Pneumonia is one of the most common lower respiratory tract infections which is caused by a variety of pathogens such as viruses, bacteria and fungus. This disease causes a high burden of hospitalization and mortality in younger children. In 2019, World Health Organization stated that pneumonia was the cause of death in children under 5 years with around 740,000 deaths per year worldwide [1]. In Thailand, the Department of Disease Control reported the incidence of pneumonia at around 400,000–500,000 people per year, with elderly patients over 65 years old and children under 5 having high morbidity and mortality [2].

Vitamin C is a water-soluble vitamin that has an antioxidant function, preventing tissue damage from oxidative stress and limiting the production of new free radicals. It also affects the immune system by stimulating neutrophil migration to the infection site and regulating macrophage function [3,4]. Vitamin C has a beneficial effect on respiratory tract infection due to its antioxidant properties. In viral or bacterial infection, the activation of neutrophils causes the consumption of extracellular vitamin C which reduces the vitamin C level [5]. These suggest that providing vitamin C supplements may alleviate the symptoms of respiratory tract infection.

Guidelines for treatment in community-acquired pneumonia (CAP) suggest treating pneumonia with appropriate antibiotics, oxygen therapy and supportive care [6,7]. There was much research on the treatment of pneumonia to improve the severity and clinical outcome [8-13]. The study of Mahalanabis et al. [9] with children aged 2 to 35 months did not show any benefit of vitamin C and vitamin E in severe acute lower respiratory tract infections, in contrast to other studies on childhood pneumonia that did show the benefit of vitamin C [11-13]. For instance, a study by Hotiyana et al. [14] in children under 5 years of age, using 25 mg of oral vitamin C, reported a reduction in hospital stay duration. Similarly, other studies using different oral vitamin C dosages have also shown benefits in reducing the length of hospital stay (LOS) [13]. However, most prior studies have not examined the correlation between vitamin C levels and hospital duration. Furthermore, most studies in children have used single dose oral vitamin C and primarily focused on children under 5 years old.

The route of vitamin C administration significantly influences plasma concentration levels. Intravenous vitamin C produces higher plasma concentrations than oral supplementation, which is limited by gastric absorption [15]. In critically ill patients, and reduced oral intake further hinder effective vitamin C absorption. To address these limitations, we opted for intravenous vitamin C administration in this study. Additionally, pneumonia etiology varies by age group: in younger children (2 months to 5 years), viral pathogens are more common, while in older children (over 5 years), bacterial and atypical pathogens predominate. Viral pneumonia is typically managed with supportive care, while bacterial pneumonia often requires a more specific treatment and may result in more complications [7]. Pneumonia surveillance studies in Thailand indicate that the highest incidence occurs in children under 5 years old, followed by children aged 5–9 years 10–14 years [16,17].

Given these variations in pneumonia etiology, age-related differences, and vitamin C administration routes, the role of vitamin C in the treatment of pneumonia remains controversial. Further evidence is needed to determine its efficacy and optimal dosage in pediatric patients. This study aimed to assess the effects of vitamin C in childhood pneumonia, including both younger and older hospitalized children, by evaluating its impact on symptom scores, the LOS, and the optimal dosage of vitamin C supplementation for treatment.

A total of 150 patients were recruited, 1 patient was excluded due to renal insufficiency, and 6 patients were withdrawn (3 voluntarily withdrew and 3 were diagnosed with a different pulmonary disease). Consequently, 143 patients were included in the final analysis and were divided into 3 groups: 49 in the placebo group, 45 in the low-vit C group, and 49 in the high-vit C group (Fig. 1). The median age of patients in the placebo group was 2.92 years, in the low-vit C group it was also 2.92 years, and in the high-vit C group was 2.83 years. There were 97 male patients and 46 female patients, and 120 participants had normal nutrition status. Of the 99 patients diagnosed with viral pneumonia, 37 were in the placebo group, 30 in the low-vit C group and 32 in the high-vit C group. Also, 32 patients were diagnosed with bacterial pneumonia and these were distributed as 10 in the placebo group, 10 in the low-vit C group and 12 in the high-vit C group. In screening for other viral infections, respiratory syncytial virus (RSV) was found in 20.41% of the patients in the placebo group, 15.56 % in the low-vit C group and 28.57 % in the high-vit C group at enrollment. Oxygen therapy; mainly oxygen corrugate, was needed for more than 50% of the patients in each group. Other baseline characteristics were the same for all 3 groups, except for white blood counts which was found to be lower in the low-vit C group than the other groups (Table 1).

At enrollment, the clinical severity score of the low-vit C group was higher than that of the other 2 groups. The difference was statistically significant (P=0.025). The clinical score values of each group were recorded every 12 hours. Therefore, we use a comparison between the mean clinical score at the time of evaluation and the score at the time of enrollment (mean difference score). The mean difference changes of clinical score from the enrollment are shown in Fig. 2. Both the low-vit C and high-vit C groups showed improvement in their clinical scores more rapidly than seen in the placebo group over the 48 hours to 72 hours of the treatment period. The greatest change in clinical score occurred at 48 hours of treatment, in the low-vit C group (P=0.039). That change was greater than the change recorded for the high-vit C group, and both of these groups showed a greater improvement in clinical score than was recorded in the placebo group. LOS was lowest in the high-vit C group (71.72 hours), the placebo group (76.05 hours) and the low-vit C group (82.55 hours). None of these values showed a statistically significant difference. (Table 2).

Recordings at the time of enrollment showed a weak correlation between the vitamin C levels and clinical severity scores of the patients (Spearman correlation, 0.029; P=0.730). Subsequently, after the intervention period, a converse correlation was shown between the vitamin C levels of the patients and their clinical severity scores (Spearman correlation, -0.067; P=0.437).

Subgroup analysis of the patients who required a high-flow nasal cannula indicated that these patients had a higher clinical severity score than all other patients in all groups. The median length of stay in the high-vit C group was 86.67 hours and 93.75 hours in the low-vit C group. Both times were shorter than the placebo group (95.07 hours). The values and differences were not statistically significant. Also, the duration of the need for a high-flow nasal cannula was shorter in both the high-vit C group and low-vit C group than in the placebo group, with no statistical significance demonstrated by those values (Table 3).

In each subgroup of diagnoses of viral pneumonia and RSV pneumonia, both the high-vit C group and low-vit C group demonstrated a reduced length of stay, shorter than the placebo group. However, again, there was no statistical significance in those differences (P=0.730). For those patients diagnosed with bacterial pneumonia, the length of stay of the high-vit C group was 65.30 hours, for the low-vit C group it was 91.01 hours and for the placebo group (66.35 hours). These values indicate that the low vitamin C supplement did not help the length of stay in bacterial pneumonia. (Table 4).

Complications and side effects such as gastrointestinal symptoms and renal abnormalities were monitored. Urine output and renal function showed normal levels after the intervention. Some side effects were found in both the high-vit C group and the low-vit C group. Two patients developed mild diarrhea, one in each of the high-vit C and low-vit C groups. As well. 2 patients in the high-vit C group had urine calcium oxalate identified 3 days after enrollment. However, no patient withdrew from the study due to any side effects from the intervention. Also, no patient had any drug allergies.

This study is the first study of vitamin C supplementation in children older than 5 years whereas previous studies were mainly of children younger than 5 years [9,11,12]. However, in this study found only 18 patients (12.6%) that older than 5 years and the median age of the participating patients in this study was less than 5 years (3 years). This trial reflected the incidence of CAP requiring hospitalization in Thailand occurring mainly in younger children. The majority of infections were viral, consistent with previous studies [23-26].

The baseline vitamin C level of the patients in this study at enrollment showed as normal or marginally below normal. Similarly, the study by Wahed et. al. [12] showed that the patients with CAP in that study had vitamin C levels normal or marginally below normal for members of the community. This is in contrast with the study of Carr et al. [27] that showed significantly lower vitamin C levels in their cohort of patients with pneumonia than would be found in healthy people. This study demonstrated that after vitamin C supplementation, the levels significantly increased (P≤0.001). This study provides clearer evidence that intravenous vitamin C can significantly increase vitamin C levels in the bloodstream.

Previous studies have not reached a consensus regarding the effectiveness of vitamin C in reducing hospital length of stay. Several studies [12-14,27,28] have reported a reduction in hospital stay, while others found no significant effect [6,29,30]. This study corroborates the findings of previous research, indicating that vitamin C supplementation does not reduce the LOS. However, in contrast, it was observed that vitamin C supplementation significantly improved clinical symptoms, with statistical significance. The clinical severity score in both the low-vit C and high-vit C groups improved within 48–72 hours after receiving vitamin C supplementation. However, upon discontinuation of vitamin C, a deterioration in clinical symptoms was observed, particularly in the high-vit C group. This finding suggests that vitamin C plays a beneficial role in the management of CAP.

We hypothesize that the lack of impact on hospital stay is potentially due to insufficient duration of vitamin C administration. Given vitamin C’s half-life of approximately 2 hours, its active concentration in the bloodstream rapidly decreases due to both metabolic breakdown and renal excretion. While traces of vitamin C or its metabolites may be detectable in urine for up to 24 hours, clinically significant levels are eliminated from the bloodstream within approximately 10 hours of discontinuation. Therefore, stopping the administration of vitamin C may result in symptom recurrence and no reduction in hospital stay duration. We recommend further research to investigate the effects of administering vitamin C for a longer duration, specifically 5 to 7 days, to clarify its potential benefits.

Subgroup analysis in our study revealed no significant benefit of vitamin C supplementation in cases of bacterial pneumonia (primarily caused by Streptococcus pneumoniae) and atypical pneumonia (primarily caused by Mycoplasma pneumoniae). Streptococcus pneumoniae is the most common cause of bacterial pneumonia, though other bacteria including Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila, can also contribute. These pathogens infect the lungs, triggering inflammation that leads to symptoms such as cough, fever, and difficulty breathing. The infection typically follows an upper respiratory tract infection or arises from a weakened immune system.

The mechanism of infection generally involves the secretion of cytokines that recruit neutrophils and macrophages to eliminate the pathogen. Additionally, toxins produced by S. pneumoniae and M. pneumoniae can cause cellular damage and exacerbate inflammation. However, vitamin C does not possess direct bactericidal or bacteriostatic properties. Therefore, effective management of bacterial pneumonia requires appropriate antibiotic therapy to eliminate the infection. While vitamin C may help mitigate inflammation-related symptoms, it does not directly target or resolve bacterial infections.

Viral pneumonia, commonly caused by influenza viruses, RSV, and coronaviruses (including SARS-CoV-2), involves direct respiratory tract infection lung inflammation. Symptoms may range from mild to severe and often follow a cold or flu-like illness. Although generally less severe than bacterial pneumonia, viral pneumonia can lead to complications, particularly in the very young, elderly, or immunocompromised individuals. In our study, both vitamin C intervention groups showed a trend towards shorter lengths of stay in viral pneumonia compared to the placebo group, although this was not statistically significant. This suggests that the benefits of vitamin C supplementation in viral pneumonia remain unclear, conflicting with the results reported in previous studies [31,32]. While vitamin C has immunomodulatory effects, including enhanced T-lymphocyte proliferation, improved phagocyte function, interferon production, and viral replication suppression, its overall impact on viral pneumonia outcomes remain uncertain.

In a previous study [33], there was an inverse correlation of vitamin C with the severity of the disease shown, especially in patients presenting with acute respiratory distress syndrome, and who showed a significantly lower vitamin C level. However, in our study vitamin C levels did not show any correlation with the clinical severity of pneumonia. This may be due to the overall clinical severity in our study being mild to moderate with no patients experiencing respiratory failure or acute respiratory distress syndrome. These findings are similar to those in previous studies which showed that vitamin C did not affect the less ill patients [12] and patients with severe viral pneumonia [12,26,30]. Also, in our study, the effect of the vitamin C supplement on patients with higher severity who needed a high-flow nasal cannula showed both a shorter length of stay and a shorter duration of needing the high-flow nasal cannula, but these findings were not statistically significant. Vitamin C supplementation may be beneficial for patients with CAP, through its effects on reducing inflammation and oxidative stress [12,26]. However, further studies are needed to confirm these findings and provide clearer clinical evidence. Current treatment for severe CAP primarily relies on antibiotics (for bacterial infections) and supportive care.

The dosage of vitamin C supplementation has varied across previous studies [12,13,31]. Most past studies administered the vitamin orally, but the research team believes that the route of vitamin C administration may affect drug absorption, especially in patients who have difficulty eating or in children with issues related to taking medication. In our study, we administered the vitamin intravenously and used 2 doses: a low dose of 15 mg/kg/dose intravenously every 6 hours for the low-vit C group, and a higher dose of 30 mg/kg/dose intravenously every 6 hours for the high-vit C group. Both dosages were effective in reducing the clinical severity of the patients; however, we emphasize that the low dosage was particularly effective. These findings represent novel insights, as previous studies have typically used oral administration daily dose [12,13] or focused on adult populations [30,31,34]. There is limited data on the appropriate dosage and duration of vitamin C treatment in pediatric patients. Our study suggests that a low dosage of 15 mg/kg/day, administered every 6 hours for 3 days, can significantly improve clinical symptoms within 48 hours, with minimal side effects.

Adverse side effects were observed in both the high-vit C and low-vit C groups. Two patients, one from each group, experienced mild, self-limited diarrhea, which resolved after discontinuing vitamin C supplementation. This effect is likely due to vitamin C’s osmotic properties; at high concentrations in the intestines, it draws water from surrounding tissues, increasing intestinal water content and potentially leading to diarrhea [35].

Two patients in the high-vit C group developed urine calcium oxalate 3 days after enrollment. Excessive vitamin C intake promotes oxalate crystal formation in the kidneys, potentially increasing the risk of kidney stones, particularly in individuals with predisposing factors (e.g., dehydration or preexisting kidney conditions). This occurs because vitamin C is metabolized into oxalate, which can accumulate in the urine [36]. However, follow-up urinalysis on the seventh day after discontinuing vitamin C supplementation showed normal results in both patients.

This study had some limitations. First of all, the study did not include patients with high severity of pneumonia such as acute respiratory failure and acute respiratory distress syndrome. Secondly, we did not record the effect of vitamin C on the needed duration of oxygen supplementation other than by the high-flow nasal cannula. A further limitation is the use of concomitant therapies, which were determined by the attending physician. These included antibiotics for bacterial pneumonia, bronchodilators for bronchospasm, oxygen supplementation for hypoxemia, and fluids for dehydration. These interventions could have influenced the study's results, potentially prolonging hospital stays or affecting clinical scores. While these confounding variables were beyond our control, we believe that the study outcomes reflect real-world clinical practice, where is often used in conjunction with these other medications. Therefore, we are confident that the results are applicable to settings similar to our hospital.

For future research, we suggest that the following situations be included in the study (1) the effect of vitamin C supplementation on childhood pneumonia with critical severe illness, (2) the effect of vitamin C supplement on each pathogen of viral or bacterial pneumonia, (3) patients with pneumonia who have vitamin C deficiency should be specifically studied to identify the effect of vitamin C supplementation.

In conclusion, vitamin C supplementation for patients with childhood pneumonia requiring hospitalization did not show a reduction in the LOS. However, vitamin C supplementation improved the clinical severity score, with the reduction maximized at 48 hours after treatment. The recommended dosage of 15 mg/kg/dose has been demonstrated to be effective with minimal side effects.