Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study
Prabowo Raharusuna*, Sadiah Priambada, Cahni Budiarti, Erdie
Agung, Cipta Budi
*Correspondence:
[email protected]
RSUD Kabupaten Sukamara
Kec. Sukamara, Kabupaten Sukamara,
Kalimantan Tengah 74171, Indonesia
April 26, 2020
Data Availability:
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
Statement of Conflict of Interest:
The authors declare no conflict of interest.
Source of Funding:
The study was not funded by external sources.
This preprint research paper has
not been peer reviewed. Electronic copy available at:
https://ssrn.com/abstract=3585561
Disclaimer: This is a preliminary study for early dissemination of results. Data are subject to changes.
KEY FINDINGS:
• Majority of the COVID-19 cases with insufficient and
deficient Vitamin D status died.
• The odds of death was higher in older and male cases with
pre-existing condition and below normal Vitamin D levels.
• When controlling for age, sex, and comorbidity, Vitamin D
status is strongly associated with COVID-19 mortality.
• Randomized controlled trials are warranted to investigate
the role of vitamin D supplementation on COVID-19 outcomes
and to establish the underlying mechanisms.
ABSTRACT
This is a retrospective cohort study which included two cohorts (active and expired) of 780 cases with laboratory-confirmed infection of SARS-CoV-2 in Indonesia. Age, sex, co-morbidity, Vitamin D status, and disease outcome (mortality) were extracted from electronic medical records. The aim was to determine patterns of mortality and associated factors, with a special focus on Vitamin D status. Results revealed that majority of the death cases were male and older and had pre-existing condition and below normal Vitamin D serum level. Univariate analysis revealed that older and male cases with pre-existing condition and below normal Vitamin D levels were associated with increasing odds of death. When controlling for age, sex, and comorbidity, Vitamin D status is strongly associated with COVID-19 mortality outcome of cases.
INTRODUCTION
The Coronavirus-2019 (COVID-19) pandemic remains a pressing
problem in the world and will continually surface as more than
30 different mutations of the disease strain, severe acute
respiratory syndrome-coronavirus (SARS-CoV-2), were detected
from the latest study in China.1 With the increasing number of
novel strains, researchers across the world are driven to conduct
clinical trials for potential anti-viral treatments. However,
the likelihood of potential vaccines for the disease went down,
due to more evidence debuting previous claims on the efficacy
of the tested drugs. Scientists continue to search for effective
treatments, with efforts focused on several existing drugs.
Vitamin D has been proven to enhance expression of anti
oxidation-related genes, modulates adaptive immunity, and
improves cellular immunity.2,3,4,5With the remarkable potential of
Vitamin D, several researchers proposed Vitamin D
supplementation could possibly treat COVID-19 or reduce severity,
at least.6,7,8,9,10,11,12
In a previous report, a significant association between vitamin
D status and severity of COVID-19 disease has been documented
in Southeast Asia.11 The report suggests that serum 25(OH)D level
was lowest in critical cases, but highest in mild cases which
thereby increase the odds of having a mild clinical outcome
rather than a critical outcome by approximately 19.61 times. The
result further fortified initial hypotheses of Vitamin D
proponents that a decrease in serum 25(OH)D level in the body
could worsen clinical outcomes of COVID-19 patients while an
increase in serum 25(OH)D level in the body could either mitigate
worst outcome or improve clinical outcomes.
Existing literature provides evidence that pre-hospitalization
serum 25(OH)D is linked to outcomes of respiratory diseases.
Using cross-sectional data from 6789 participants in the
nationwide 1958 British birth cohort who had measurements of
25(OH)D, Berry et al.13 reported that vitamin D status had a
linear relationship with respiratory infections and lung
function. Pre-admission 25(OH)D deficiency was also predictive
for short-term and long-term mortality.14,15
This study has focused on identifying patterns of mortality among
patients infected with Covid-19 and the possible association
between serum 25(OH)D level and mortality outcomes. In this study,
age, sex, and co-morbidity were added as factors and an outcome
variable, mortality, was analyzed to further provide strong
evidence of Vitamin D potency for SARS-CoV-2.
METHODS
Study Design and Participants
This is a retrospective cohort study which included two cohorts
(active and expired) of 780 cases with laboratory-confirmed
infection of SARS-CoV-2. Data between March 2, 2020 (start of
outbreak in Indonesia) and April 24, 2020 were obtained from
medical records of Indonesia government hospitals. The
requirement for informed consent was waived by the Ethics
Commission. To ensure anonymity, all names were preserved
throughout the analysis.
Data Collection
Age, sex, co-morbidity, Vitamin D status, and disease outcome
(mortality) were extracted from electronic medical records. Co
morbidity status was classified as with or without pre-existing
condition.
For Vitamin D status, cases were classified based on their serum
25(OH)D levels: (1) normal - serum 25(OH)D of > 30 ng/ml, (2)
insufficient - serum 25(OH)D of 21-29 ng/ml, and (3) deficient
- serum 25(OH)D of < 20 ng/ml. This classification was based on
existing literature.16 The pre-admission serum 25(OH)D levels
were considered for the analysis. Serum 25(OH)D level was checked
by two physicians based on the available clinical data of the
patients.
Statistical Analysis
Analysis was carried out using SPSS 21.0 statistical software.
Mean was used for continuous variable (age), while frequency and
percentage were employed for categorical variables. To compare
differences in the outcomes, Mann-Whitney U and χ² tests were
used. Meanwhile, univariate logistics regression was used to
determine the association between each predictor variable and
mortality outcome. The odds ratio (OR) associated with the effect
of a one standard deviation increase in the predictor was used
in the interpretation of data. To determine the association of
Vitamin D status and mortality outcome, all ORs were adjusted
for age, sex, and comorbidity using a generalized linear model.
A p-value less than 0.05 was considered statistically
significant.
RESULTS AND DISCUSSION
Descriptive Statistics
The demographic and clinical characteristics of two cohorts
(active and expired) are presented (Table 1). Mean overall age
was 54.5 years, mean age for expired cases was 65.2 years, higher
compared to active cases (46.3 years). Of the 780 sample,
majority (58.8%) aged below 50 years, most of the them (83.0%)
are still admitted in the hospital. Of the 321 samples aged 50
years and above, majority (66.6%) died due to the disease.
Females (51.3%) outnumbered males (48.7%); however, there were
more male cases who died (66.6%) than female (33.4%). Patients
with existing condition (84.9%) comprised majority of the death
cases. Interestingly, majority of the cases had normal Vitamin
D status (49.7%), most of them (93.0%) are still hospitalized.
Of the 213 cases with insufficient Vitamin D status, majority
(49.1%) died. The same distribution was observed in Vitamin D
deficient cases where majority (46.7%) died due to the disease.
Univariate Analysis
Each predictor was separately analyzed using univariate logistic
regression (Table 2). Older cases (50 years and above) were
approximately 10.45 times more likely to die than younger cases
(at most 50 years) (OR=10.45; p<0.001). Male cases were
approximately 5.73 times more likely to die from the disease
than female cases (OR=5.73; p<0.001). Meanwhile, cases with pre
existing condition had increased odds of mortality compared to
cases without (OR=11.24; p<0.001). With reference to normal
cases, Vitamin D insufficient cases were approximately 12.55
times more likely to die (OR=12.55; p<0.001) while Vitamin D
deficient cases were approximately 19.12 times more likely to
die from the disease (OR=19.12; p<0.001).
Generalized Linear Model
To control for possible confounding of age, sex, and comorbidity
on the association of Vitamin D status and mortality outcome, a
generalized linear model was employed (Table 3). After
accounting for these variables in the model, a significant
association has been obtained between Vitamin D status and
mortality. In particular, the odds of death was higher in cases
with insufficient Vitamin D status (OR=7.63; p<0.001). When
compared to cases with normal Vitamin D status, death was
approximately 10.12 times more likely for Vitamin D deficient
cases (OR=10.12; p<0.001).
Table 1. Demographic and clinical characteristics of sample
Variables Total Expired Active p-value
(N=780) (N=380) (N=400)
Age, mean 54.5 65.2 46.3
< 50 years 459 (58.8%) 127 (33.4%) 332 (83.0%) <0.001
≥ 50 years 321 (41.2%) 253 (66.6%) 68 (17.0%)
Sex
Female 400 (51.3%) 128 (33.4%) 332 (83.0%) <0.001
Male 380 (48.7%) 252 (66.6%) 68 (17.0%)
Comorbidity
Yes 383 (49.1%) 323 (84.9%) 60 (15.0%) <0.001
No 397 (50.9%) 57 (15.1%) 340 (85.0%)
Vitamin D Status
Normal 388 (49.7%) 16 (4.2%) 372 (93.0%) <0.001
Insufficient 213 (27.3%) 187 (49.1%) 26 (6.5%)
Deficient 179 (23.0%) 177 (46.7%) 2 (0.5%)
Table 2. Univariate analysis for factors associated with
mortality
Table 3. Association between Vitamin D status and mortality
(adjusted for age, sex, and comorbidity)
Variables OR p-value
Age, mean
< 50 years -
≥ 50 years 10.45 <0.001
Sex
Female -
Male 5.73 <0.001
Comorbidity
Yes 11.24 <0.001
No -
Vitamin D Status
Normal -
Insufficient 12.55 <0.001
Deficient 19.12 <0.001
Variable OR p-value
Vitamin D Status
Normal -
Insufficient 7.63 <0.001
Deficient 10.12 <0.001
CONCLUSION
To the best of the researchers’ knowledge, this is the first
retrospective study which determines the association of Vitamin
D status and COVID-19 mortality outcome. Older and male cases
with pre-existing condition and below normal Vitamin D levels
were associated with increasing odds of death. When controlling
for age, sex, and comorbidity, Vitamin D status is strongly
associated with COVID-19 mortality outcome of cases. Randomized
controlled trials are warranted to investigate the role of
vitamin D supplementation on COVID-19 outcomes and to establish
the underlying mechanisms.
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