The Raharusun Preprint

Results of the age-corrected clinical study by the working group of Dr. Prabowo Raharusun

MD/GP Dr. Prawodo Raharusun, lead author of the so far largest study on C-19 patients
with 780 participants, tragically died on 13.5.2020, only 57 years old.

By means of cultural reasons, the author's info page was deleted within hours after his
death and is not available anymore since 14th of may 2020 (see link: Err 404)

The preprint of his study "Pattern of Covid-19 Mortality and Vitamin D" remained
online until 18th of June, when it was deleted from the SSRN servers. On question, SSRN
replies, it had been removed "by the author". That clearly cannot be, as Dr. Raharusun is
dead. It may have been a confirmation request from SSRN to Dr. Raharusun via email,
which he couldn't reply anymore. In such cases, SSRN removes papers after four weeks of
getting no answer. Which is clearly something else than this statement:

He did not as he just could not, and as we know how engaged he was on the topic, it's
more than doubtful, that he would have drawn back the paper. That's why we decided to
take the paper on our website to make it available again.

Dr. Raharusun did not die because of Corona, but most likely because of his extensive and
grueling commitment against the pandemia.

More about the data in his study and the genesis of the curve seen above, as well as a
brief "in memoriam" and an appreciation of his work can be found here.

Lorenz Borsche and Dr. Bernd Glauner, June 2020

 Disclaimer: This is a preliminary study for early dissemination of results. Data are subject to changes.

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This preprint research paper has not been peer reviewed.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.

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.

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.

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.

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

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.

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

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.

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

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.

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.

A total of 179 cases had Vitamin D deficiency (Vitamin D < 20

ng/ml), mean level of serum 25(OH)D and mean age for this group

were 18.2 ± 0.6 ng/ml and 66.9 ± 13.8 years, respectively (Table

2). 213 cases had Vitamin D insufficiency (Vitamin D 20-30 ng/ml),

mean level of serum 25(OH)D and mean age for this group were

26.7 ± 1.3 ng/ml and 62.9 ± 14.7 years, respectively. 388 cases

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.

had normal Vitamin D levels (Vitamin D > 30 ng/ml), mean level

of serum 25(OH)D and mean age for this group were 32.2 ± 1.2

ng/ml and 46.6 ± 12.6 years, respectively. 80.0% of Vitamin D

deficient cases had pre-existing conditions (comorbidity). 73.8%

of Vitamin D insufficient cases had pre-existing conditions

(comorbidity). 18.8% of cases with normal Vitamin D levels had

pre-existing conditions (comorbidity). 98.9% of Vitamin D

deficient cases died while only 1.1% of them were active cases.

87.8% of Vitamin D insufficient cases died while only 12.2% of

them were active cases. Only 4.1% of cases with normal Vitamin

D levels died while 95.9% of them were active cases.

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).

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.

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).

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.

Table 1. Demographic and clinical characteristics of sample

Variables Total Expired Active p-

(N=780) (N=380) (N=400) value

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. Dynamics of Vitamin D status

Vitamin D < 20 ng/ml Vitamin D 20-30 ng/ml Vitamin D > 30 ng/ml

(18.2 ± 0.6) (26.7 ± 1.3) (32.2 ± 1.2)

Overall, N 179 213 388

Mean age 66.9 ± 13.8 62.9 ± 14.7 46.6 ± 12.6
Comorbidity, % 80.0 73.8 18.8
Death, % 98.9 87.8 4.1
Active, % 1.1 12.2 95.9

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 Disclaimer: This is a preliminary study for early dissemination of results. Data are subject to changes.

Table 3. Univariate analysis for factors associated with

mortality

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

Table 4. Association between Vitamin D status and mortality

(adjusted for age, sex, and comorbidity)

Variable OR p-value

Vitamin D Status

Normal -

Insufficient 7.63 <0.001

Deficient 10.12 <0.001

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.

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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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.

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3585561