Acute infective skin disorders are frequently encountered in pediatric practice and include conditions such as impetigo, cellulitis, infected dermatitis, abscesses, and furunculosis. While many children only have local symptoms that respond to the correct antimicrobial treatment, some will have a more extensive inflammatory response, systemic symptoms, dehydration, tachycardia and tachypnea, and other physiological disturbances. The severity of the infection conditions is not only related to the microorganism causing the infection and the involvement of tissues but also to the host immune competence, the nutritional condition and the regulation of the inflammatory response. Determination of biological factors that lead to severe illness, therefore, could facilitate earlier identification of children who are at risk (1-3).

There is growing appreciation of the role of micronutrients in regulating immune and epithelial function. Zinc is needed for maintenance of the integrity of skin barrier, cell growth, wound healing, antioxidant activity and normal function of innate and adaptive immune cells. Deficiency of zinc may affect the function of neutrophils and lymphocytes, the cytokine response and epithelial resistance to microbial invasion. The skin is an important physical and immunological barrier to pathogens, and zinc deficiency may lead to weakened local immunity and increased inflammatory reactions when challenged by pathogens (4, 5).

In addition to its classical functions in calcium and bone metabolism, vitamin D plays a significant and important role in immune regulation. It has active metabolites that affect the activity of macrophages and monocytes, regulate inflammatory signaling pathways and promote production of antimicrobial peptides, including cathelicidin and defensins. These are actions especially relevant to skin defence since vitamin D receptors are found in keratinocytes and in a number of immune cell populations in the skin. This may be linked to sub-optimal antimicrobial activity and inflammation in the body, but the extent, and direction, of these relationships may depend on the type of infection and the underlying nutritional status (6, 7).

Children are especially vulnerable to micronutrient deficiencies because of rapid growth, dietary inadequacy, limited sunlight exposure, recurrent infections, and socioeconomic factors. The level of some micronutrients could also be altered in the circulation during acute infection, as a consequence of the inflammatory response. Therefore, decreased zinc or vitamin D levels in serum may be due to pre-existing deficiencies, effect of acute illness or a combination of both. The study of these micronutrients along with physiological and inflammatory parameters can give a wider context to the correlation between nutritional status and clinical manifestation of infective skin diseases (8, 9).

Despite the biological relevance of zinc and vitamin D, relatively limited clinical evidence has simultaneously evaluated both micronutrients in relation to severity and physiological disturbances in children with acute infective skin disorders. Most previous research has focused on individual micronutrients, chronic inflammatory skin diseases, or systemic pediatric infections. Therefore, the present study was conducted to determine the association of serum zinc and vitamin D levels with disease severity, inflammatory markers, and physiological abnormalities in children with acute infective skin disorders and to assess whether these micronutrients may serve as supportive predictors of moderate-to-severe disease.

This descriptive cross-sectional study was conducted at Khalifa Gul Nawaz Teaching Hospital, Dera Ismail Khan, from January 2025 to June 2025. The study was designed to evaluate the role of serum zinc and vitamin D levels in relation to disease severity and associated physiological disturbances among children presenting with acute infective skin disorders. A total of 76 children fulfilling the predefined eligibility criteria were enrolled during the study period using a consecutive non-probability sampling technique. Children of both sexes with clinically diagnosed acute infective skin disorders (AISSD) (e.g. impetigo, cellulitis, infected dermatitis or eczema, abscesses, and furunculosis) were deemed eligible. Children who had a chronic dermatological disease with no evidence of acute infection, a known chronic renal or hepatic disease, metabolic or endocrine disorder known to affect zinc or vitamin D metabolism, had been taking zinc or vitamin D supplements just before enrolling, or were taking long-term corticosteroid or immunosuppressive therapy were excluded. Children with incomplete clinical or laboratory information were also excluded from the final analysis. Demographic and clinical data were collected on a structured data collection form after enrollment. All recorded data were concerned with the age, sex, weight, nutritional status, duration of illness, type and distribution of skin lesions, presence of fever and erythema, swelling and discharge, presence of pain, and associated systemic manifestations. A thorough clinical assessment was carried out for all participants. The degree of severity was rated as mild, moderate, or severe based on the proportion of skin covered, the intensity of local inflammatory changes, systemic symptoms, and physiologic abnormalities. Children were classified as mild, moderate or severe according to whether they had localized lesions or mild systemic disturbance, or extensive infection with marked systemic or physiological disturbance. Physiological parameters such as body temperature, HR, RR, SBP, DBP and peripheral oxygen saturation were assessed. Tachycardia and tachypnea were defined by age appropriate clinical parameters. Other systemic effects such as fever, hypotension, dehydration, poor feeding, lethargy were noted. Other measures of clinical severity, such as hospital admission, were also documented as appropriate. Blood samples were drawn from the veins and subjected to laboratory analysis. A laboratory method of measurement of serum zinc concentration was used in the institutional laboratory, preferably by a standardized colourimetric or spectrophotometric method. 25(OH)D was used as a marker of vitamin D status, as the available laboratory method to measure it was based on an immunoassay. Zinc deficiency was defined by the reference range on the hospital laboratory test. Vitamin D status was defined by typical ranges in serum 25(OH)D levels, <20 ng/mL (deficient), 20-29.9 ng/mL (insufficient), and ≥30 ng/mL (sufficient). Consistently all subjects used laboratory reference ranges and assay specific cut offs. Body's inflammatory response was evaluated by performing additional laboratory tests, which comprised total leukocyte count, differential leukocyte count, and C-reactive protein (CRP). Where clinically indicated, microbiological specimens from infected lesions were obtained for culture and identification of the causative organism. All investigations were carried out following standard laboratory procedures and in-house quality control. The main finding of the study was the correlation between the levels of serum zinc and serum vitamin D with the severity of acute infective skin disorders. Secondary outcomes were their association with physiological disturbances such as fever, tachycardia, tachypnea, blood pressure changes, oxygen saturation, leukocyte count and CRP levels. The ability of zinc deficiency and vitamin D deficiency to predict moderate-to-severe disease was also evaluated. The IBM SPSS Statistics 25.0 software was used for data entry and analysis. Data were presented as mean ± standard deviation or median (interquartile range), as appropriate, for continuous variables, and as frequencies and percentages for categorical variables. Shapiro-Wilk test

A total of 76 children with acute infective skin disorders were included in the study. Mean age of the participants was 7.8 ± 3.4 years (range 2-14 years). Of the 76 children, 43 (56.6%) were male and 33 (43.4%) were female. Impetigo was the most common clinical diagnosis followed by cellulitis and infected dermatitis. Twenty-nine children (38.2%) were diagnosed with mild disease, 30 children (39.5%) were diagnosed with moderate disease and 17 children (22.4%) were diagnosed with severe disease.

Table 1. Baseline demographic and clinical characteristics of the study participants (n = 76)

The mean serum Zinc level was 68.7 ± 14.6 µg/dL and the mean serum 25-hydroxyvitamin D level was 21.8 ± 8.1 ng/mL. The majority of children exhibited zinc deficiency (34, 44.7%) while the majority of the participants had vitamin D deficiency (39, 51.3%). 22.4% more children were vitamin D insufficient.

Table 2. Serum zinc and vitamin D status among study participants

As clinical severity increased, serum zinc levels and serum vitamin D levels were progressively decreased. The mean serum Zn concentration was 78.9 ± 10.7 µg/dL in mild, 66.8 ± 11.9 µg/dL in moderate and 54.7 ± 10.5 µg/dL in severe disease groups. This difference was statistically significant (p < 0.001). A similar pattern was observed for vitamin D, with mean values of 27.8 ± 7.1 ng/mL, 20.2 ± 5.8 ng/mL, and 14.5 ± 5.2 ng/mL in mild, moderate, and severe disease, respectively (p < 0.001).

Table 3. Serum zinc and vitamin D levels according to disease severity

Abnormalities also became more apparent as the severity of the disease increased. However, children with severe disease had significantly higher temperatures, heart rates and respiratory rates than children with mild or moderate disease. There was a slight difference between the mean oxygen saturation in the severe group and the non-severe group. The number of leukocytes and C-reactive protein (CRP) in the blood also rose significantly in each of the severity categories.

Table 4. Physiological and inflammatory parameters according to disease severity

Children with severe infections had significantly more systemic symptoms. The proportion of cases with fever was higher among severe cases (15, 88.2%) than mild cases (9, 31.0%). There were also significant relationships between tachycardia and tachypnea with disease severity. 14 (82.4%) of the children with severe disease had to be admitted to hospital.

Table 5. Clinical and physiological disturbances according to disease severity

There was an inverse correlation between serum zinc levels and disease severity (r = −0.56, p < 0.001) and between vitamin D levels and disease severity (r = −0.52, p < 0.001) by correlation analysis. An inverse correlation was also seen between the serum zinc and the CRP and the T-LC. Vitamin D had moderate negative correlation with CRP, temperature and heart rate.

Table 6. Correlation of serum zinc and vitamin D with selected clinical and inflammatory parameters

After adjusting for age, nutritional status and duration of illness, multivariable logistic regression analysis showed that zinc deficiency and vitamin D deficiency were independently associated with moderate-severe disease. The children with zinc deficiency were about three times more likely to be moderately to severely infected, and those with vitamin D deficiency were nearly three times more likely to be moderately to severely infected.

Table 7. Multivariable logistic regression for predictors of moderate-to-severe acute infective skin disease

Overall, children with more severe acute infective skin disorders exhibited lower serum zinc and vitamin D concentrations together with greater inflammatory activity and physiological disturbance. Both micronutrient deficiencies showed significant associations with clinical severity, although elevated CRP also emerged as an important independent marker of more severe disease.

Figure 1. Prevalence of Zinc Deficiency and Vitamin D Deficiency According to Disease Severity.
The frequency of both zinc deficiency and vitamin D deficiency increased progressively from mild to moderate and severe acute infective skin disorders, indicating a significant association between micronutrient deficiency and greater disease severity in children.

The present study evaluated the relationship of serum zinc and vitamin D with the severity and physiological disturbances associated with acute infective skin disorders in children. A clear decline in both micronutrients was observed as disease severity increased. Mean serum zinc decreased from 78.9 ± 10.7 µg/dL in mild disease to 54.7 ± 10.5 µg/dL in severe disease, while serum vitamin D declined from 27.8 ± 7.1 ng/mL to 14.5 ± 5.2 ng/mL across the same severity categories. Zinc deficiency was present in 44.7% and vitamin D deficiency in 51.3% of the overall study population, with substantially greater frequencies among children with severe infection. These findings suggest that poor zinc and vitamin D status may accompany a more pronounced clinical response to acute infectious disease. Similar observations have been reported in other pediatric infections. Studies found markedly greater frequencies of both zinc and vitamin D deficiency among children with urinary tract infections than among healthy controls, supporting the association between inadequate micronutrient status and susceptibility to infection (10-12).

Zinc plays a key function in regulating inflammatory activity, innate and adaptive immune responses, and epithelial integrity, as well as in wound healing. Our study thus establishes a biological plausibility for the inverse association we identified between serum zinc and clinical severity. Children with severe skin infection not only had low zinc levels, but also high CRP, leukocyte numbers and neutrophil percentages. Similar findings have been reported with infectious diseases in children. Patients with low zinc in their serum were found to have hospitalisation rates significantly higher in COVID- 19 children in a prospective study. A correlation between low zinc status and increased systemic inflammation has been further supported by the fact that children with zinc deficiency during acute infection had elevated concentrations of CRP, neutrophil-to-lymphocyte ratio and fibrinogen. Likewise, another study on acute gastroenteritis in children found that children with lower serum zinc had more clinical severity and dehydration. Taken together, the results presented here suggest that zinc deficiency might be used to identify children who have a higher inflammatory load in acute infection (13-15).

Vitamin D also had an important association with disease severity as observed in the present study. Severe disease had a higher prevalence of vitamin D deficiency than mild disease (88.2% vs 24.1%) and there was a significant inverse association between serum 25(OH)D and clinical severity, CRP, white blood cell count, body temperature and heart rate. A deficiency of vitamin D could potentially affect the production of antimicrobial peptides, barrier function and the regulation of inflammatory immune responses to infectious diseases. The association between vitamin D and susceptibility to microbial infections was also examined in childhood and was confirmed by pediueis that improvement of vitamin D status was linked to reduced burden of infections, though supplementation did not significantly decrease infections compared to placebo in a randomized trial in school children. Therefore, vitamin D could be a parameter of immune competence of the host and not just a direct factor of the severity of infection (16, 17).

The other significant finding was that as the severity of skin infections increased, so did the occurrence of physiological changes. Children who were severely ill had elevated temperature, heart rate and respiratory rate at the same time as reduced oxygen saturation and significantly increased CRP and leukocytes. The severe group also showed more often fever, tachycardia, and tachypnea, lethargy and dehydration. Clinically expected changes when the inflammatory response to a localized infectious process is more significant. Of particular interest, zinc and vitamin D levels were both inversely related to some of these physiological and inflammatory parameters. The discovery indicates a possible interaction between micronutrient deficiency and systemic physiological disturbance, which can therefore be considered an aspect of the clinical phenotype of more severe infection. But this relationship is not identifiable from a cross-sectional study only as acute inflammation can change the concentration of circulating micronutrients. It is important to remember that a low level in the serum does not necessarily imply that deficiency led to the severe infection, and thus should not automatically be considered to be proof of a deficiency (18).

Zinc deficiency, vitamin D deficiency and elevated CRP remained significant independent predictors of moderate-to-severe disease after multivariable analysis in which selected clinical characteristics were included. The findings suggest that serum zinc and vitamin D could be used as an additional biomarker for the identification of children that need further monitoring. However, they should not be used as a substitute to clinical examination, known inflammatory markers or assessment of systemic instability. The results of the supplementation evidence are also conflicting. Zinc supplementation has been found to be beneficial in a number of paediatric infectious diseases, whilst low-level zinc has been reported to have a negative impact on clinical outcomes in some infections, but there are no consistent findings from supplementation studies in infections. As such, the present findings do not prove the efficacy of routine zinc or vitamin D supplementation to decrease the severity of acute infective skin diseases, but are supportive evidence for assessing micronutrient status (19, 20).

There are several weaknesses to the study. It took place at one institution with a relatively small number of children (76), limiting generalizability and the accuracy of multivariable estimates. The cross-sectional design does not allow the determination of temporal or causal relationships between micronutrient deficiency and the severity of disease. Moreover, serum zinc levels may also drop during inflammatory responses and serum vitamin D levels may be affected by nutritional status, seasonal variation, socioeconomic factors and pre-existing nutritional status. Also, most of the infective skin disorders were compared under a unified scale of severity, although they exhibited differences in their microbiological and pathological features. Multicenter prospective studies with larger patient numbers are needed in the future to measure levels of micronutrients during acute illness and after clinical recovery, and to determine whether correction of confirmed zinc deficiency or vitamin D deficiency leads to better clinical recovery and reduced complications, and to include microbiological data and standardised paediatric severity measurements.

Lower serum zinc and vitamin D concentrations were significantly associated with increasing severity of acute infective skin disorders in children. Deficiencies of both micronutrients were more frequent among children with severe disease and were accompanied by greater inflammatory activity and physiological disturbances, including fever, tachycardia and tachypnea. Zinc and vitamin D deficiency remained associated with moderate-to-severe disease after adjustment for selected clinical factors, suggesting their potential usefulness as supportive biomarkers of disease severity. Serum zinc and vitamin D assessment may therefore contribute to the overall evaluation of children with significant infective skin disease, particularly when systemic manifestations are present. Larger prospective studies are required to determine whether these deficiencies precede severe infection and whether targeted correction of confirmed deficiencies can improve clinical outcomes.

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