predominantly lower respiratory infections. Twelve patients (26.7%) experienced recurrent infections involving both the upper and lower respiratory tracts.

At least one respiratory infection-related hospitalization during the preceding year was reported by 13 patients (28.9%), while 24 patients (53.3%) had received three or more courses of antibiotics.

Table 3. Clinical characteristics of patients with recurrent respiratory tract infections

A progressive reduction in serum 25(OH)D concentration was observed with increasing frequency of respiratory infections. Patients reporting three episodes during the previous year had a mean serum vitamin D concentration of 24.2 ± 6.5 ng/mL, whereas those reporting four to five episodes had a mean concentration of 18.1 ± 6.1 ng/mL. The lowest serum vitamin D concentrations were observed among patients with six or more infections per year (13.1 ± 4.7 ng/mL).

The difference among the three infection-frequency categories was statistically significant (P<0.001). Furthermore, serum 25(OH)D concentration demonstrated a significant inverse correlation with annual infection frequency (Spearman's ρ = −0.58, P<0.001), indicating that lower vitamin D concentrations were associated with a greater number of respiratory infection episodes.

Table 4. Relationship between frequency of recurrent respiratory infections and serum 25(OH)D concentration

Vitamin D deficiency was substantially more common among patients with recurrent RTIs than among controls. Participants with vitamin D deficiency had approximately five-fold higher unadjusted odds of recurrent RTI compared with participants without vitamin D deficiency (OR 4.98; 95% CI 2.03–12.25; P<0.001).

When vitamin D sufficiency was used as the reference category, vitamin D-deficient participants had an odds ratio of 6.44 (95% CI 2.03–20.45) for recurrent RTI. Vitamin D insufficiency alone was associated with a smaller and statistically non-significant increase in odds.

Combining vitamin D deficiency and insufficiency into a single suboptimal vitamin D category (<30 ng/mL) also demonstrated a significant association with recurrent RTI.

Table 5. Association between vitamin D status and recurrent respiratory tract infection

Binary logistic regression was performed to determine whether vitamin D deficiency remained independently associated with recurrent RTI after accounting for potentially relevant confounding factors. Vitamin D deficiency remained a significant independent predictor of recurrent RTI, with an adjusted odds ratio of 4.12 (95% CI 1.53–11.10; P=0.005).

Low sunlight exposure showed a positive association with recurrent RTI, although this relationship became statistically non-significant after adjustment (P=0.074). Nutritional status and smoke exposure were also not independently associated with recurrent RTI in the final model.

Table 6. Multivariable logistic regression analysis of factors associated with recurrent respiratory tract infection

The study demonstrated a strong association between reduced serum vitamin D concentration and recurrent respiratory tract infections. Patients with recurrent RTIs had significantly lower mean serum 25(OH)D concentrations and a markedly greater prevalence of vitamin D deficiency than controls. Furthermore, serum vitamin D concentration showed a significant inverse relationship with the number of respiratory infection episodes. Even after adjustment for sunlight exposure, nutritional status, smoke exposure, age, and sex, vitamin D deficiency remained independently associated with recurrent RTI.

Figure 1 illustrates the distribution of vitamin D status among patients with recurrent respiratory tract infections and controls. Vitamin D deficiency (<20 ng/mL) was markedly more common in the recurrent RTI group than in controls (64.4% vs. 26.7%), whereas vitamin D sufficiency (≥30 ng/mL) was more frequently observed among controls (35.6% vs. 13.3%). Vitamin D insufficiency (20–29 ng/mL) was present in 22.2% of recurrent RTI cases and 37.8% of controls. Overall, the figure demonstrates a clear shift toward lower vitamin D status among patients with recurrent respiratory tract infections.

Figure 2 compares the mean serum 25-hydroxyvitamin D [25(OH)D] concentrations between patients with recurrent respiratory tract infections and healthy controls. The mean serum 25(OH)D level was significantly lower in recurrent RTI cases (17.9 ± 7.8 ng/mL) than in controls (27.6 ± 9.4 ng/mL). The difference between the two groups was statistically highly significant (P < 0.001), indicating that lower vitamin D levels were strongly associated with recurrent respiratory tract infections in the study population.

The present study demonstrated a significant association between reduced vitamin D status and recurrent respiratory tract infections (RTIs). Patients with recurrent RTIs had substantially lower serum 25-hydroxyvitamin D [25(OH)D] concentrations than controls, with mean values of 17.9 ± 7.8 ng/mL and 27.6 ± 9.4 ng/mL, respectively. Vitamin D deficiency was identified in 64.4% of patients with recurrent RTIs compared with 26.7% of controls, and deficient participants had nearly five-fold greater unadjusted odds of recurrent RTI. An additional important observation was the progressive decline in serum 25(OH)D concentration with increasing frequency of respiratory infections. The significant inverse correlation between serum vitamin D concentration and annual infection frequency (Spearman's ρ = −0.58, P<0.001) suggests a possible exposure-response relationship. Furthermore, vitamin D deficiency remained independently associated with recurrent RTI after adjustment for relevant clinical and environmental factors.

These findings are consistent with previous observational evidence suggesting that inadequate vitamin D status may increase susceptibility to respiratory infections. In a prospective cohort of healthy adults, Sabetta et al. evaluated serial serum 25(OH)D concentrations during the autumn and winter months and observed that individuals maintaining higher vitamin D concentrations experienced fewer acute viral respiratory infections. Higher serum concentrations were also associated with a reduced duration of illness [14]. These observations support the present finding that lower serum 25(OH)D concentrations occur among individuals with a greater burden of recurrent RTIs.

Similar evidence was reported by Berry et al. in a large British population-based study involving 6,789 adults. They demonstrated a linear inverse association between serum 25(OH)D concentrations and respiratory infection, with each 10 nmol/L increment in vitamin D associated with a reduction in infection risk even after adjustment for lifestyle, socioeconomic and adiposity-related factors [15]. The graded relationship observed in that study is particularly relevant to the present investigation, in which mean vitamin D concentrations decreased from 24.2 ng/mL among patients reporting three infections per year to 13.1 ng/mL among those experiencing six or more episodes. Together, these findings suggest that the relationship between vitamin D and respiratory morbidity may not simply represent a distinction between deficient and sufficient individuals but may extend across a range of circulating vitamin D concentrations.

Evidence supporting this relationship has also been reported early in life. Belderbos et al. prospectively evaluated cord-blood 25(OH)D concentrations and subsequent respiratory syncytial virus (RSV) lower respiratory tract infection during infancy. Infants with cord-blood concentrations below 50 nmol/L had a substantially increased risk of developing RSV-associated lower respiratory infection during the first year of life compared with infants with concentrations of at least 75 nmol/L [16]. Although the clinical population and infection spectrum differed from the present study, these findings support the possibility that inadequate vitamin D status may be associated with increased susceptibility to respiratory pathogens.

Studies focusing specifically on recurrent upper respiratory disease provide further support. Aydın et al. investigated vitamin D status in children undergoing tonsillectomy because of recurrent tonsillitis and reported differences in serum vitamin D status compared with healthy children [17]. Yildiz et al. subsequently studied children with recurrent tonsillopharyngitis and found significantly lower mean serum 25(OH)D concentrations in affected children than in healthy controls [18]. The latter authors reported mean concentrations of 142.7 ± 68.1 nmol/L in children with recurrent tonsillopharyngitis compared with 192.3 ± 56.1 nmol/L in controls. These observations are compatible with the current finding of substantially lower vitamin D levels among patients with recurrent respiratory disease and suggest that the association may extend across different anatomical patterns of respiratory tract infection.

Vitamin D status has also been investigated in disorders characterized by recurrent wheezing, which frequently coexist with or are precipitated by respiratory infections. Özaydın et al. compared infants with recurrent wheezing with healthy controls and reported an association between vitamin D status and recurrent wheezing [19]. Although recurrent wheezing should not be considered synonymous with recurrent respiratory infection, the overlap between viral respiratory infections, airway inflammation and repeated wheezing episodes highlights the potential importance of vitamin D in respiratory immune homeostasis.

Several biological mechanisms may explain the association observed in the present study. Vitamin D is increasingly recognized as an immunomodulatory hormone rather than merely a regulator of calcium and bone metabolism. Airway epithelial cells, alveolar macrophages, dendritic cells and lymphocytes possess vitamin D receptors and components of the enzymatic machinery required for local metabolism of vitamin D. Vitamin D signalling enhances production of antimicrobial peptides, including cathelicidin, which can contribute to defence against respiratory pathogens. It also modulates chemokine production, dendritic-cell activity and T-cell responses, thereby influencing both innate and adaptive immunity [20]. Deficient vitamin D status may therefore weaken mucosal antimicrobial defence or alter regulation of respiratory inflammatory responses, potentially increasing susceptibility to repeated infections.

The association with sunlight exposure observed in the present study is also noteworthy. Low habitual sunlight exposure was reported in 60.0% of recurrent-RTI cases compared with 37.8% of controls. As cutaneous ultraviolet-B exposure represents a major source of vitamin D, limited sunlight may contribute to reduced circulating 25(OH)D concentrations. However, after multivariable adjustment, low sunlight exposure did not remain statistically significant, whereas vitamin D deficiency retained an independent association with recurrent RTI. This finding suggests that circulating vitamin D status may capture the combined influence of sunlight, dietary intake, nutritional status and other determinants more effectively than self-reported sunlight exposure alone. Nevertheless, residual confounding related to outdoor activity, socioeconomic circumstances, diet, adiposity and seasonal behaviour cannot be excluded.

The present study also showed that deficient participants had an unadjusted odds ratio of 4.98 (95% CI 2.03–12.25) for recurrent RTI compared with non-deficient participants. After adjustment for age, sex, sunlight exposure, nutritional status and smoke exposure, vitamin D deficiency remained significantly associated with recurrent RTI (adjusted OR 4.12; 95% CI 1.53–11.10). Persistence of the association after multivariable adjustment strengthens the epidemiological relationship. However, it does not establish causality. Low vitamin D concentrations could predispose individuals to recurrent infection, but recurrent illness itself might reduce outdoor activity, dietary intake or general health, thereby contributing to lower vitamin D concentrations.

This distinction is particularly important because randomized supplementation studies conducted before 2015 produced heterogeneous findings. Murdoch et al., in the VIDARIS randomized controlled trial, evaluated high-dose monthly vitamin D3 supplementation in healthy adults and found no significant reduction in the incidence, duration or severity of upper respiratory tract infections despite a substantial increase in circulating 25(OH)D concentrations [21]. Similarly, a meta-analysis by Mao and Huang involving seven randomized controlled trials and 4,827 participants found no significant overall reduction in RTI risk with vitamin D supplementation in healthy populations [22]. These findings indicate that an epidemiological association between low vitamin D and respiratory infections should not automatically be interpreted as evidence that indiscriminate vitamin D supplementation will prevent recurrent infections.

Conversely, other intervention studies suggested possible benefit under specific conditions. Goodall et al. randomized university students to vitamin D3 supplementation or placebo and found that although the reduction in clinically defined upper respiratory infections did not reach statistical significance, vitamin D supplementation was associated with a significantly lower risk of laboratory-confirmed upper respiratory infection and a lower viral load [23]. Such differences among clinical trials may reflect variation in baseline vitamin D status, dosing schedules, study populations, pathogen exposure, outcome definitions and duration of follow-up. Individuals who are genuinely vitamin D deficient may differ in their response to supplementation from vitamin D-replete populations.

A review by Bryson et al. emphasized that pre-2015 observational evidence generally demonstrated an association between lower vitamin D status and respiratory viral infection, while the available intervention evidence remained less consistent [24]. This interpretation is appropriate for the present findings. Our results identify a strong association between vitamin D deficiency and recurrent respiratory morbidity, but they should not be considered proof that vitamin D deficiency is the sole cause of recurrence or that vitamin D supplementation alone would eliminate recurrent infection.

Another notable finding was the predominance of upper respiratory infection among cases, accounting for 55.6%, while 17.8% predominantly experienced lower RTIs and 26.7% experienced both upper and lower respiratory infections. More than half of affected patients required three or more courses of antibiotics during the previous year, and 28.9% had experienced at least one infection-related hospitalization. This clinical burden emphasizes the potential value of identifying modifiable factors associated with recurrent respiratory disease. Vitamin D assessment may therefore be clinically relevant in selected patients with recurrent infections, particularly when additional risk factors for deficiency are present. However, vitamin D measurement should complement rather than replace evaluation for established causes of recurrent RTI, including structural airway disease, allergic disorders, nutritional deficiencies, environmental exposures and immune dysfunction.

The present study has several strengths. Cases and controls were evaluated during the same study period, reducing major seasonal differences in vitamin D exposure. Serum 25(OH)D, the established biochemical indicator of vitamin D status, was measured in both groups, and potential confounders including age, sex, nutritional status, sunlight exposure and smoke exposure were considered in multivariable analysis. Moreover, assessment of infection frequency permitted evaluation of a gradient between vitamin D concentration and recurrent disease burden rather than relying solely on a dichotomous case-control comparison.

Several limitations should also be considered. First, the relatively small sample size of 90 participants limits the precision of effect estimates, as reflected by the relatively wide confidence interval surrounding the adjusted odds ratio. Second, the hospital-based design may introduce selection bias and may limit generalizability to the wider community. Third, information regarding respiratory infection frequency during the preceding year was partly dependent on patient or caregiver recall when complete medical records were unavailable, introducing the possibility of recall misclassification. Fourth, although several important confounders were considered, unmeasured factors such as detailed dietary vitamin D intake, duration of outdoor exposure, socioeconomic status and specific respiratory pathogens could have influenced the observed relationship. Fifth, recruitment over six months from September 2015 to February 2016 did not encompass an entire annual cycle, and seasonal variation in serum 25(OH)D concentrations cannot therefore be completely excluded. Most importantly, the observational case-control design does not establish temporal direction or causality.

Despite these limitations, the present findings demonstrate a consistent relationship between low serum vitamin D status and recurrent respiratory infection. Patients with recurrent RTIs had significantly lower mean serum 25(OH)D concentrations, a substantially greater prevalence of vitamin D deficiency and progressively lower vitamin D levels with increasing infection frequency. The persistence of the association after adjustment for relevant confounding variables suggests that vitamin D deficiency may represent an important marker associated with susceptibility to recurrent respiratory infection. Larger prospective studies with longitudinal vitamin D measurements, pathogen-specific assessment and appropriately designed supplementation trials are required to determine whether correction of vitamin D deficiency can reduce the frequency or severity of recurrent RTIs.

The present study demonstrated a significant association between low serum vitamin D status and recurrent respiratory tract infections. Patients with recurrent RTIs had significantly lower mean serum 25-hydroxyvitamin D concentrations than controls, and vitamin D deficiency was substantially more common among affected individuals. A progressive decline in serum vitamin D levels was also observed with increasing frequency of respiratory infection episodes, indicating an inverse relationship between vitamin D status and recurrent respiratory morbidity. Vitamin D deficiency remained independently associated with recurrent RTIs even after adjustment for relevant confounding factors.

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