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Table of Contents
ORIGINAL ARTICLE
Year : 2023  |  Volume : 22  |  Issue : 1  |  Page : 117-123  

Association of vitamin D with the severity of disease and mortality in COVID-19: Prospective study in central India


1 Department of General Medicine, AIIMS, Nagpur, Maharashtra, India
2 Department of Biochemistry, University College of Medical Sciences, New Delhi, India
3 Department of Virology, ICMR-NICED, Kolkata, West Bengal, India
4 Department of ENT, AIIMS, Nagpur, Maharashtra, India

Date of Submission22-Jan-2022
Date of Decision18-Feb-2022
Date of Acceptance06-Jun-2022
Date of Web Publication24-Jan-2023

Correspondence Address:
Bharatsing Deorao Rathod
Department of General Medicine, AIIMS, Plot No 2, Sector 20, MIHAN, Nagpur, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aam.aam_21_22

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   Abstract 


Background: Many factors have been proposed to be associated with the severity of disease and mortality in COVID-19. Vitamin D had recently been reviewed as one of these factors. Aim and Objectives: To evaluate the association between Vitamin D and the disease severity and mortality in COVID-19. Materials and Methods: After approval from Institutional Ethics Committee, this prospective cohort study was carried out in selected tertiary care teaching medical institutes of Central India. Participants were COVID-19 patients of the age group of 18 years and above admitted during the study period. They were categorized into four groups as asymptomatic (Group A), mild (Group B), moderate (Group C), and severe (Group D) based on clinical symptoms, respiratory rate, oxygen saturation, and chest imaging. Serum level of Vitamin 25(OH) D was measured using chemiluminescent immunoassay. The outcome of the disease was classified as recovery and death during hospitalization. The association of sociodemographic and medical characteristics with treatment outcome was studied using an appropriate statistical test. A full logistic regression model was built for the assessment of the relationship between treatment outcomes with Vitamin D level. Further, one receiver operating characteristic curve was developed to examine the prognostic significance of Vitamin D levels in COVID-19 patients. Results: Out of 748 enrolled patients, 44 (5.88%), had severe disease (Group D). A total of 721 cases (96.39%) recovered and were discharged, whereas 27 (3.61%) died during hospitalization. Mean Vitamin D level was found to be significantly different in discharged patients compared to those who were deceased. Increasing age-adjusted odds ratio (AOR) (95% confidence interval [CI]=1.07 [1.02–1.12]), known hypertension AOR (95%CI) = 3.38 (1.13–10.08), and diabetes mellitus AOR (95%CI) =28.5 (6.04–134.13) were found to be significant predictors of death among COVID-19 patients. Increasing Vitamin D level was found to be protective against COVID-19-related death (AOR (95% CI = 0.87 [0.80–0.94]). Conclusion: Vitamin D was significantly associated with the disease severity and mortality in COVID-19.

   Abstract in French 

Résumé
Contexte: Il a été proposé que de nombreux facteurs soient associés à la gravité de la maladie et de la mortalité dans le Covid - 19. La vitamine D avait récemment été examinée comme l'un de ces facteurs. Objectif et objectifs: évaluer l'association entre la vitamine D et la gravité de la maladie et la mortalité dans le Covid-19. Matériel et méthodes: Après l'approbation du comité d'éthique institutionnel, cette étude de cohorte prospective a été réalisée dans des instituts médicaux d'enseignement des soins tertiaires de l'Inde centrale. Les participants étaient des patients Covid-19 du groupe d'âge de 18 ans et plus admis au cours de la période d'étude. Ils ont été classés en quatre groupes comme asymptomatiques (groupe A), légers (groupe B), modérés (groupe C) et sévères (groupe D) sur la base des symptômes cliniques, de la fréquence respiratoire, de la saturation en oxygène et de l'imagerie thoracique. Niveau sérique de la vitamine 25 (OH) DWAS mesuré en utilisant l'immunodosage chimioluminescent. L'issue de la maladie a été classée comme récupération et décès pendant l'hospitalisation. L'association des caractéristiques sociodémographiques et médicales avec les résultats du traitement a été étudiée à l'aide d'un test statistique approprié. Un modèle de régression logistique complet a été construit pour l'évaluation de la relation entre les résultats du traitement au niveau de la vitamine D. De plus, une courbe caractéristique de fonctionnement du récepteur a été développée pour examiner la signification pronostique des niveaux de vitamine D chez les patients COVID-19. Résultats: Sur 748 patients inscrits, 44 (5,88%), avaient une maladie grave (groupe D). Un total de 721 cas (96,39%) ont récupéré et ont été libérés, tandis que 27 (3,61%) sont décédés pendant l'hospitalisation. Le niveau moyen de la vitamine D s'est révélé significativement différent chez les patients libérés par rapport à ceux qui ont été décédés. Augmentation du rapport de cotes ajusté à l'âge (AOR) (intervalle de confiance à 95% [IC] = 1,07 [1,02–1,12]), hypertension connue AOR (IC à 95%) = 3,38 (1,13–10,08) et diabète mellite aor (IC 95% ) = 28,5 (6,04–134.13) se sont révélés être des prédicteurs significatifs de la mort chez les patients COVID-19. L'augmentation du niveau de vitamine D s'est avérée protectrice contre la mort liée au Covid - 19 (AOR (IC à 95% = 0,87 [0,80–0,94]). Conclusion: La vitamine D était significativement associée à la gravité de la maladie et à la mortalité dans le Covid - 19.
Mots clés: Covid - 19, tempête de cytokines, mortalité, gravité, vitamine D

Keywords: COVID-19, cytokine storm, mortality, severity, Vitamin D


How to cite this article:
Rathod BD, Ahirwar AK, Banerjee S, Joshi PP, Khot RS, Dube AH, Kumbhalkar SD, Dabhekar SB. Association of vitamin D with the severity of disease and mortality in COVID-19: Prospective study in central India. Ann Afr Med 2023;22:117-23

How to cite this URL:
Rathod BD, Ahirwar AK, Banerjee S, Joshi PP, Khot RS, Dube AH, Kumbhalkar SD, Dabhekar SB. Association of vitamin D with the severity of disease and mortality in COVID-19: Prospective study in central India. Ann Afr Med [serial online] 2023 [cited 2023 Feb 1];22:117-23. Available from: https://www.annalsafrmed.org/text.asp?2023/22/1/117/368404




   Introduction Top


The recent COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. Globally, there are more than 5,560,700 deaths including more than 487,600 deaths from India to date.[1] The prevalence is expected to increase over a period due to the possibility of subsequent waves. Many risk factors have been associated with the severity of disease and mortality in COVID-19.[2] Vitamin D plays important role in regulating components of the innate and adaptive immune systems, inflammation, and the renin-angiotensin-aldosterone system.[3],[4],[5] Aggressive inflammatory response to SARS-COV-2 can lead to “cytokine storm” correlating directly with lung injury, multi-organ failure, and unfavorable prognosis of severe COVID-19.[6],[7] In light of possible immune-enhancing effects of Vitamin D, there are recent retrospective analysis articles documenting the potential association between the severity of COVID-19 in cases of hypovitaminosis D. A systematic review found that low serum concentrations of 25(OH) D were associated with increased mortality and severity of COVID-19.[8] Recently published randomized clinical trials of supplementation of Vitamin D in COVID-19 cases have shown mixed results, some showing a decrease in intensive care unit (ICU) admission while other trials failed to show any effect on disease outcome. However, there is a lack of studies from this region regarding the same. In the absence of clear evidence, the value of either supplementing or maintaining adequate Vitamin D levels to reduce the symptom burden in those with COVID-19 infection remains unclear. Strong evidence on this issue may have important therapeutic potential in the management of COVID-19 patients and the population at risk for developing COVID-19. With this background, the current study has been carried out to estimate the mean serum Vitamin D level and to find out the association of serum Vitamin D level with the severity of disease and treatment outcome (recovery or death) among laboratory-confirmed cases of COVID-19 admitted in a tertiary care teaching medical institute of Nagpur city, Central India.


   Materials and Methods Top


This prospective cohort study was carried out in selected tertiary care teaching medical institutes of Nagpur city. Nagpur was one of the highest disease burden cities in India, especially during the second wave of COVID-19. All consecutive cases of COVID-19 hospitalized for 1 year (from July 7, 2020 to June 6, 2021) were included in this study. Patients <18-year-old, pregnant women, critically ill patients (unable to talk/give interview), not knowing Hindi/English or Marathi language, and those refusing to give consent were excluded from the study.

The participants were recruited within 24 h of their admission. The data were collected by the investigators using a predesigned structured schedule. Apart from sociodemographic information, the patients were asked about details of their current illness, past illness, comorbidities, and substance use patterns. After obtaining medical history, clinical examinations were done and recorded in the schedule. All the interview and clinical examinations were carried out maintaining COVID-19-related government protocol, i.e., social distancing and aseptic procedure. The diagnosis of COVID-19 was made by positive reverse transcriptase-polymerase chain reaction test for SARS-COV-2 from nasopharyngeal or oropharyngeal sampling. The reports of those participants who got COVID tested from any government-registered Virus Research and Diagnostic Laboratory outside the hospital were also considered valid. Blood samples were collected immediately after their recruitment using institutional standard operating procedures (SOPs), for testing complete blood count, Vitamin D level, serum ferritin, and C-reactive protein. All diagnostic tests were carried out using the validated technique in accredited laboratories maintaining SOPs. The patients were categorized into four groups as asymptomatic (Group A), mild (Group B), moderate (Group C), and severe (Group D) based on clinical symptoms, respiratory rate, oxygen saturation, and chest imaging (see definition part). Serum level of Vitamin 25(OH) D was measured by chemiluminescent immunoassay. The outcome of the disease was classified as recovery and death during hospitalization.

Operational definitions

Vitamin D status was categorized as normal (more than or equal to 30 ng/mL), Insufficiency (20–29 ng/mL), and deficiency (<20 ng/mL). The severity of COVID-19 disease was categorized according to the guidelines of the World Health Organization and as per the interim treatment guidelines issued by the Ministry of Health and Family Welfare, Government of India, based on the patient's respiratory status and oxygen saturation, cases were divided into four groups: asymptomatic, mild, moderate, and severe.[9],[10]

Asymptomatic

No symptoms. Vital parameters – stable, SpO2 ≥94%, no clinical and/or radiological evidence of lower respiratory tract infection/pneumonia.

Mild: Mild symptoms of upper respiratory tract infection, Vital parameters – stable, SpO2 ≥94%, no clinical and/or radiological evidence of lower respiratory tract infection/pneumonia.

Moderate

Any one of these (1) Respiratory rate ≥24/min (2) SpO2 ≤93%, along with symptoms like shortness of breath.

Severe

Any one of these – (1) Respiratory rate > 30/min (2) SpO2 ≤90%, along with symptoms like shortness of breath/evidence of acute respiratory distress syndrome (ARDS), respiratory failure requiring assisted ventilation, multiple-organ dysfunction syndrome (MODS).

Patients were monitored daily throughout their hospitalization course and their treatment outcome were recorded. The patients who did not take the complete course of treatment and left against medical advice were excluded from the study.

Main outcome variables include the severity of the illness and treatment outcome (death/discharge).

Ethical issues

Institutional Ethics Committee approval was obtained before initiating the study (IEC/Pharmac/2020/140 dated July 2, 2020). After approaching the study participants at their convenient time, they were explained the purpose of the study. They were included in the study after obtaining informed written consent. Anonymity and confidentiality were maintained throughout the process. Separate permission was obtained for blood collection and testing. It was ensured that they could opt-out at any time during study and that their routine services will not be hampered if they deny participating. The data were stored in the password-protected file and data security was ensured.

Statistical analysis

The study participants were distributed according to their severity of disease and treatment outcome. Vitamin D level was found to be approximately normally distributed for the study participants. The mean standard deviation (SD) value of Vitamin D was calculated in patients with different severity of the disease. The association of sociodemographic and medical characteristics with treatment outcome was studied using an appropriate statistical test. A full logistic regression model was built for the assessment of the relationship between treatment outcome with Vitamin D level in the presence of other potential confounders, using SPSS software, version 19.0 (Statistical Package for the Social Sciences Inc., Chicago, IL, USA), where the sociodemographic and biological variables (potential confounders) were entered into a multivariable logistic regression model (binary logistic) using forced entry method. Age and Vitamin D levels were entered in the model as a continuous variable, and others as a categorical variable. Further, one receiver operating characteristic (ROC) curve was developed to examine the prognostic significance of Vitamin D level in COVID-19 patients, and a cut-off of Vitamin D showing the best combination of sensitivity and specificity for predicting COVID-19-related mortality was also calculated.


   Results Top


A total of 827 patients got admitted to the respective hospital during the study period, and out of them, 766 were eligible. After excluding the participants who were lost to follow-up, a total of 748 patients were included in the study for the analysis [Figure 1]. A sizable number of participants were asymptomatic (35.2%) or had mild symptoms (48.9%) during admission. The proportion of moderately and severe symptomatic patients was 10.0% and 5.9%, respectively. Among the respondents, 721 cases (96.39%) recovered and were discharged, while 27 (3.61%) died during hospitalization. Background information revealed that the mean age (SD) of the participants was 43.85 (17.6) years, 63.6% were male, and the median (IQR) duration of hospital stay was 9 (5–10) days. The proportion of participants having diabetes mellitus, hypertension, preexisting heart, and lung diseases were 15.6%, 20.9%, 4.8%, and 5.1%, respectively. The mean Vitamin D level was 24.58 ± 9.58 ng/mL. Among the participants, 232 cases (31.02%) had Vitamin D deficiency, 259 (34.63%) cases had Vitamin D insufficiency and 257 (34.36%) cases had Vitamin D sufficiency. The distribution of mean Vitamin D levels in patients with varying severity of disease is described in [Figure 2].
Figure 1: Recruitment and assessment flowchart for the participants

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Figure 2: Distribution of average Vitamin D level in different categories of Covid-19 patients based on the severity of disease: an Error Bar diagram (n = 746)

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Mean Vitamin D level was found to be significantly different in discharged patients compared to those who are deceased [Table 1]. Demographic and medical characteristics were also compared based on treatment outcome, to identify those variables which can act as potential confounders in the relationship between Vitamin D level and treatment outcome [Table 2]. The multivariable logistic regression model was used to find out whether Vitamin D level is predicting treatment outcome in the presence of potential confounders. The model was significant as revealed by the omnibus Chi-square statistic (χ2 = 116.74, P < 0.01). This model was a good fit as evident from the nonsignificant Hosmer–Lemeshow statistic (P = 0.99). In the adjusted model, increasing age-adjusted odds ratio (AOR) (95% confidence interval [CI] = 1.07 [1.02–1.12]), known hypertension AOR (95% CI) = 3.38 (1.13–10.08), and diabetes mellitus AOR (95%CI) = 28.5 (6.04–134.13) were found to be significant predictors of death among COVID-19 patients. Increasing Vitamin D level was found to be protective against COVID-19-related death, and the association remained significant after adjusting for potential confounders (AOR 95% CI = 0.87 [0.80–0.94]). The model was able to explain 61% variance of the model as observed from Negelkarke R square. Data of two samples were deleted during regression analysis because they are outliers (the value of Vitamin D outstandingly high) [Table 2].
Table 1: Demographic and medical characteristic of the study participants categorized by outcome (n=748)

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Table 2: Association of Vitamin D level with treatment outcome among study participants: Bivariate and multivariable logistic regression (n=746)

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To examine the prognostic significance of Vitamin D levels in COVID-19 patients, a ROC curve analysis was made [Figure 3]. The ROC curve with respect to discharge versus. death of COVID-19 patients showed a possible cut-off value of 18.5, where sensitivity and specificity were found to be 88.9% and 73.6%, respectively. Considering the conventional cut-off of Vitamin D level as 20, sensitivity and specificity were calculated as 96.30% and 66.76%, respectively. The model was statistically significant and area under the curve was 0.85.
Figure 3: Predictive accuracy of low Vitamin D level in estimating unfavorable treatment outcome among Covid-19 patients (n = 746) , Area Under the Curve -0.85, 95% CI -0.78-0.91, P < 0.001

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   Discussion Top


There is wide variation in the clinical severity of COVID-19 ranging from an asymptomatic state to severe disease characterized by ARDS, respiratory failure, and MODS. In-hospital case fatality due to COVID-19 has been reported as 2%–3% by multiple studies.[11] Various factors have been proposed to affect disease severity in COVID-19. The aim of the present study was to assess the association between Vitamin D status and severity of disease and mortality in COVID-19. We found a significant difference in Vitamin D levels among discharged and death groups. There was a significant difference in age, comorbidities, inflammatory markers between discharged and death groups. Overall, these findings are consistent with the results of previous similar studies.[12],[13],[14],[15],[16] Increasing Vitamin D levels were found to be protective against COVID-19-related death, and the association remained significant after adjusting for potential confounders (AOR [95% CI = 0.87 [0.80–0.94]). A recent meta-analysis which included 35 studies investigating the association between Vitamin D status and severity of disease or mortality related to COVID-19 indicated that low Vitamin D levels, assessed at the time of hospitalization, are associated with greater COVID-19 severity and COVID-19-related mortality.[17]

Various underlying pathophysiological mechanisms have been proposed to explain the possible role of Vitamin D against SARS-COV-2 infection. Apart from its role in the maintenance of bone health and calcium-phosphorous metabolism, Vitamin D plays an important role in the immune system. It interferes with the majority of immune system cells like macrophages, T-lymphocytes, B-lymphocytes, neutrophils, and dendritic cells.[18] The active metabolite of Vitamin D inhibits T-cell activation and proliferation, also inhibits the production of pro-inflammatory cytokines, and increases the production of anti-inflammatory cytokines.[19],[20] Unrestricted immune reaction in the host can lead to a marked release of pro-inflammatory cytokines like interleukin-6 (IL-6), leading to a “cytokine storm” causing extensive tissue damage and dysfunctional coagulation.[21],[22] Cytokine storm is the main cause of death in the late stage of SARS-CoV-2 infection.[23] T regulatory lymphocytes (Tregs) provide a principal defense against uncontrolled inflammation. Treg levels have been reported to be markedly lower in severe cases of COVID-19. Increasing Treg levels might be beneficial in decreasing the severity of viral illness including COVID-19. Treg levels can be increased by Vitamin D supplementation.[24],[25] Vitamin D supplementation has reduced interleukin-6 levels in several clinical trials.[26]

Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point for SARS-CoV-2 into cells. When SARS-CoV-2 is attached to ACE2 its expression is reduced, thus causing lung injury and pneumonia.[27],[28] Vitamin D acts as a negative RAS modulator by inhibition of renin expression and stimulation of ACE2 expression. It, therefore, has a protective role against ARDS caused bySARS-CoV-2. Sufficient Vitamin D levels prevent the development of ARDS by reducing the levels of angiotensin II and increasing the level of angiotensin.[29],[30]

Vitamin D reduces coagulation abnormalities in critically ill COVID-19 patients.[31],[32],[33] Vitamin D plays a direct role in protecting the integrity of the pulmonary epithelial barrier.[34] Vitamin D deficiency has been associated with an increased risk of developing ARDS and its correction in the deficient subject may reduce the alveolar-capillary damage.[35]

There are many ongoing randomized clinical trials at present to establish the effect of Vitamin D supplementation on the severity of disease and mortality in COVID-19. A recently conducted randomized clinical trial by Murai et al. revealed that among hospitalized patients with COVID-19, a single high dose of Vitamin D3, compared with placebo, did not significantly reduce hospital length of stay.[36] Pal et al., in their systemic review and meta-analysis, identified 13 studies (10 observational, 3 randomized control trials) pooling data retrieved from 2933 COVID-19 patients.[17] They concluded that Vitamin D use in COVID-19 was significantly associated with reduced ICU admission/mortality (OR 0.41, 95% CI: 0.20, 0.81, P = 0.01, I2 = 66%, random-effects model). Similarly, Vitamin D was also found to reduce the risk of adverse outcomes (pooled OR 0.27, 95% CI: 0.08, 0.91, P = 0.03, I2 = 80%, random-effects model).

The main strength of this study was that it tried to highlight a relatively unexplored domain on the prognosis of COVID-19 patients. Further, this research captured COVID-19 patients with a wide range of disease severity and compared Vitamin D levels in patients with different disease severity. Our study has several limitations. Being a single-center study, the study has limited external validity. Further, a single measurement of Vitamin D level, and lack of control group, are some other limitations. We suggest multicenter, double-blind randomized clinical trials or cohort studies clarify the association between Vitamin D and the severity of disease and mortality in COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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