The Role of Some Vitamins in Respiratory-related Viral Infections: A Narrative Review

Jae-Hee Park; Yunjung Lee; Mijoo Choi; Eunju Park

doi:10.7762/cnr.2023.12.1.77

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The Role of Some Vitamins in Respiratory-related Viral Infections: A Narrative Review

Clinical Nutrition Research 2023;12(1):77-89.
Published online: January 31, 2023

DOI: https://doi.org/10.7762/cnr.2023.12.1.77

Department of Food and Nutrition, Kyungnam University, Changwon 51767, Korea.

Correspondence to Eunju Park. Department of Food and Nutrition, Kyungnam University, 7 Kyungnamdaehak-ro, Changwon 51767, Korea. pej@kyungnam.ac.kr

• Received: January 12, 2023 • Revised: January 19, 2023 • Accepted: January 25, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
NOTES
REFERENCES

ABSTRACT

This study aimed to find out the effect of vitamins on respiratory-related viral infections, including coronavirus disease 2019 (COVID-19), through the literature reviews. From January 2000 to June 2021, the studies (cohort studies, cross-sectional studies, case-control studies, randomized control trials) related to vitamins (vitamin A, D, E, C, B₆, folate, and B₁₂) and COVID-19/severe acute respiratory syndrome/Middle East respiratory syndrome/cold/influenza were selected from the PubMed, Embase, and Cochrane libraries and analyzed. The relationship between vitamins and virus-related respiratory diseases was identified. Through the review, 39 studies were selected on vitamin D, one study on vitamin E, 11 studies on vitamin C, and 3 studies on folate. Regarding COVID-19, 18 studies on vitamin D, 4 studies on vitamin C, and 2 studies on folate showed significant effects of the intake of these nutrients in preventing COVID-19. Regarding colds and influenza, 3 studies on vitamin D, 1 study on vitamin E, 3 studies on vitamin C, and 1 study on folate demonstrated that the intake of these nutrients significantly prevents these diseases. Therefore, this review suggested the intake of vitamins D, E, C, and folate is important for preventing respiratory diseases related to viruses, such as COVID-19, colds, and influenza. The relationship between these nutrients and virus-related respiratory diseases should be continuously monitored in the future.
Keywords: COVID-19; Vitamins; Respiratory tract infection; Virus

INTRODUCTION

Since the coronavirus disease 2019 (COVID-19) outbreak in 2019, the global death toll has approached 6 million, and the pandemic, now in its third year, is not over [1]. The new coronavirus, the causative agent of COVID-19, is a family of RNA viruses [2]. RNA viruses are considered to have high mutation rates and frequent mutations [3]. Therefore, it is not easy to manufacture COVID-19-related vaccines or therapeutics. Among the top 10 infectious diseases that have caused the most deaths in the world (Spanish flu, Asian flu, Hong Kong flu, 7th cholera epidemic, swine influenza, Ebola, Congo measles, West African meningitis, and severe acute respiratory syndrome [SARS]), excluding cholera and meningitis, the remaining diseases are infectious diseases caused by RNA viruses. Currently, there is no specific treatment for coronavirus infection. In early 2020, the World Health Organization (WHO) declared that SARS-coronavirus 2 had established a pandemic infection and was added to the WHO list of blueprint priority diseases [4].

In 2020, the COVID-19 guidelines published by the WHO, the United Nations Food and Agriculture Organization, the European Food Information Commission, the Centers for Disease Control and Prevention, and the American Nutrition Society identified 4 common nutritional issues. 1) Eat foods that improve immune function, such as vitamins, minerals, dietary fiber, and antioxidants, from fresh, not processed foods. 2) Maintain an adequate intake of minerals (copper, iron, zinc) and vitamins (A, B₆, B₁₂, C, D, and folate) directly involved in immune function. 3) Eat whole grains and healthy fats, such as omega-3 fatty acids and nuts. 4) Avoid the intake of high-carbohydrate, high-fat, high-salt foods, alcohol, and frozen foods.

Some nutrients were reported to be actively involved in the proper functioning and strengthening of the immune system, including dietary protein, omega-3 fatty acids, vitamins A, D, E, B₁, B₆, B₁₂, and C. Supplementation with some of these dietary components was also reported to be effective in improving the health status of patients with viral infections [5]. Viral infections are characterized by compromised immune function and deficient micronutrient stores, particularly vitamins, including vitamins A, B₆, B₁₂, C, D, and E [6].

Therefore, based on the studies showing that vitamins are effective in preventing COVID-19, this study attempted to investigate the effects of vitamins on respiratory-related viral infections, including COVID-19, through a review.

MATERIALS AND METHODS

Data extraction

Research searches were performed by 4 independent reviewers, focusing on literature published from January 2000 to June 2021 in the PubMed, Embase, and Cochrane libraries. To identify the publications, individual nutrients and COVID-19/SARS/Middle East respiratory syndrome (MERS)/cold/influenza descriptors were adopted. The articles only written in English, Korean, and Japanese were reviewed. The target nutrients were vitamins A, D, E, C, B₆, folate, and B₁₂.

Data selection

The selection criteria for literature in this review were cross-sectional studies, cohort studies, case-controlled studies, and randomized clinical trials (RCTs). The exclusion criteria were: in vitro laboratory research, cell experiments, animal experiments, reviews, systematic literature reviews, meta-analysis studies, and conference proceedings. The lists of bibliographical references of the relevant studies were examined to identify potentially eligible studies. The publications were managed in Rayyan to remove duplicates and apply the inclusion criteria. Whether publications met the selection criteria or not was determined by reviewing the titles and abstracts of the searched papers. When it was difficult to judge a paper based on the title and abstract alone, the text was reviewed to decide whether to select the paper. Through this process, the selected articles were re-examined, and the finally selected papers were included in the review.

RESULTS

A search for individual nutrients and respiratory-related viral infections in the PubMed, Embase, and Cochrane libraries found 168 papers on vitamin A, 982 papers on vitamin D, 431 papers on vitamin E, 901 papers on vitamin C, 151 papers on vitamin B₆, 220 papers on folate, and 167 papers on vitamin B₁₂ (Figure 1). Among these publications, only studies related to cohort studies, cross-sectional studies, case-controlled studies, and RCTs were selected.

Figure 1

Flow diagram of study selection for systematic review of each nutrient.

Vitamin A

Of the total 168 studies on vitamin A, 156 were not related to COVID-19/SARS/MERS/cold/influenza, and 2 animal studies, 3 systematic reviews, and 7 reviews were excluded. Therefore, no cohort studies, cross-sectional studies, case-control studies, or RCTs of vitamin A were found, so a review of vitamin A could not be performed (Figure 1A).

Vitamin D

A total of 982 articles related to vitamin D were found. Among them, 877 articles were excluded by reviewing the title and abstract, and 2 in vitro research studies, 3 meta-analyses, 21 systemic reviews, and 40 reviews were also excluded (Figure 1B). Finally, an article review was conducted on 39 studies, which were classified into 13 cohort studies [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19], 11 cross-sectional studies [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30], 6 case-control studies [31, 32, 33, 34, 35, 36], and 9 RCTs [37, 38, 39, 40, 41, 42, 43, 44, 45] (Table 1). The cohort study included 10 COVID-19-related studies and 3 respiratory disease-related studies. The subjects of the study were people infected with COVID-19 in the COVID-19 study and normal people in the study related to respiratory diseases. The cross-sectional study was classified into 9 studies on COVID-19, one study each on influenza, legionella, and pneumonia, and one study each on lung function, respiratory tract infections, and colds. The case-control study consisted of 5 COVID-19-related studies and one influenza-related study. The RCT consisted of 3 studies related to COVID-19 topics, 4 studies related to respiratory diseases, and 2 studies related to influenza. The subjects were divided into a placebo group and an experimental group and took different doses of various forms of vitamin D.

Table 1

Main characteristics of the articles evaluating the association between vitamin D and respiratory-related viral infection

Table 1
Authors	Study design	Sample size	Biomarker	Dose	Result^*	Mean or range of age (yr)	Target
Baktash et al. (2020) [7]	Cohort	70 (66.7%), COVID-19-positive group	25(OH)D	-	+	81 (79.46–81.16)	COVID-19
Baktash et al. (2020) [7]	Cohort	35 (33.3%), COVID-19-negative group	25(OH)D	-	+	81 (79.46–81.16)	COVID-19
D’Avolio et al. (2020) [8]	Cohort	107, patients who underwent a nasopharyngeal swab PCR analysis for SARS-CoV-2 and a 25(OH)D measurement	25(OH)D	-	+	73	COVID-19
Meltzer et al. (2020) [9]	Cohort	489, patients with a 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol level measured within 1 year before being tested for COVID-19 from March 3 to April 10, 2020	25(OH)D or 1,25(OH)₂D	-	+	49.2	COVID-19
Cereda et al. (2021) [10]	Cohort	129, consecutive adult COVID-19 patients hospitalized	25(OH)D	-	+	73.6 ± 13.9	COVID-19
Gavioli et al. (2021) [11]	Cohort	437, COVID-19 patients	25(OH)D	-	−	67 (56–79)	COVID-19
Hastie et al. (2021) [12]	Cohort	341,184, UK Biobank participants, of which 656 had inpatient confirmed COVID-19 infection and 203 died of COVID-19 infection	25(OH)D	-	−	37–73	COVID-19
Infante et al. (2021) [13]	Cohort	137, consecutive patients with SARS-CoV-2 infection	25(OH)D	-	+	34–89	COVID-19
Lohia et al. (2021) [14]	Cohort	270, patients with confirmed COVID-19	Vitamin D	-	−	63.81 ± 14.69	COVID-19
Orchard et al. (2021) [15]	Cohort	50, SARS-CoV-2 PCR positive hospitalizations	Vitamin D	-	+/−	60 (51.2–67.0)	COVID-19
Osman et al. (2021) [16]	Cohort	445, hospitalized patients	Vitamin D	-	+	50.8 (15–94)	COVID-19
Sabetta et al. (2010) [17]	Cohort	198, healthy adults	25(OH)D	-	+	20–88	Acute viral respiratory tract infections
Berry et al. (2011) [18]	Cohort	6,789, participants in the nationwide 1958 British birth cohort	25(OH)D	-	+	45	Respiratory infections and lung function
Brenner et al. (2020) [19]	Cohort	9,940, recruited by their general practitioners during a routine health check-up between 2000 and 2002	25(OH)D	-	+	50–75, 62.1	Respiratory disease
Ling et al. (2020) [20]	Cross-sectional	444, patients had symptoms and signs suggestive of SARS-CoV-2 infection	Cholecalciferol	Approximately ≥ 280,000 IU in a time period of up to 7 wk)	+	63–83	COVID-19
Ling et al. (2020) [20]	Cross-sectional		Serum 25(OH)D	Approximately ≥ 280,000 IU in a time period of up to 7 wk)	−	63–83	COVID-19
Abdollahi et al. (2021) [21]	Cross-sectional	118, patients with COVID-19 who were hospitalized in ICU	25(OH)D	-	+	65.05 ± 15.75	COVID-19
De Smet et al. (2021) [22]	Cross-sectional	186, severe acute respiratory syndrome coronavirus 2 infected individuals hospitalized	25(OH)D	-	Male, +	52–80	COVID-19
De Smet et al. (2021) [22]	Cross-sectional		25(OH)D	-	Female, −	52–80	COVID-19
Katz et al. (2021) [23]	Cross-sectional	884, patients positively diagnosed with COVID-19	Vitamin D	-	+	All ages	COVID-19
		31,950, patients had vitamin D deficiency
		87, patients had both vitamin D deficiency and COVID-19
Luo et al. (2021) [24]	Cross-sectional	560, individuals who underwent the physical examination program	25(OH)D	-	+	Control, 49–60	COVID-19
Luo et al. (2021) [24]	Cross-sectional	335, COVID-19 patients	25(OH)D	-	+	COVID-19, 43–64	COVID-19
Nasiri et al. (2021) [25]	Cross-sectional	329, confirmed cases of COVID-19	Vitamin D	-	+/−	64.7 ± 18.5 (15–99)	COVID-19
Meoli et al. (2021) [26]	Cross-sectional	735, adolescents enrolled during the compulsory military fitness-for-duty evaluation	25(OH)D	-	−	18–19	COVID-19
Pugach and Pugach (2021) [27]	Cross-sectional	10 countries	25(OH)D	-	+	37.8–47.8	COVID-19
Yadav et al. (2021) [28]	Cross-sectional	37 countries	Vitamin D	-	+	-	COVID-19
Pletz et al. (2014) [29]	Cross-sectional	101, control	25(OH)D, 1,25(OH)₂D	-	−	Control, 59.43	Influenza
		50, influenza			+	Influenza, 60.13	Legionella
		49, legionella				Legionella, 62.65	Streptococcus pneumoniae
		100, Streptococcus pneumoniae				Streptococcus pneumoniae, 57.41
Rafiq et al. (2018) [30]	Cross-sectional	6,138, participants in the NEO study	25(OH)D	-	BMI > 30, +	45–65	Lung function, airway inflammation, common colds
Abdollahi et al. (2021) [31]	Case-control	201, patients with coronavirus infection	25(OH)D	-	+	Case, 48	COVID-19
Abdollahi et al. (2021) [31]	Case-control	201, controls	25(OH)D	-	+	Control, 46.34	COVID-19
Al-Daghri et al. (2021) [32]	Case-control	138, RT-PCR-confirmed SARS-CoV-2 positive	25(OH)D	-	+	43 ± 15	COVID-19
Al-Daghri et al. (2021) [32]	Case-control	82, negative controls	25(OH)D	-	+	43 ± 15	COVID-19
Alguwaihes et al. (2021) [33]	Case-control	150, SARS-CoV-2 (+)	25(OH)D	-	+	56.6 ± 16.2	COVID-19
Alguwaihes et al. (2021) [33]	Case-control	72, SARS-CoV-2 (−)	25(OH)D	-	+	56.6 ± 16.2	COVID-19
Hernández et al. (2021) [34]	Case-control	197, COVID-19 with confirmed COVID-19, COVID-19 patients on oral vitamin D supplements for more than 3 mon, 197 control	25(OH)D	Cholecalciferol, 25,000 IU/monthly in 10 cases, 5,600 IU/weekly in 1, and calcifediol 0.266 mg/monthly in 8 patients were on	+	COVID-19 patients, 61 (47.5–70.0)	COVID-19
						COVID-19 patients + vitamin D supplementation, 60 (59.0–75.0)
						Controls, 61 (56.0–66.0)
Ye et al. (2021) [35]	Case-control	80, healthy controls and 62 patients diagnosed with COVID-19	25(OH)D	-	+	Control, 42 (31–52)	COVID-19
Ye et al. (2021) [35]	Case-control		25(OH)D	-	+	Case 43, (32–59)	COVID-19
Nanri et al. (2017) [36]	Case-control	179, cases who reported influenza diagnosis	25(OH)D	-	−	37.6 ± 11.6	Influenza
Nanri et al. (2017) [36]	Case-control	353, participants who did not reported influenza diagnosis	25(OH)D	-	−	37.6 ± 11.6	Influenza
Rastogi et al. (2020) [37]	RCT	16, vitamin D supplementation group	25 (OH)D	60,000 IU/day, 7 day	+	Intervention group, 50	COVID-19
Rastogi et al. (2020) [37]	RCT	24, control group for asymptomatic and mildly symptomatic SARS-CoV-2 positive individuals	25 (OH)D	60,000 IU/day, 7 day	+	Control group, 47.5	COVID-19
Ohaegbulam et al. (2020) [38]	RCT	2, vitamin D-high dose	Vitamin D	1,000 IU cholecalciferol, 50,000 IU ergocalciferol, 1 mon	+	Vitamin D-high dose, 41, 57	COVID-19
Ohaegbulam et al. (2020) [38]	RCT	2, vitamin D-standard dose	Vitamin D	1,000 IU cholecalciferol, 50,000 IU ergocalciferol, 1 mon	+	Vitamin D-standard dose, 74, 53	COVID-19
Murai et al. (2021) [39]	RCT	119, vitamin D₃ group	Mortality rate	200,000 IU, 4 mon	−	200,000 IU of vitamin D₃ 56.5 or placebo 56	COVID-19
Murai et al. (2021) [39]	RCT	118, placebo group	Mortality rate	200,000 IU, 4 mon	−	200,000 IU of vitamin D₃ 56.5 or placebo 56	COVID-19
Rees et al. (2013) [40]	RCT	399, vitamin D3 group	Cold, influenza prevalence	Vitamin D₃ (1,000 IU/day) + Ca (1,200 mg/day)	−	Vitamin D3 group, 57.9	Upper respiratory tract
Rees et al. (2013) [40]	RCT	360, placebo group	Cold, influenza prevalence	Vitamin D₃ (1,000 IU/day) + Ca (1,200 mg/day)	−	Placebo group, 57.8	Upper respiratory tract
Aglipay et al. (2017) [41]	RCT	354, vitamin D dose 400 IU/d	No. of subjects	Vitamin D 400 IU/d or 2,000 IU/d, 4 mon	−	Vitamin D dose 400 IU/d, 2.76	Viral upper respiratory tract infections
Aglipay et al. (2017) [41]	RCT	349, vitamin D dose 2,000 IU/d	No. of subjects	Vitamin D 400 IU/d or 2,000 IU/d, 4 mon	−	Vitamin D dose 2,000 IU/d, 2.70	Viral upper respiratory tract infections
Shimizu et al. (2018) [42]	RCT	105, placebo group	25(OH)D	10 μg/, 16 wk	Prevalence, −	Placebo, 52.6 ± 6.7	Upper respiratory tract infection
Shimizu et al. (2018) [42]	RCT	110, 25(OH)D group	25(OH)D	10 μg/, 16 wk	Duration, +	25(OH)D group, 52.8 ± 6.2	Upper respiratory tract infection
Loeb et al. (2019) [43]	RCT	650, vitamin D group	25(OH)D	14,000 U/wk, 8 mon	−	Vitamin D, 8.6	Respiratory infections
Loeb et al. (2019) [43]	RCT	650, placebo group	25(OH)D	14,000 U/wk, 8 mon	−	Placebo, 8.4	Respiratory infections
Urashima et al. (2014) [44]	RCT	148, vitamin D3 group	Influenza A prevalence	2,000 IU/day, 2 mon	−	-	Influenza A
Urashima et al. (2014) [44]	RCT	99, placebo group	Influenza A prevalence	2,000 IU/day, 2 mon	−	-	Influenza A
Zhou et al. (2018) [45]	RCT	168, low dose vitamin D	Person infected with influenza A	400 IU or 1,200 IU, 4 mon	+	Low dose vitamin D, 7.7 ± 2.5	Seasonal influenza A
Zhou et al. (2018) [45]	RCT	164, high dose vitamin D	Person infected with influenza A	400 IU or 1,200 IU, 4 mon	+	High dose vitamin D, 8.0 ± 2.7	Seasonal influenza A

COVID-19, coronavirus disease 2019; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; 25(OH)D, 25-hydroxyvitamin D; ICU, intensive care unit; NEO, Netherlands Epidemiology of Obesity; BMI, body mass index; RT-PCR, reverse transcription polymerase chain reaction; RCT, randomized control trial.

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

Vitamin E

We identified 431 studies related to vitamin E in our database. Of these, 415 papers were excluded by reviewing the study titles and abstracts. Only one case was eligible for a literature review, with exclusion of 6 animal experiments, 2 systematic reviews, and 7 reviews (Figure 1C, Table 2). The eligible study was an RCT study to confirm the efficacy of vitamin E in respiratory infections [46].

Table 2

Main characteristics of included article evaluated the association between vitamin E and respiratory-related viral infection

Table 2
Authors	Study design	Sample size	Biomarker	Dose	Result^*	Mean or range of age (yr)	Target
Meydani et al. (2004) [46]	RCT	70 (66.7%), COVID-19-positive group	Incidence, No. of subjects and No. of days with respiratory infections (upper and lower), and No. of new antibiotic prescriptions	Vitamin E 200 IU	+	Vitamin E, 84.7 or placebo, 84.3	Respiratory infection
Meydani et al. (2004) [46]	RCT	35 (33.3%), COVID-19-negative group		Vitamin E 200 IU	+	Vitamin E, 84.7 or placebo, 84.3	Respiratory infection

COVID-19, coronavirus disease 2019.

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

Vitamin C

In vitamin C, 901 papers were searched (Figure 1D), and 855 papers were excluded based on the titles and abstracts. A total of 11 documents were used in the study after excluding 2 in vitro studies, 3 animal experiments, 5 meta-analyses, 5 systematic reviews, one mixed meta-analysis and systematic review, and 19 literature reviews (Table 3). Of these, 3 cross-sectional studies were COVID-19-related studies [47, 48, 49], and 8 RCTs included 3 studies related to COVID-19 [50, 51, 52] and 5 studies related to the common cold [53, 54, 55, 56, 57].

Table 3

Main characteristics of included article evaluated the association between VC and respiratory-related viral infection

Table 3
Authors	Study design	Sample size	Biomarker	Dose	Result^*	Mean or range of age (yr)	Target
Xing et al. (2021) [47]	Cross-sectional	25, COVID-19 patients treated with VC	VC	Patients with COVID-19: IV VC at a dose of 100 mg/kg/day	+	Patients treated with VC (n = 39)	COVID-19
		6, COVID-19 patients				Patients treated without VC (n = 35.63), Healthy (n = 31.42)
		51, healthy volunteers
Zhao et al. (2021) [48]	Cross-sectional	6, severe	Inflammatory response, immune	Severe, 162.7 mg/kg/days	+	Severe, 56 Critical, 63	COVID-19
Zhao et al. (2021) [48]	Cross-sectional	6, critical	Inflammatory response, immune	Critical, 178.6 mg/kg/days	+	Severe, 56 Critical, 63	COVID-19
Zhao et al. (2021) [49]	Cross-sectional	55, HDIVC group	No. of patients, duration of systemic inflammatory response syndrome	100 mg/kg/day	−	HDIVC, 36	COVID-19
Zhao et al. (2021) [49]	Cross-sectional	55, control group		100 mg/kg/day	−	Control, 36	COVID-19
Zhang et al. (2021) [50]	RCT	27, severe SARS-CoV-2-related pneumonia. HDIVC group	Mortality, P/F ratio, IL-6	IV VC 24 g	+	HDIVC, 66.7	COVID-19
Zhang et al. (2021) [50]	RCT	29, placebo group	Mortality, P/F ratio, IL-6	IV VC 24 g	+	Control, 66.3	COVID-19
Thomas et al. (2021) [51]	RCT	50, usual care	50% reduction in symptoms	Ascorbic acid 8,000 mg, Zinc gluconate 50 mg, Ascorbic acid 8,000 mg + Zinc gluconate 50 mg	−	45.2	COVID-19
		48, ascorbic acid				Standard of care, 42.0
		58, zinc gluconate				Ascorbic acid only, 45.6
		58, ascorbic acid + zinc gluconate				Zinc only, 44.1
						Ascorbic acid with zinc, 48.7
Kumari et al. (2020) [52]	RCT	75, intervention (standard of care + IV VC)	No. of days required for treatment, hospital stay	VC 50 mg/kg/day	+	Intervention, 52	COVID-19
Kumari et al. (2020) [52]	RCT	75, placebo (standard of care)	No. of days required for treatment, hospital stay	VC 50 mg/kg/day	+	Placebo, 53	COVID-19
Audera et al. (2001) [53]	RCT	42, VC 0.03 g	Daily symptoms, severity	VC 0.03 g	−	VC 0.03 g, 38.6	Common cold
		47, VC 1 g		VC 1 g		VC 1 g, 40.1
		50, VC3 g		VC 3 g		VC 3 g, 39.9
		45, VC 3 g + additives		VC 3 g + bioflavenoids 75 mg, rutin 150 mg, hisperidin 150 mg, rose hip extract 750 mg acerola 150 mg		VC 3 g + additives, 45.1
Van Straten and Josling (2002) [54]	RCT	84, active treatment	Recorded any common cold infections and symptoms in a daily diary	VC 500 mg	+	Active treatment, 47.7	Common cold
Van Straten and Josling (2002) [54]	RCT	84, placebo		VC 500 mg	+	Placebo, 48.5	Common cold
Sasazuki et al. (2006) [55]	RCT	120, 50 mg of VC	Symptom, cold duration	VC 50/500 mg	−	Low dose, 58.7	Common cold
Sasazuki et al. (2006) [55]	RCT	144, 500 mg of VC	Symptom, cold duration	VC 50/500 mg	−	High dose, 56.3	Common cold
Johnston et al. (2014) [56]	RCT	15, VC	Plasma vitamin, cold episodes, duration, cold duration and severity	VC 1,000 mg	+	VC, 23.0	Cold incidence
Johnston et al. (2014) [56]	RCT	13, placebo		VC 1,000 mg	+	Placebo, 23.2	Cold incidence
Kim et al. (2020) [57]	RCT	695, VC group	Diagnosis of common colds	VC 6,000 mg	+	< 19, 491	Common cold
		749, placebo group				20–22, 878
						> 23, 75

IV, intravenous; VC, vitamin C; COVID-19, coronavirus disease 2019; HDIVC, high-dose intravenous vitamin C; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; P/F, PaO₂/FiO₂; IL, interleukin; RCT, randomized control trial.

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

Vitamin B₆

For vitamin B₆, 151 articles were searched, and 147 articles were excluded by reviewing the titles and abstracts. One systematic review and 3 reviews were also excluded (Figure 1E). Thus, no articles were eligible for a literature review.

Folate

A total of 220 articles on folic acid were searched (Figure 1F). As a result of reviewing the titles and abstracts, 217 were excluded. Three papers were classified into 2 cross-sectional studies and one cohort study and underwent literature reviews (Table 4).

Table 4

Main characteristics of included article evaluated the association between folate and respiratory-related viral infection

Table 4
Authors	Study design	Sample size	Biomarker	Dose	Result^*	Mean or range of age (yr)	Target
Acosta-Elias and Espinosa-Tanguma (2020) [58]	Cross-sectional	94, pregnant women	The likelihood of requiring hospitalization for SARS-CoV-2 infection	-	+	-	COVID-19
		137, non-pregnant in 2009 A-H1N1 pandemic					A-H1N1 pandemic
		908 of those patients were non-pregnant women in reproductive age
		55, pregnant women in COVID-19 pandemic
Hamer et al. (2009) [59]	Cross-sectional	352	Vitamins and minerals concentration	-	+	Men, 75.8	Respiratory infections
Hamer et al. (2009) [59]	Cross-sectional	352	Vitamins and minerals concentration	-	+	Women, 73.7	Respiratory infections
Itelman et al. (2020) [60]	Cohort	162	Blood folate concentration	-	+	52	COVID-19

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

The cross-sectional studies consisted of one study on COVID-19 [58] and A-H1N1 and one study on respiratory infections [59]. A cohort study related to COVID-19 was conducted [60].

Vitamin B₁₂

The search yielded 167 studies related to vitamin B₁₂, and among them, 164 papers were excluded by reviewing the titles and abstracts (Figure 1G). No papers underwent a literature review because one systematic review and 2 reviews were excluded.

DISCUSSION

This review was conducted to investigate the effects of vitamins on COVID-19/SARS/MERS/cold/influenza-related viral infections.

Eighteen of the 27 studies related to vitamin D and COVID-19 reported the effect of low levels of vitamin D in the blood on the occurrence of COVID-19. The 25-hydroxyvitamin D (25(OH)D) blood levels of COVID-19-positive patients were reported to be lower than 10–11.1 ng/mL [8, 11]. Patients with vitamin D deficiency have seemed more than 5 times higher to be infected with COVID-19 than patients without vitamin D deficiency [23]. In addition, it was reported that for every 1% increase in the prevalence of vitamin D deficiency, the number of deaths from COVID-19 increases by 55 per million [27]. Serum 25(OH)D concentrations in COVID-19-positive patients were 25.95 ± 14.56 ng/mL [20]. Ye et al. [35] identified a potential threshold of serum 25(OH)D of 41.19 nmol/L for COVID-19 prevention. COVID-19-positive patients were hospitalized for a prolonged period if they had low vitamin D levels at the time of admission [25]. It has been reported that the normalization of serum 25(OH)D levels shortened hospital stays and reduced inflammatory biomarkers [37]. Of the 16 subjects who consumed 60,000 IU/d of vitamin D for 7 days, 10 tested negative for COVID-19, and only 5 of the 24 subjects who did not take vitamin D tested negative for COVID-19 [37]. However, 9 studies reported that vitamin D had no significant effect on COVID-19 prevention. Among the 12 studies related to respiratory diseases, 5 studies reported that vitamin D had a significant effect on the prevention of respiratory diseases. Serum 25(OH)D concentrations above 38 ng/mL lowered the risk of developing acute viral respiratory infections by about half [17], and mortality from respiratory diseases increased significantly as 25(OH)D levels fell below 50 nmol/L [19]. The group that consumed 1,200 IU of vitamin D for 4 months (8.0 ± 2.7 years) had a significantly lower number of influenza A infections than the group that consumed 400 IU (7.7 ± 2.5 years) [45].

Vitamin E has not been studied for its effect on COVID-19, and only one study was related to respiratory infections. The number of respiratory infections was significantly lower in the vitamin E intake group (200 IU, 84.7 years) than in the vitamin E non-intake group (84.3 years) [46].

Vitamin C reduced COVID-19-positive diagnoses in 4 out of 6 studies involving COVID-19. The vitamin C concentration in the plasma of COVID-19 patients was 5 times lower than that of healthy people (p < 0.001) [47], and C-reactive protein levels were significantly reduced when 162.7–178.6 mg/kg/day of vitamin C was consumed (p < 0.05), and lymphocyte counts, CD4+ T-cells, and respiratory function were significantly increased (p < 0.05) [48]. The intravenous administration of 24 g of vitamin C reduced COVID-19-induced mortality and interleukin-6 (p = 0.04) levels [50], an inflammatory index. The duration of symptoms and duration of hospitalization were significantly reduced when 50 mg/kg/day of vitamin C was supplied in the same way (p <0.001) [52]. In the studies on vitamin C and colds, 3 out of 5 studies showed the effect of reducing the cold diagnosis rate and the duration of cold symptoms by a vitamin C intake of 500–6,000 mg [54, 56, 57].

Two studies related to folate and COVID-19 found that folate had a positive effect on COVID-19 prevention. Folate supplementation was a factor in protecting patients from COVID-19 infection [58]. The reason is that folate inhibits furin protease, which is necessary for viruses to enter host cells, and folate inactivates protease 3C-like protease, a protein that the virus needs to replicate [58]. Indeed, it has been reported that blood folate levels were low in patients with severe COVID-19 (p = 0.014) [60]. A study related to folate and respiratory infections also reported that a deficiency in micronutrients, such as folate, was closely related to the occurrence of pneumonia or cold (p < 0.001) [59]. In this study, no publications on the relationship between vitamins and SARS/MERS were found during the study period.

Thus, the results of this study found that maintaining normal blood levels of vitamin D, vitamin E, vitamin C, and folate had a positive effect on the prevention of COVID-19/cold/influenza. This effect is thought to be possible by maintaining normal blood levels through the daily intake of these nutrients. However, due to the limited period of this study, additional research publications related to these vitamins and COVID-19/SARS/MERS/cold/influenza will need to be collected, analyzed and evaluated periodically in the future.

Amway corporation

NOTES

Funding: This work was supported by the Amway corporation.

Conflict of Interest: The authors declare that they have no competing interests.

Author Contributions:

Conceptualization: Park E.
Funding acquisition: Park E.
Investigation: Park JH, Lee Y, Choi M.
Methodology: Lee Y.
Project administration: Lee Y.
Supervision: Park EJ.
Writing - original draft: Park JH, Lee Y, Choi M.
Writing - review & editing: Park JH.

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The Role of Some Vitamins in Respiratory-related Viral Infections: A Narrative Review

Clin Nutr Res. 2023;12(1):77-89. Published online January 31, 2023

DOI: https://doi.org/10.7762/cnr.2023.12.1.77

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The Role of Some Vitamins in Respiratory-related Viral Infections: A Narrative Review

Clin Nutr Res. 2023;12(1):77-89. Published online January 31, 2023

DOI: https://doi.org/10.7762/cnr.2023.12.1.77

Figure

The Role of Some Vitamins in Respiratory-related Viral Infections: A Narrative Review

Figure 1 Flow diagram of study selection for systematic review of each nutrient.

Figure 1

The Role of Some Vitamins in Respiratory-related Viral Infections: A Narrative Review

Streptococcus pneumoniae 100, Streptococcus pneumoniaeStreptococcus pneumoniae, 57.41Rafiq et al. (2018) [30]Cross-sectional6,138, participants in the NEO study25(OH)D-BMI > 30, +45–65Lung function, airway inflammation, common coldsAbdollahi et al. (2021) [31]Case-control201, patients with coronavirus infection25(OH)D-+Case, 48COVID-19201, controlsControl, 46.34Al-Daghri et al. (2021) [32]Case-control138, RT-PCR-confirmed SARS-CoV-2 positive25(OH)D-+43 ± 15COVID-1982, negative controlsAlguwaihes et al. (2021) [33]Case-control150, SARS-CoV-2 (+)25(OH)D-+56.6 ± 16.2COVID-1972, SARS-CoV-2 (−)Hernández et al. (2021) [34]Case-control197, COVID-19 with confirmed COVID-19, COVID-19 patients on oral vitamin D supplements for more than 3 mon, 197 control25(OH)DCholecalciferol, 25,000 IU/monthly in 10 cases, 5,600 IU/weekly in 1, and calcifediol 0.266 mg/monthly in 8 patients were on+COVID-19 patients, 61 (47.5–70.0)COVID-19COVID-19 patients + vitamin D supplementation, 60 (59.0–75.0)Controls, 61 (56.0–66.0)Ye et al. (2021) [35]Case-control80, healthy controls and 62 patients diagnosed with COVID-1925(OH)D-+Control, 42 (31–52)COVID-19Case 43, (32–59)Nanri et al. (2017) [36]Case-control179, cases who reported influenza diagnosis25(OH)D-−37.6 ± 11.6Influenza353, participants who did not reported influenza diagnosisRastogi et al. (2020) [37]RCT16, vitamin D supplementation group25 (OH)D60,000 IU/day, 7 day+Intervention group, 50COVID-1924, control group for asymptomatic and mildly symptomatic SARS-CoV-2 positive individualsControl group, 47.5Ohaegbulam et al. (2020) [38]RCT2, vitamin D-high doseVitamin D1,000 IU cholecalciferol, 50,000 IU ergocalciferol, 1 mon+Vitamin D-high dose, 41, 57COVID-192, vitamin D-standard doseVitamin D-standard dose, 74, 53Murai et al. (2021) [39]RCT119, vitamin D₃ groupMortality rate200,000 IU, 4 mon−200,000 IU of vitamin D₃ 56.5 or placebo 56COVID-19118, placebo groupRees et al. (2013) [40]RCT399, vitamin D3 groupCold, influenza prevalenceVitamin D₃ (1,000 IU/day) + Ca (1,200 mg/day)−Vitamin D3 group, 57.9Upper respiratory tract360, placebo groupPlacebo group, 57.8Aglipay et al. (2017) [41]RCT354, vitamin D dose 400 IU/dNo. of subjectsVitamin D 400 IU/d or 2,000 IU/d, 4 mon−Vitamin D dose 400 IU/d, 2.76Viral upper respiratory tract infections349, vitamin D dose 2,000 IU/dVitamin D dose 2,000 IU/d, 2.70Shimizu et al. (2018) [42]RCT105, placebo group25(OH)D10 μg/, 16 wkPrevalence, −Placebo, 52.6 ± 6.7Upper respiratory tract infection110, 25(OH)D groupDuration, +25(OH)D group, 52.8 ± 6.2Loeb et al. (2019) [43]RCT650, vitamin D group25(OH)D14,000 U/wk, 8 mon−Vitamin D, 8.6Respiratory infections650, placebo groupPlacebo, 8.4Urashima et al. (2014) [44]RCT148, vitamin D3 groupInfluenza A prevalence2,000 IU/day, 2 mon−-Influenza A99, placebo groupZhou et al. (2018) [45]RCT168, low dose vitamin DPerson infected with influenza A400 IU or 1,200 IU, 4 mon+Low dose vitamin D, 7.7 ± 2.5Seasonal influenza A164, high dose vitamin DHigh dose vitamin D, 8.0 ± 2.7

Table 1 Main characteristics of the articles evaluating the association between vitamin D and respiratory-related viral infection

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

Table 2 Main characteristics of included article evaluated the association between vitamin E and respiratory-related viral infection

COVID-19, coronavirus disease 2019.

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

Table 3 Main characteristics of included article evaluated the association between VC and respiratory-related viral infection

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

Table 4 Main characteristics of included article evaluated the association between folate and respiratory-related viral infection

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^*+: significant effect on the prevention of respiratory-related viral infection; −: no significant effect on the prevention of respiratory-related viral infection.

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The Role of Some Vitamins in Respiratory-related Viral Infections: A Narrative Review

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INTRODUCTION

MATERIALS AND METHODS

RESULTS

Flow diagram of study selection for systematic review of each nutrient.

Main characteristics of the articles evaluating the association between vitamin D and respiratory-related viral infection

Main characteristics of included article evaluated the association between vitamin E and respiratory-related viral infection

Main characteristics of included article evaluated the association between VC and respiratory-related viral infection

Main characteristics of included article evaluated the association between folate and respiratory-related viral infection

DISCUSSION

NOTES

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