Safety of High-Dose Vitamin C in Non-Intensive Care Hospitalized Patients with COVID-19: An Open-Label Clinical Study

Abstract

Background: Vitamin C has been used as an antioxidant and has been proven effective in boosting immunity in different diseases, including coronavirus disease (COVID-19). An increasing awareness was directed to the role of intravenous vitamin C in COVID-19. Methods: In this study, we aimed to assess the safety of high-dose intravenous vitamin C added to the conventional regimens for patients with different stages of COVID-19. An open-label clinical trial was conducted on patients with COVID-19. One hundred four patients underwent high-dose intravenous administration of vitamin C (in addition to conventional therapy), precisely 10 g in 250 cc of saline solution in slow infusion (60 drops/min) for three consecutive days. At the same time, 42 patients took the standard-of-care therapy. Results: This study showed the safety of high-dose intravenous administration of vitamin C. No adverse reactions were found. When we evaluated the renal function indices and estimated the glomerular filtration rate (eGRF, calculated with the CKD-EPI Creatinine Equation) as the main side effect and contraindication related to chronic renal failure, no statistically significant differences between the two groups were found. High-dose vitamin C treatment was not associated with a statistically significant reduction in mortality and admission to the intensive care unit, even if the result was bound to the statistical significance. On the contrary, age was independently associated with admission to the intensive care unit and in-hospital mortality as well as noninvasive ventilation (N.I.V.) and continuous positive airway pressure (CPAP) (OR 2.17, 95% CI 1.41–3.35; OR 7.50, 95% CI 1.97–28.54; OR 8.84, 95% CI 2.62–29.88, respectively). When considering the length of hospital stay, treatment with high-dose vitamin C predicts shorter hospitalization (OR −4.95 CI −0.21–−9.69). Conclusions: Our findings showed that an intravenous high dose of vitamin C is configured as a safe and promising therapy for patients with moderate to severe COVID-19.

Full text

Citation: Corrao, S.; Raspanti, M.;
Agugliaro, F.; Gervasi, F.; Di Bernardo,
F.; Natoli, G.; Argano, C., on behalf of
Internal Medicine IGR COVID-19
Investigators. Safety of High-Dose
Vitamin C in Non-Intensive Care
Hospitalized Patients with COVID-19:
An Open-Label Clinical Study. J. Clin.
Med. 2024,13, 3987. https://
doi.org/10.3390/jcm13133987
Academic Editors: Kiriakos
Karkoulias and Dimosthenis
Lykouras
Received: 11 May 2024
Revised: 30 June 2024
Accepted: 2 July 2024
Published: 8 July 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Clinical Medicine
Article
Safety of High-Dose Vitamin C in Non-Intensive Care
Hospitalized Patients with COVID-19: An Open-Label
Clinical Study
Salvatore Corrao 1, 2, * , Massimo Raspanti 3, Federica Agugliaro 1, Francesco Gervasi 4, Francesca Di Bernardo 5,
Giuseppe Natoli 1and Christiano Argano 1, † on behalf of Internal Medicine IGR COVID-19 Investigators
1
Department of Internal Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico,
Di Cristina, Benfratelli, 90127 Palermo, Italy; federica.agugliaro@gmail.com (F.A.);
peppenatoli@gmail.com (G.N.); chargano@yahoo.it (C.A.)
2Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical
Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
3Cardiology and Intensive Care Unit, A. Aiello Hospital, 91026 Mazzara del Vallo, Italy;
massimoraspanti1991@gmail.com
4Specialized Laboratory of Oncology, National Relevance and High Specialization Hospital Trust ARNAS
Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; francesco.gervasi@arnascivico.it
5Department of Microbiology and Virology, National Relevance and High Specialization Hospital Trust
ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; francesca.dibernardo@arnascivico.it
*
Correspondence: salvatore.corrao@unipa.it or s.corrao@tiscali.it; Tel.: +39-091-655-2065; Fax: +39-091-666-3167
†Investigators of the Internal Medicine IGR COVID-19 is provided in the Acknowledgments.
Abstract: Background: Vitamin C has been used as an antioxidant and has been proven effective in
boosting immunity in different diseases, including coronavirus disease (COVID-19). An increasing
awareness was directed to the role of intravenous vitamin C in COVID-19. Methods: In this study,
we aimed to assess the safety of high-dose intravenous vitamin C added to the conventional regimens
for patients with different stages of COVID-19. An open-label clinical trial was conducted on patients
with COVID-19. One hundred four patients underwent high-dose intravenous administration of
vitamin C (in addition to conventional therapy), precisely 10 g in 250 cc of saline solution in slow
infusion (60 drops/min) for three consecutive days. At the same time, 42 patients took the standard-
of-care therapy. Results: This study showed the safety of high-dose intravenous administration of
vitamin C. No adverse reactions were found. When we evaluated the renal function indices and
estimated the glomerular filtration rate (eGRF, calculated with the CKD-EPI Creatinine Equation) as
the main side effect and contraindication related to chronic renal failure, no statistically significant
differences between the two groups were found. High-dose vitamin C treatment was not associated
with a statistically significant reduction in mortality and admission to the intensive care unit, even
if the result was bound to the statistical significance. On the contrary, age was independently
associated with admission to the intensive care unit and in-hospital mortality as well as noninvasive
ventilation (N.I.V.) and continuous positive airway pressure (CPAP) (OR 2.17, 95% CI 1.41–3.35;
OR 7.50,
95% CI 1.97–28.54
; OR 8.84, 95% CI 2.62–29.88, respectively). When considering the length
of hospital stay, treatment with high-dose vitamin C predicts shorter hospitalization (OR
−
4.95
CI −0.21–−9.69
). Conclusions: Our findings showed that an intravenous high dose of vitamin C is
configured as a safe and promising therapy for patients with moderate to severe COVID-19.
Keywords: vitamin C; safety; length of hospital stay; in-hospital mortality; admission to ICU
1. Introduction
It is four years since the World Health Organization declared COVID-19 a pandemic
on 11 March 2020 [
1
] after the first pneumonia cases caused by severe acute respiratory
syndrome coronavirus (SARS-CoV2) occurred in late December 2019 [
2
]. Globally, as of
J. Clin. Med. 2024,13, 3987. https://doi.org/10.3390/jcm13133987 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2024,13, 3987 2 of 17
3 March 2024, there have been 774,833,487 confirmed cases, and 7,036,994 deaths have been
reported worldwide [
3
]. This pandemic notably challenged the healthcare system and med-
ical care, highlighting the lack of preparation and inadequacy to manage this public health
crisis and simultaneously provide general and specialized medical care [
4
]. Despite a more
in-depth understanding of the pathophysiologic mechanisms behind COVID-19 [
5
,
6
] and
the recent progress in managing and averting COVID-19 by utilizing vaccines and antiviral
drugs, effective interventions have remained a significant challenge [
7
,
8
], especially in older
people with comorbidities [
9
]. From the beginning of COVID-19, researchers have studied
and used molecules and drugs with anti-inflammatory and antioxidant properties [
9
–
14
].
In this sense, an increasing interest was developed in utilizing vitamin C [
15
–
17
]. Vitamin
C, also known as ascorbic acid, is a water-soluble vitamin that acts as a strong antioxidant
and plays a role as a cofactor in various biosynthetic pathways in the immune system. It is
an essential nutrient that the human body cannot produce on its own [
18
]. Its antioxidant
properties stem from its ability to donate electrons, which helps protect molecules from
oxidative damage.
For this reason, many studies have focused on the antioxidant properties of vitamins,
particularly their potential anticancer and antiatherosclerosis properties [
19
]. In addition,
vitamin C stimulates immunity through the raised activity of neutrophils by increasing
chemotaxis and phagocytosis and in T-cell maturation, as well as through the mechanism
of ascorbate-mediated enhancement of immune function [
20
–
22
]. Individuals with a
deficiency in vitamin C face an increased likelihood of developing severe respiratory
infections, such as pneumonia [
23
,
24
]. A meta-analysis has shown that oral vitamin
C supplements can reduce the risk of pneumonia, especially in those with low dietary
intakes [
25
]. On the contrary, a recent meta-analysis showed no reduction in mortality
among people with community-acquired pneumonia [
26
]. Vitamin C deficiency can also
elevate the risk of sepsis during pneumonia.
Moreover, among patients with a diagnosis of sepsis and clinically significant vitamin
C deficiency, a more rapid progression of multiorgan failure was observed [
27
]. In this
sense, contrasting data are available about the combination of thiamine, vitamin C, and
hydrocortisone for the treatment of septic shock; in fact, Marik and colleagues [
28
] dis-
covered that early intravenous administration of vitamin C, complemented with thiamine
and corticosteroids, is effective in preventing progressive organ dysfunction. Litwak et al.
showed that triple therapy did not improve hospital or ICU mortality in patients with
septic shock [
29
]. Various clinical studies evaluating high-dose intravenous vitamin C ad-
ministration in patients with severe sepsis, acute lung injury, and acute respiratory distress
syndrome admitted to intensive care units have shown mixed results regarding laboratory
and clinical outcomes [
30
–
32
]. A systematic review and meta-analysis of intravenous
vitamin C therapy in critically ill patients showed favorable results regarding decreased
mechanical ventilation support to reduce overall mortality [
33
]. A recent systematic review
and meta-analysis showed no significant effect on infection episodes, length of stay in the
hospital or ICU, or duration of mechanical ventilation of administration of intravenous vi-
tamin C treatment in critically ill patients. However, the study did indicate a mild tendency
towards reducing mortality [
34
]. However, a recent meta-analysis revealed a decrease in
the duration of mechanical ventilation [35].
In addition, vitamin C inhibits viral growth, stimulates interferon production, and
enhances lung epithelial cells’ antiviral activity [
36
,
37
]. The antiviral properties of vitamin
C are believed to be particularly beneficial in treating COVID-19. However, how vitamin
C is administered is crucial for both its effectiveness and safety. It is crucial to remember
that while injections and infusions provide the highest dose of vitamin C, they also pose
a greater risk of overdose and renal side effects. This is because they bypass the natural
limits of intestinal transporters. It is important to note that higher doses of vitamin C
administered via infusion may lead to more serious side effects, such as severe kidney
injury [38].

J. Clin. Med. 2024,13, 3987 3 of 17
Since the outbreak of the SARS-CoV-2 pandemic, the safety and effectiveness of high-
dose vitamin C have been the focus of scientific research. Numerous studies have tried to
assess the effectiveness of vitamin C in preventing COVID-19 and its capacity to prevent the
progression to more severe diseases. Additionally, the impact of high doses of vitamin C
on critically ill patients was evaluated [
15
,
39
,
40
]. Given this background, this study aimed
at evaluating the safety and, secondly, the effectiveness of the administration of a high dose
of vitamin C (10 g for three consecutive days) in addition to standard-of-care therapy in a
cohort of hospitalized patients with COVID-19 in the non-intensive care ward, as well as
the effect on mortality, length of hospital stays, and admission to the intensive care unit.
2. Materials and Methods
From 30 March 2020 to 1 April 2021, 146 patients with confirmed COVID-19 (RT-PCR
positive for SARS-CoV-2 and presence of typical radiological signs) who were admitted
to the COVID Unit of the Department of Internal Medicine of the National Relevance
and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, Italy, were
consecutively enrolled in this longitudinal study. The patients admitted to the Department
of Internal Medicine all provided written informed consent upon admission. Eligible
patients were adults with proven COVID-19 admitted to the hospital. There are no exclusion
criteria other than the lack of informed consent signature. The Ethics Committee has
approved the conduct of the study at our institution. The approval number assigned to this
study is 3143. Of these patients, 104 underwent high-dose intravenous administration of
vitamin C (in addition to conventional therapy); precisely, 10 g in 250 cc of saline solution
in slow infusion (60 drops/min) for three consecutive days, according to the therapeutic
protocol “Use of Ascorbic Acid in patients with COVID-19” developed by our center and
registered in March 2020 on the platform Clinicaltrials.gov (accessed on 14 January 2024).
NCT04323514 [
41
]. The other 42 patients underwent the standard of care therapy. Variables
taken into consideration for all patients at the time of admission included age, sex, pre-
existing comorbidities, whether or not oxygen therapy was required, the method used
[nasal cannula (N.C.), Venturi Mask (MV), Continuous Positive Airway Pressure (CPAP),
or noninvasive ventilation (N.I.V.)], and levels of inflammatory markers, such as lactate
dehydrogenase (L.D.H.), procalcitonin (P.C.T.), C-reactive protein (C.R.P.), D-Dimer (D-D),
and interleukin-6 (IL-6).
Statistical Analysis
Quantitative variables are summarized as mean (95% confidence intervals), medians
(interquartile range: first–third), and categorical variables, reported as percentages. The
safety of vitamin C administration represented the primary outcome. The secondary
outcome included mortality and length of hospital stay. In order to establish the safety of
administering high doses of intravenous ascorbic acid, all adverse events were recorded
during and after administration. Furthermore, a patient’s control group was consecutively
recruited to use multivariable logistic regression to study a possible association with the
hospital mortality of treated subjects. The following clinically relevant variables were
considered to demonstrate safety or lack of safety: sex, age, use of noninvasive ventilation
methods, obesity, and diabetes. The quantitative variables were compared using the non-
parametric Mann–Whitney U test. A multivariate regression analysis investigated the
relationship between variables and in-hospital mortality, admission to the intensive care
unit, and length of hospital stays.
The Hosmer–Lemeshow methodology [
42
] was used to select variables for analy-
sis [
39
]. After univariate analysis, only variables with a p-value less than 0.20 were included
in the final model. The variables were excluded through a backward process until each
variable reached a significance level of p< 0.20. The Hosmer–Lemeshow test was used
to measure how well the model fits the data without the researcher having to choose any
variables for the multivariate model. Statistical significance was set at a two-tailed p-value

J. Clin. Med. 2024,13, 3987 4 of 17
of less than 0.05. Stata Statistical Software 2017 (StataCorp, College Station, TX, USA) was
used for database management and analyses.
3. Results
During the recruitment period, 146 hospitalized patients were examined. Among these,
59.6% were male, with a median age of 64.3 years. Table 1shows the clinical characteristics
of the study population.
Table 1. Clinical variables of the analyzed population.
N 146
Patients undergoing Intravenous High-Dose Vitamin C (IHDVC) 104
Patients not undergoing Intravenous High-Dose Vitamin C (IHDVC) 42
Age §64.3 (54.9–76.0)
Men (%) * 59.6 (51.3–67.2)
Pre-existing comorbidities * 80.4 (73.0–86.0)
Hypertension * 70.0 (61.8–76.9)
Obesity (BMI ≥30 Kg/m2) * 40.8 (33.0–49.2)
Diabetes mellitus * 35.6 (28.2–43.9)
Chronic ischemic heart disease * 29.3 (22.4–37.4)
Chronic cerebrovascular disease * 29.1 (22.1–36.9)
Chronic renal failure * 14.7 (9.7–21.5)
Neoplasm (active or previous) * 11.1 (6.9–17.5)
Atrial fibrillation * 9.0 (5.3–15.1)
Body temperature at admission * 37.7 (37.1–38.4)
Oxygen support at admission: None * 37 (29.5–45.2)
Oxygen support at admission: Nose cannulas * 10.2 (6.3–16.4)
Oxygen support at admission: Venturi mask * 25.3 (18.9–33.1)
Oxygen support at admission: CPAP * 15.8 (10.7–22.7)
Oxygen support at admission: NIV S/T * 11.0 (6.8–17.2)
Hospitalization days §19.0 (13.0–29.5)
Admission to intensive care/ICU (%) 8.3
Death (%) 10.2
* Data reported as means (95% confidence intervals); §Data reported as medians (Q1–Q3).
In total, 80.4% of all patients had at least one pre-existing condition at admission.
Disease distribution showed that arterial hypertension, obesity (B.M.I.
≥
30 kg/m
2
), and
diabetes mellitus were the most represented comorbidities in patients with COVID-19 (70%,
40.8%, and 35.6%, respectively). Furthermore, almost a third of patients reported a previous
major ischemic event (myocardial infarction and stroke). For approximately two-thirds
of patients, oxygen supportive therapy was necessary on admission or during a hospital
stay, with over a quarter of subjects requiring ventilation with continuous positive airway
pressure (CPAP) or noninvasive ventilation with pressure support ventilation (NIV/ST).
Due to severe hypoxemia, 8.3% were admitted to intensive care. Death occurred in 10.2%
of patients. The average length of hospital stay was 19 days.
The clinical characteristics of patients with COVID-19 who underwent intravenous
vitamin C and conventional therapy are shown in Table 2. No significant differences in
the main variables were found between the two groups. A more significant percentage
of patients not undergoing IHDVC required venturi mask and CPAP in comparison with
people undergoing IHDVC (30.9% vs. 23.1% and 23.8% vs. 12.5%, respectively), while the
percentage of patients that require NIV S/T was higher in people who received IHDVC
(12.5% vs. 7.1%). Almost 10 percent of patients taking vitamin C were admitted to the

J. Clin. Med. 2024,13, 3987 5 of 17
intensive care unit (9.7% vs. 5.0%). It is worth outlining that a shorter hospital length of stay
and mortality were present in patients who underwent high doses of vitamin C compared
to those who took conventional therapy (18.0% vs. 24.0% and 8.6% vs. 14.3%, respectively).
Table 2. Clinical variables of the analyzed population according to patients undergoing IHDVC
categorization.
Variable Patients Undergoing IHDVC
(n = 104)
Patients Not Undergoing IHDVC
(n = 42) p
Age §64 (53–76) 64 (56–76) 0.8086
Men (%) 61.5 54.8 0.4500
Pre-existing comorbidities (%) 79.6 82.5 0.6960
Hypertension (%) 71.8 65.0 0.4230
Obesity (BMI ≥30 Kg/m2)(%) 39.2 45.0 0.5282
Diabetes mellitus (%) 35.9 35.0 0.9177
Chronic ischemic heart disease or
Chronic cerebrovascular disease (%) 29.1 30.0 0.9180
Chronic renal failure (%) 13.6 17.5 0.5535
Neoplasm (active or previous) (%) 10.7 12.5 0.7566
Oxygen support at admission: None (%) 39.4 30.9 0.3372
Oxygen support at admission: Nose cannulas (%) 11.5 7.1 0.4284
Oxygen support at admission: Venturi mask (%) 23.1 30.9 0.3220
Oxygen support at admission: CPAP (%) 12.5 23.8 0.0895
Oxygen support at admission: NIV S/T (%) 12.5 7.1 0.3482
Hospitalization days §18 (13–27) 24 (13–31) 0.1596
Admission to intensive care/ICU (%) 9.7 5.0 0.3620
Death (%) 8.6 14.3 0.3103
§Data reported as medians (Q1–Q3).
Table 3shows the laboratory characteristics of patients who underwent intravenous
vitamin C and conventional therapy. This table represents the median percentage change
(Q1–Q3) between the value recorded at discharge and the value recorded at admission for
patients who took intravenous high doses of vitamin C and those who did not.
A significant increase in the median percentage change of neutrophils was found in
patients who took an intravenous high dose of vitamin C compared to those who took
conventional therapy (p= 0.0126). Compared to the control group, no significant changes
were highlighted in other laboratory variables, such as C-reactive protein and procalcitonin.
During the observation, there were no differences in terms of adverse drug events between
the intervention group and the control group. We did not record any adverse events. Since
the main side effect and the main contraindication are related to chronic renal failure, we
evaluated the renal function indices and estimated the glomerular filtration rate (eGRF)
(calculated with the CKD-EPI Creatinine Equation). No statistically significant differences
were found between the two groups. Furthermore, no allergic reactions occurred.
As illustrated in Figure 1, the high-dose vitamin C treatment did not result in a sta-
tistically significant decrease in mortality and admission to the intensive care unit, even
if the result bordered on statistical significance. On the contrary, age was independently
associated with in-hospital mortality and admission to the intensive care unit, as well as
N.I.V. and CPAP (OR 2.17, 95% CI 1.41–3.35; OR 7.50, 95% CI 1.97–28.54; OR 8.84, 95% CI
2.62–29.88, respectively). When we consider the length of hospital stay (Table 4), treatment
with high-dose vitamin C represents a predictor of shorter length of hospitalization. Al-
though length of hospital stay was not statistically significantly different between the two
groups, a statistically significant difference was found when correcting the confounding
variables. This difference was not only statistically significant but also clinically relevant.

J. Clin. Med. 2024,13, 3987 6 of 17
The data mentioned above allowed us to demonstrate an excellent safety profile of vitamin
C in the short term.
Table 3. Laboratory variables, % variation of the analyzed population (signed rank).
Variable
Patients Undergoing
High-Dose Vitamin C Treatment
(n = 104)
Patients Not Undergoing High-Dose
Vitamin C Treatment
(n = 42)
p
Hemoglobin (gr/dL) −5.2 (−10.9–1.8) −3.6 (−14.9–4.4) 0.5064
White cells (cell/uL) 24.4 (−6.8–75.9) 1.1 (−23.7–52.5) 0.0656
Neutrophils (cell/uL) 16.2 (−22.9–81.5) −18.6 (−40.6–31.8) 0.0126
Linfocytes (cell/uL) 43.2 (2.8–99.6) 38.6 (−7.4–125) 0.9161
Platelets (cell/µL) 12.1 (−19.4–48.6) 0 (−15.8–27.7) 0.1735
PCR (mg/dL) −83.9 (−95.0–−10.1) −82.5 (−95.0–−19.2) 0.7957
Procalcitonin (PCT) (of/L) 0 (−51.4–0) 0 (−63.1–0) 0.5827
eGFR (mL/min/m2)7.7 (0.4–24.2) 4.5 (−7.7–31.0) 0.3599
D-Dimer (ng/mL) −2.6 (−50.3–40.7) −14.1 (−58.6–2.1) 0.2604
Hematocrit (%) −4.1 (−9.6–2.4) −1.3 (−10.1–4.9) 0.3407
Monocytes (cell/µL) 21.6 (−16.0–71.9) 18.7 (−15.0–103.7) 0.9335
Sodium (mmol/L) 0 (−2.1–2.2) 1.4 (−0.7–2.9) 0.1853
Glycemia (mg/dL) −11.2 (−29.9–24.5) −10.2 (−28.8–16.5) 0.9702
Data reported as medians (Q1–Q3).
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 7 of 18
Although length of hospital stay was not statistically significantly different between the
two groups, a statistically significant difference was found when correcting the
confounding variables. This difference was not only statistically significant but also
clinically relevant. The data mentioned above allowed us to demonstrate an excellent
safety profile of vitamin C in the short term.
Figure 1. Multivariable logistic regression according to composite outcome mortality and/or
admission to the intensive care unit (p < 0.0001; pseudo R2 31.3%). Only the final model is shown
according to the Hosmer–Lemeshow methodology for selecting variables; see the statistical analysis
section.
Table 4. Multivariable regression according to length of hospital stay. Only the final model is shown
according to the Hosmer–Lemeshow methodology; for the selection of variables, see the statistical
analysis section.
Outcome: Length of Hospital Stays
Variables Coefficient (I.C. 95%) p Value
Age 0.13 (−0.02–0.28) 0.089
Male sex 1.26 (−3.06–5.59) 0.565
High-dose Vitamin C treatment −4.95 (−0.21–−9.69) 0.041
4. Discussion
4.1. Vitamin C (Ascorbic Acid)
Vitamin C (ascorbic acid) is a water-soluble vitamin that potentially benefits patients
with different disease severities. It is a “scavenger” molecule (a substance capable of
transforming oxygen radicals into non-radical compounds, lacking reactivity and
therefore toxicity) that has anti-inflammatory properties, influences vascular integrity and
cellular immunity, works as a cofactor in the endogenous generation of catecholamines,
and has been studied in many disease states (predominantly inflammatory states),
including COVID-19 [31]. Vitamin C is crucial in forming and depositing type IV collagen
in the basement membrane. It also promotes endothelial proliferation, inhibits apoptosis,
and preserves endothelial cell-derived nitric oxide to help regulate blood flow [43].
Vitamin C plays a vital role in the functioning and regulation of the immune system.
Leukemic cells and neutrophils accumulate vitamin C intracellularly, which depends on
its availability in plasma. In neutrophils, vitamin C affects the phagocytosis of
microorganisms and chemotaxis. In addition, vitamin C protects neutrophils and
phagocytes from damage following an oxidative burst through its antioxidant and
Figure 1. Multivariable logistic regression according to composite outcome mortality and/or admis-
sion to the intensive care unit (p< 0.0001; pseudo R
2
31.3%). Only the final model is shown according
to the Hosmer–Lemeshow methodology for selecting variables; see the statistical analysis section.

J. Clin. Med. 2024,13, 3987 7 of 17
Table 4. Multivariable regression according to length of hospital stay. Only the final model is shown
according to the Hosmer–Lemeshow methodology; for the selection of variables, see the statistical
analysis section.
Outcome: Length of Hospital Stays
Variables Coefficient (I.C. 95%) pValue
Age 0.13 (−0.02–0.28) 0.089
Male sex 1.26 (−3.06–5.59) 0.565
High-dose Vitamin C treatment −4.95 (−0.21–−9.69) 0.041
4. Discussion
4.1. Vitamin C (Ascorbic Acid)
Vitamin C (ascorbic acid) is a water-soluble vitamin that potentially benefits patients
with different disease severities. It is a “scavenger” molecule (a substance capable of
transforming oxygen radicals into non-radical compounds, lacking reactivity and therefore
toxicity) that has anti-inflammatory properties, influences vascular integrity and cellu-
lar immunity, works as a cofactor in the endogenous generation of catecholamines, and
has been studied in many disease states (predominantly inflammatory states), including
COVID-19 [
31
]. Vitamin C is crucial in forming and depositing type IV collagen in the
basement membrane. It also promotes endothelial proliferation, inhibits apoptosis, and
preserves endothelial cell-derived nitric oxide to help regulate blood flow [43].
Vitamin C plays a vital role in the functioning and regulation of the immune system.
Leukemic cells and neutrophils accumulate vitamin C intracellularly, which depends on its
availability in plasma. In neutrophils, vitamin C affects the phagocytosis of microorgan-
isms and chemotaxis. In addition, vitamin C protects neutrophils and phagocytes from
damage following an oxidative burst through its antioxidant and scavenging capacity and
activates a caspase-dependent cascade that induces programmed apoptosis and inhibits
necrosis [44,45].
A similar protective effect against oxidative stress has also been observed in lym-
phocytes. Vitamin C’s impact on controlling inflammation includes modifying nuclear
transcription factor kappa B (NFkB) and reducing inflammatory cytokine production [
46
].
A recent systematic review and meta-analysis showed that the use of vitamin C reduces
hospital mortality in patients with COVID-19 [17].
4.2. Role of Intravenous Vitamin C in Hospitalized Patients with COVID-19
The World Health Organization has identified vitamin C as a potential adjunctive ther-
apy for patients with critical COVID-19 [
47
]. Several trials have indicated some potentially
beneficial effects of intravenous vitamin C in severe COVID-19 [
48
,
49
]. In a pilot study
in China, 56 adults in the ICU with COVID-19 were given either vitamin C or a placebo.
The study was stopped early due to decreased COVID-19 cases. The results showed no
differences in mortality, mechanical ventilation duration, or SOFA score change between the
groups. The study showed that the treatment arm had more significant respiratory function
improvements than the placebo arm. The improvement was evaluated by calculating the
ratio of partial blood pressure of oxygen to inspired oxygen fraction (PaO
2
/FiO
2
) from
day 1 to day 7. The change in the treatment arm was +20.0, while in the placebo arm, it
was
−
51.9. The difference between the two arms was statistically significant (p= 0.04) [
48
].
Khumari found that intravenous vitamin C can significantly improve the clinical symptoms
of patients affected by COVID-19. Although it may not impact mortality and the need
for mechanical ventilation, patients who received vitamin C became asymptomatic earlier
(7.1 days vs. 9.6 days; p< 0.0001) and had a shorter duration of hospitalization (8.1 days
versus 10.7 days; p< 0.0001) compared to those who received standard therapy alone. There
were no significant differences in mortality and the need for mechanical ventilation [
49
].
Li and colleagues, on the contrary, demonstrated that adjunctive IV vitamin C may not

J. Clin. Med. 2024,13, 3987 8 of 17
reduce mortality, vasopressor requirements, SOFA scores, or ventilator settings in critically
ill COVID-19 patients [50]
4.3. The Immune System
The immune system is the body’s foremost defense against infectious agents. Through-
out biological evolution, it has developed two central and different defense systems: non-
specific (or innate) immunity and specific (or adaptive) immunity [51].
Innate and adaptive immune responses interact to create immune defenses [
52
]. The
innate immune response occurs immediately after infection and is usually involved in
virus elimination but with reduced antiviral capacity. Adaptive immunity is essential in
complete virus elimination [
52
]; this immune pathway is activated 4–7 days after infection.
The innate immune response is enhanced if the adaptive antiviral response fails to suppress
the virus in time. However, it cannot effectively eliminate the virus, leading to a systemic
inflammatory response with uncontrolled release of inflammatory cytokines [
53
–
56
]. El-
derly patients and patients with chronic diseases require more time to develop an adaptive
or innate immune response due to progressive cellular aging. Such patients rely solely on
an enhanced antiviral innate immune response in the early stages of infection and are at
increased risk for cytokinin storms. Whether the enhanced immunity is due to ongoing
viral replication or immunomodulatory dysregulation remains unclear [
57
]. Finally, the
NLR family containing pyrin domain 3 (NLRP3) is the most recognizable inflammasome
pattern in COVID-19 and includes most of the above-mentioned immune–inflammatory
pathways [
58
]. NLRP3 is a critical component of innate immunity and promotes inflam-
mation by producing IL-1
β
/18 and inducing pyroptosis. Later, IL-1
β
and IL-18 play a
role in promoting the release of other NLRP3 cytokines, including IL-6 [
59
]. For example,
a study demonstrated that activation of the NLRP3 inflammasome of S. suis results in
the production of IL-1
β
, leading to a cytokine release syndrome [
60
]. Consequently, a
positive correlation has been observed between IL-18, caspase-1, and other inflammatory
markers like C-reactive protein, lactate dehydrogenase (L.D.H.), and IL-6, in association
with inflammasome activation in COVID-19 [
61
], suggesting an essential role of the NLRP3
inflammasome in forming cytokine storms and the pathogenesis of COVID-19. Thus,
controlling NLRP3 inflammasome activation is a potential therapeutic strategy for these
conditions. Ascorbic acid, or vitamin C, has been studied for its effects on the NLRP3
inflammasome, given its roles in immune function, antioxidant defense, and inflammation
modulation. The interaction between ascorbic acid and the NLRP3 inflammasome involves
several mechanisms. One of the known triggers for NLRP3 inflammasome activation is
oxidative stress, characterized by a derangement between the generation of reactive oxygen
species (R.O.S.) and the body’s ability to detoxify these reactive products or repair the
resulting damage. Ascorbic acid, with its potent antioxidant properties, can scavenge
R.O.S., thereby reducing oxidative stress and potentially preventing the inappropriate
activation of the NLRP3 inflammasome. In addition, ascorbic acid can modulate the pro-
duction and activity of various inflammatory molecules and cytokines, some of which are
involved in the activation pathway of the NLRP3 inflammasome. By influencing these
pathways, ascorbic acid might indirectly impact the activation and function of the NLRP3
inflammasome. Finally, emerging evidence suggests that ascorbic acid may directly inhibit
the NLRP3 inflammasome. This direct inhibition can occur through the modulation of
mitochondrial integrity, reduction of mitochondrial R.O.S., and preservation of cellular
homeostasis, all of which are critical factors in activating the NLRP3 inflammasome. By
stabilizing mitochondria and reducing mitochondrial R.O.S., ascorbic acid may prevent the
assembly and activation of the NLRP3 inflammasome complex. However, while preclinical
studies have shown promising results, clinical evidence supporting the efficacy of ascorbic
acid in modulating the NLRP3 inflammasome in humans is still limited. Further research,
including rigorous clinical trials, is imperative for a comprehensive understanding of the
potential of ascorbic acid in managing conditions associated with NLRP3 inflammasome

J. Clin. Med. 2024,13, 3987 9 of 17
dysregulation. Additionally, the optimal dosing, safety, and long-term effects of ascorbic
acid supplementation for these specific purposes need to be thoroughly evaluated.
4.4. Role of the Immune System in COVID-19
Patients with COVID-19 often exhibit mild neutrophilia and T-cell lymphopenia, leading to
an increased neutrophil-to-lymphocyte ratio (NLR), which serves as a valuable prognostic marker
for the severity of COVID-19 [
62
]. Other leukocyte subpopulations also undergo characteristic
fluctuations and modifications, although these are more heterogeneous.
During an infection, viral PAMPs are detected by Toll-like receptors (TLRs), which
then trigger intracellular signaling cascades. These cascades activate transcription factors,
such as nuclear factor-kappa B (NF-
κ
B) and interferon regulatory factors, leading to the pro-
duction of type I interferons (IFNs) and proinflammatory cytokines. A proper IFN response
usually leads to an antiviral immune state in infected cells, limiting viral replication and
inducing apoptosis to protect the host from viral spread. However, certain SARS-CoV-2
proteins (e.g., open reading frames 6 and 3b) have been found to suppress type I IFN
production and the antiviral signal [
63
]. The initial delay of the IFN response is followed by
uncontrolled viral replication and spread in the infected host, contributing to a final surge in
IFN that may worsen hyperinflammation in the progression to severe disease [
64
]. Another
important component of the innate immune response is the complement system, which
serves as a rapid immune surveillance system against invading pathogens, connecting
innate and adaptive immunity.
In COVID-19 infection, excessive complement activation results in inflammation,
endothelial cell dysfunction, and intravascular coagulation [
65
]. Data indicated that in
patients with moderate to severe COVID-19 infection, there is an accumulation of Natural
Killer (NK) cells in the lungs. In contrast, the number of the same cells decreases in the
peripheral blood. Current evidence on the immune function of NK cells in COVID-19 is con-
tradictory. While some studies have reported signs of hyporesponsiveness and depletion
of NK cells in the blood of patients with COVID-19, others recorded a marked activation of
these cells [
66
]. Finally, the innate immune system interacts with coagulation—a process
known as “immuno-thrombosis”—which is thought to be dysregulated in severe
COVID-19
infection, probably because of increased tissue factor expression (TF). This action, in turn,
triggers the extrinsic pathway of coagulation [
57
]. Neutrophils, when activated, release
neutrophil extracellular traps (NETs) which are composed of neutrophil-derived DNA and
acetylated histones. These NETs function to trap and kill pathogens, but they can also
trigger a strong procoagulant response. They can promote the activation of the intrinsic
coagulation pathway through the activation of factor XII. Furthermore, they can bind TF
to activate the extrinsic coagulation pathway or form aggregates with platelets, influenc-
ing the severity of the disease [
67
]. The adaptive immune system is essential in clearing
SARS-CoV-2, utilizing activated cytotoxic T lymphocytes that destroy infected cells and
B lymphocytes that produce neutralizing antibodies against virus-specific antigens. A
significant characteristic of COVID-19 is blood lymphopenia, leading to reduced numbers
of CD4+ T cells, CD8+ T cells, and B cells [
68
]. The decrease in lymphocyte levels in
COVID-19 patients can be attributed to various factors. One reason is the low levels of
IFN-I, which hinders the production of the viral material necessary for antigen presen-
tation and the activation of adaptive immunity. Additionally, lymphopenia may occur
due to direct infection of T cells by SARS-CoV-2, cytokine-induced lymphocyte apoptosis,
and pyroptosis, MAS-related hemophagocytosis, the sequestration of lymphocytes in the
lungs or other organs, the reduction of bone marrow hematopoiesis, and the damage to
lymphoid organs induced by the virus (pathological alterations such as atrophy of the
splenic white pulp and alteration of the structure of the lymph nodes), suggesting that the
direct cytotoxicity of SARS-CoV-2 in lymphatic organs may impair the adaptive immune
response in COVID-19 [
69
]. The failure of germinal center formation in the spleen and
lymph nodes may explain why some individuals have suboptimal humoral immunity,
potentially leading to the risk of reinfection. However, most COVID-19 patients with

J. Clin. Med. 2024,13, 3987 10 of 17
mild-to-moderate disease have a strong adaptive immune response. This response includes
T cells that target antigens from protein S and nucleoprotein/membrane protein, as well
as neutralizing antibodies against protein S-derived antigens. These immune responses
can persist for months after the initial infection. It is crucial to note that coordinated adap-
tive immune responses specific to SARS-CoV-2 play a key role in mitigating the severity
of the disease [
70
]. Variations in individuals’ defense mechanisms may account for the
differences in disease progression following infection. Inadequate and uncoordinated
adaptive immune responses, often linked to aging, can result in a failure to control the
disease. This insufficient response can be attributed to “immunosenescence”, a concept
involving the age-related decline in immune function, which includes impairments in
both innate and adaptive immune responses, such as compromised pathogen recognition.
Other age-related factors contributing to this include low-level systemic inflammation in
older adults (“inflammasome”), a higher prevalence of comorbidities in this demographic,
and varying degrees of frailty [
71
–
74
]. The immune responses to SARS-CoV-2 may vary
based on sex, which could contribute to men being more susceptible to the disease. A
study examining differences between sexes in immune characteristics found that male
patients have a stronger initial immune response, indicated by higher levels of plasma
cytokines. On the other hand, female patients show a more effective T-cell activation [
75
].
Subjects with multiple underlying diseases or a single serious disease are at greater risk
of developing a severe form of COVID-19 (cardiovascular disease, arterial hypertension,
diabetes, lung disease, neurodegenerative disorders, immunodeficiencies, kidney disease,
obesity, and liver damage) [
76
]. In this regard, ACE2 expression and activity variations
between individuals are believed to impact vulnerability to COVID-19 progression. Para-
doxically, increased membrane-bound ACE2 may allow SARS-CoV-2 to invade host cells.
At the same time, downregulation of ACE2 (due to SARS-CoV-2-induced endocytosis)
precipitates tissue damage, (1) decreasing the inactivation of bradykinins with consequent
risk of developing angioedema and (2) dysregulating the RAAS failing to convert Ang II
into angiotensin (1–7) [
77
]. Finally, several other host factors are believed to impact the
progression of COVID-19, including epigenetic mechanisms, nutritional status, and ABO
blood type [78].
4.5. Cytokine Storm
The term “cytokine storm” describes overactive immune responses triggered by vari-
ous factors, including autoimmune diseases, viral infections, and immunotherapy [
79
–
82
].
Cytokine storms destroy pathogens and cause histotoxicity, affecting various organs [
83
,
84
].
Cytokine release syndrome (CRS) is a systemic inflammatory syndrome caused by cy-
tokine storms and has previously been observed in individuals infected with SARS-CoV
and MERS-CoV viruses. When the body is infected with a virus, certain molecules ac-
tivate neighboring cells’ antiviral responses and attract cells of the innate and adaptive
immune systems, such as natural killer (NK) cells, macrophages, and gamma delta (gd T)
cells
[85–88]
. Interferon production helps protect neighboring epithelial cells from being in-
fected, while the release of IL-1b and IL-6 from other immune cells leads to the mobilization
of neutrophils and T cells. T cell activation or the lysis of immune cells triggers the secretion
of IFN-g and TNF-a, which in turn activates immune cells and endothelial cells, creating
a positive feedback loop leading to further release of inflammatory cytokines [
89
]. These
inflammatory mediators may contribute to thrombus formation [
57
]. This process, called
immuno-thrombosis, can also enhance cytokine production and has been attributed to the
link between thrombin and inflammasome activation and IL-1 production [
90
]. Vascular
endothelial cells are cells that line the blood vessels. These cells are exposed to various
immune mediators and cytokines circulating in the blood. Dysfunction in these cells due to
cytokine storms can cause coagulation disorders such as capillary leak syndrome, thrombus
formation, and even disseminated intravascular coagulation (D.I.C.). This dysfunction is
due to a connection between the immune response and the blood clotting system [
57
,
91
].
Cytokine storms inhibit further viral replication and cause secondary tissue damage by

J. Clin. Med. 2024,13, 3987 11 of 17
secreting large amounts of active mediators and inflammatory factors [
57
,
92
–
95
]. Inhibition
of this self-reinforcing inflammatory cascade may impair viral clearance and inhibit tissue
damage. In the COVID-19 study, Huang et al. discovered that individuals admitted to
intensive care units (ICUs) had elevated levels of the inflammatory cytokines IL-2, IL-7,
IL-10, G-CSF (granulocyte colony-stimulating factor), IFN-
γ
, M.C.P., and TNF-
α
in their
plasma compared to non-ICU patients.
High levels of cytokines were noted [
96
]. These cytokines indicated the presence of
both the Th1 response and Th2 response in COVID-19. In addition, monocyte activation
may indicate that the cytokine storm in COVID-19 is closely related to the imbalance
between innate and adaptive immunity. A recent study found that patients with severe
COVID-19 had significantly higher levels of IL-6 compared to those with mild or moderate
cases. Additionally, patients with severe COVID-19 showed decreased levels of CD4+ T
cells, CD8+ T cells, and NK cells, indicating immunosuppression [93].
On the other hand, T lymphocyte cells may be overactivated during cytokine storms
in COVID-19 patients, resulting in severe immune dysfunction [
97
]. A recent system-
atic review, based on autopsy findings, found fibrin clots with increased CD61-positive
platelets and megakaryocytes in the anterior and posterior capillaries. This was observed
without complete lumen obstruction in lung and other organ samples from COVID-19
patients [
98
]. As a result, cytokine storms can directly damage the pulmonary capillary
mucosa, leading to alveolar edema and further diffusion of inflammatory cytokines, which
damages alveolar structures and impairs pulmonary ventilation [
98
,
99
]. Similarly, cytokine
storms are associated with the order and severity of organ dysfunction in multiple organ
dysfunction syndrome (MODS). Therefore, cytokine storms are considered a crucial factor
in determining the outcome of patients with COVID-19 multiorgan pathology.
This study aimed to evaluate the safety and effectiveness of administering high-dose
vitamin C (as an add-on to the standard of care) to a population of patients with COVID-19
at different stages of the disease. The current findings suggest that high-dose vitamin
C—10 g
in 250 cc of saline solution in slow infusion (60 drops/min)—for three consecu-
tive days was safe and associated with shorter hospitalization in patients suffering from
COVID-19.
The assumption is based on the observation that ascorbic acid can directly reduce
the production of reactive oxygen species (R.O.S.), maintain endothelial barrier function,
promote vasodilation, and downregulate the expression of various proinflammatory mark-
ers [
100
]. Some studies have highlighted that vitamin C diminishes the production of
chemokines and cytokines such as IL1, IL6, IL8, and TNF
α
, thus counteracting the inflam-
matory alterations underlying the lung damage caused by sepsis; this was associated with
significantly lower mortality in severely ill patients with pneumonia [
32
,
101
]. Vitamin
C accumulates in neutrophils, enhancing their chemotaxis, phagocytosis, and microbial
killing. It also plays a vital role in apoptosis and the clearance of spent neutrophils from
infection sites by macrophages, thereby reducing necrosis and potential tissue damage.
Furthermore, vitamin C boosts the development and growth of B- and T-cells, possibly
due to its gene-regulating properties [
46
]. Vitamin C has been widely used in sepsis and
ARDS [
28
,
102
]. Severe inflammation and cytokine storms contribute to severe ARDS and
subsequent mortality in COVID-19 [
103
]. Considering these effects of the cytokine storm
and the close correlation with the prognosis in COVID-19 patients, treatment with high-
dose vitamin C was also evaluated, associated with a reduction in C-reactive protein (C.R.P.)
levels, procalcitonin (P.C.T.), Interleukin 8 (IL8), and attenuating pulmonary and systemic
inflammation. A pilot study conducted in China by Jing Zhang et al. [
48
] with the use
of high-dose vitamin C (24 g/day) in COVID-19 patients with critical illness, although
it did not lead to any results in what was the primary end-point (ventilator-free days
invasive mechanics), has, however, shown benefits in terms of improvement of the partial
pressure ratio of O
2
/inspiratory fraction of O
2
(P/F) and the safety of using the drug. A
retrospective cohort study conducted by D. Gao et al. [
104
] suggested a benefit in terms of
reduced mortality and improved oxygenation status in COVID-19 patients with the use of

J. Clin. Med. 2024,13, 3987 12 of 17
high-dose vitamin C. Multiple studies have demonstrated the beneficial effects of vitamin
C in lowering mortality and reducing hospital stays for patients with non-COVID-related
sepsis and ARDS. The CITRIS-ALI study was a significant clinical trial that included 167 pa-
tients with ARDS. It was a randomized, double-blind, placebo-controlled trial. Patients
were randomly assigned to receive 50 mg/kg of vitamin C every 6 h for four days. This
treatment resulted in a statistically significant decrease in 28-day all-cause mortality com-
pared to the placebo [
32
]. In patients who received a total of 200 mg/kg/day of high-dose
intravenous vitamin C (HDIVC) for four days (administered at 50 mg/kg/dose, every 6 h),
scores for organ failure were significantly lower than those receiving the placebo and even
lower than patients who received lower doses of intravenous vitamin C (50 mg/kg/day
administered at 12.5 mg/kg/dose, every 6 h for four days). In another study by Jamali
Moghadam Siahkali et al. [
105
], a dosage of 1.5 g of vitamin C given intravenously every
6 h for five days was used. In addition, improvements in peripheral oxygen saturation
and body temperature were found in both groups during hospitalization. The study did
not, however, find a statistically significant difference in the reduction in-hospital mortal-
ity of patients with moderate and severe disease in the intervention group compared to
the placebo, and the main reason could lie in the dosage of intravenous vitamin C used
(lower than to other studies conducted). A recent systematic review and meta-analysis of
randomized controlled trials and trial sequential analysis found that intravenous vitamin
C monotherapy may have mortality benefits for critically ill patients, especially for those at
high risk of death. However, the certainty of the evidence available is low [106].
In our study, we administered 10 g of vitamin C every 24 h for three consecutive days,
according to our therapeutic protocol, “Use of Ascorbic Acid in patients with COVID-19”,
developed by our center and registered in March 2020 on the platform Clinicaltrials.gov.
We aimed to evaluate the safety of administering vitamin C; the treatment was compared
to the standard of care alone. The aim of the study was fully achieved, and there was a
clear tendency towards the effectiveness of endovenous acid ascorbic treatment even if the
statistical significance was not reached. In our study, we did not record any adverse events
and we did not record an increase in mortality. Mortality, which we consider an essential
safety signal, correcting for all the confounding variables, suggested the effectiveness of
vitamin C even if statistical significance was not reached. In addition, a statistical reduction
in the length of stay in the hospital was reached. It is worth outlining that our study has
some limitations, such as the heterogeneity of the population (presence of patients with
different disease stages) or the tendency to use the treatment mainly on patients with more
severe forms of the disease. This selection bias could explain the absence of statistically
significant effectiveness. Another critical limitation lies in the fact that our sample size
is small. The sample size calculated at the beginning of the study was not reached, and
this fact could affect the negative results about vitamin C’s effectiveness because the small
sample size increases the probability of false negatives. However, according to our results,
we have a reasonable certainty about safety.
Finally, the total daily dose of vitamin C used in our study was moderate compared
to studies on the effectiveness of intravenous vitamin C in COVID-19 for four to seven
days of intravenous vitamin C. A more extended treatment could be necessary to reach
effectiveness in infective diseases.
5. Conclusions
According to our results, high-dose vitamin C administration showed an excellent
short-term safety profile in moderate and severe COVID-19 patients. The infusion of
vitamin C is statistically significantly associated with reduced hospital stay. Moreover, high-
dose intravenous vitamin C may reduce inflammatory reactions, improve oxygen support,
and decrease mortality in COVID-19 patients and other inflammatory diseases without
adverse events. It is therefore indicated as a promising therapy for patients with moderate
to severe COVID-19, but also for other pathologies in which the hyperinflammatory and
inflammasome state play a crucial role in the pathogenesis. More research is necessary to

J. Clin. Med. 2024,13, 3987 13 of 17
validate these encouraging findings and better understand the role of intravenous vitamin
C in treating COVID-19 and other inflammatory conditions. Furthermore, since it is an
inexpensive and widely available drug, its possible application and usefulness could
represent a change of direction in the treatment strategy for this kind of patient and a large
number of inpatients, even to blunt the inflammatory state.
Author Contributions: Conceptualization, S.C. and C.A.; methodology, S.C., G.N. and C.A.; software,
G.N.; validation, S.C. and C.A.; formal analysis, F.G., F.D.B., M.R. and F.A.; investigation, M.R. and
F.A.; resources, F.G. and F.D.B.; data curation, G.N. and M.R.; writing—original draft preparation,
C.A.; writing—review and editing, S.C.; visualization, F.G., F.D.B. and G.N.; supervision, S.C.; project
administration, C.A. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding. The study was spontaneous research supported
by the ARNAS Civico, Di Cristina, Benfratelli, Palermo, Italy.
Institutional Review Board Statement: The Ethics Committee has approved the conduct of the study
at our institution. The approval number assigned to this study is 3143-2020.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author. The data are not publicly available due to privacy.
Acknowledgments: We would like to thank the Internal Medicine IGR COVID-19 Investigators
(Salvatore Corrao, Federica Agugliaro, Federica Bellini, Egle Briulotta, Giuseppe Brunori, Adele
Busardò, Luigi Calvo, Ignazio Cangemi, Maria Grazia Cecala, Bruno Curiale, Vincenzo De Blasi, Irene
Favatella, AnnaRita Giardina, Walter Granà, Fabio Lanzarone, Santi Lauria, Umberto Lupo, Carlo
Mannina, Martina Martorana, Silvia Messina, Gianni Mingoia, Davide Morana, Salvatore Morello,
Salvo Mularo, Maurilio Palazzo, Karen Pinelli, Giovanni Pistone, Agostino Racalbuto, Massimo
Raspanti, Serena Scardina, Martina Vacca, Giorgia Virzì, and Christiano Argano).
Conflicts of Interest: The authors declare no conflicts of interest.
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