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Review
Vitamin C—An Adjunctive Therapy for Respiratory
Infection, Sepsis and COVID-19
Patrick Holford 1, *, Anitra C. Carr 2 , Thomas H. Jovic 3,4 , Stephen R. Ali 3,4 , Iain S. Whitaker 3,4 ,
Paul E. Marik 5 and A. David Smith 6
1
2
3
4
5
6
*
Institute for Optimum Nutrition, Ambassador House, Richmond TW9 1SQ, UK
Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago,
Christchurch 8140, New Zealand; anitra.carr@otago.ac.nz
Reconstructive Surgery & Regenerative Medicine Research Group, Institute of Life Sciences,
Swansea University Medical School, Swansea University, Swansea SA2 8PY, UK;
Thomas.Jovic@wales.nhs.uk (T.H.J.); Stephen.Ali@wales.nhs.uk (S.R.A.);
Iain.Whitaker@wales.nhs.uk (I.S.W.)
Welsh Centre for Burns & Plastic Surgery, Morriston Hospital, Swansea SA6 6NL, UK
Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School,
Norfolk, VA 23507, USA; marikpe@evms.edu
Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK; david.smith@pharm.ox.ac.uk
Correspondence: pat@patrickholford.com; Tel.: +44-(0)-7944-689108
Received: 19 October 2020; Accepted: 3 December 2020; Published: 7 December 2020
Abstract: There are limited proven therapies for COVID-19.
Vitamin C’s antioxidant,
anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for
the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical
care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections,
including COVID-19, and the mechanisms of action in infectious disease, including support of the
stress response, its role in preventing and treating colds and pneumonia, and its role in treating
sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2–8 g/day) may reduce the
incidence and duration of respiratory infections and intravenous vitamin C (6–24 g/day) has been
shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical
ventilation for severe respiratory infections. Further trials are urgently warranted. Given the
favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in
respiratory infections, it may be worthwhile testing patients’ vitamin C status and treating them
accordingly with intravenous administration within ICUs and oral administration in hospitalised
persons with COVID-19.
Keywords: COVID-19; SARS-CoV-2; coronavirus; vitamin C; ascorbate; colds; pneumonia; sepsis;
immunonutrition; supplementation
1. Introduction
Vitamin C, ascorbic acid, is an essential water-soluble nutrient. It is synthesised in plants
from fructose and in almost all animals from glucose. It is not synthesised by primates, most bats,
guinea pigs, and a small number of birds and fish since the final enzyme, gulonolactone oxidase
(GULO), required for ascorbic acid synthesis is missing due to gene mutations that occurred prior to
the evolution of Homo sapiens [1]. All these species are therefore dependent on vitamin C in their
food. Primates are dependent on an adequate supply provided by fruits and vegetation intake ranging
from 4.5 g/day for gorillas [2] to 600 mg/day for smaller monkeys (7.5 kg—a tenth of human size) [3].
Nutrients 2020, 12, 3760; doi:10.3390/nu12123760
www.mdpi.com/journal/nutrients
Nutrients 2020, 12, 3760
2 of 17
The EU Average Requirement of 90 mg/day for men and 80 mg/day for women is to maintain a
normal plasma level of 50 µmol/L [4], which is the mean plasma level in UK adults [5]. This is sufficient
to prevent scurvy but may be inadequate when a person is under viral exposure and physiological
stress. An expert panel in cooperation with the Swiss Society of Nutrition recommended that everyone
supplement with 200 mg “to fill the nutrient gap for the general population and especially for the
adults age 65 and older. This supplement is targeted to strengthen the immune system” [6]. The Linus
Pauling Institute recommends 400 mg for older adults (>50 years old) [7].
Pharmacokinetic studies in healthy volunteers support a 200 mg daily dose to produce a plasma
level of circa 70 to 90 µmol/L [8,9]. Complete plasma saturation occurs between 1 g daily and 3 g every
four hours, being the highest tolerated oral dose, giving a predicted peak plasma concentration of circa
220 µmol/L [10]. The same dose given intravenously raises plasma vitamin C levels approximately
ten-fold. Higher intakes of vitamin C are likely to be needed during viral infections with 2–3 g/day
required to maintain normal plasma levels between 60 and 80 µmol/L [11,12]. Whether higher plasma
levels have additional benefit is yet to be determined, but would be consistent with the results of the
clinical trials discussed in this review.
2. Vitamin C Deficiency in Pneumonia, Sepsis and COVID-19
Human plasma vitamin C levels decline rapidly under conditions of physiological stress including
infection, trauma, and surgery, not uncommonly resulting in overt vitamin C deficiency in hospitalised
patients, defined as a plasma level of vitamin C ≤ 11 µmol/L [13–18]. Two studies in hospitals in
Paris reported that 17 to 44% of patients had vitamin C plasma levels less than ≤ 11 µmol/L [14,15].
In a Canadian university hospital, it was found that 19% of patients had vitamin C plasma levels
≤ 11 µmol/L [16]. In a study of surgical patients in Australia, it was found that 21% had vitamin C
plasma levels ≤ 11 µmol/L [17]. A survey of elderly Scottish patients hospitalised as a consequence of
acute respiratory infections reported that 35% of patients had vitamin C plasma levels ≤ 11 µmol/L [18].
The UK’s National Diet and Nutrition Survey, based on a cross section of the UK population,
reports that 4% of 65+ year olds and 40% of those institutionalised in care homes have vitamin C
levels ≤ 11 µmol/L [5,19], indicating the way in which older people with low vitamin C status may be
especially susceptible to critical infection.
The vitamin C-deficiency disease scurvy has long been associated with pneumonia which led
to the view that vitamin C may influence susceptibility to respiratory infections [20]. In other
words, people deficient in vitamin C may be more susceptible to severe respiratory infections such as
pneumonia. A prospective study of 19,357 men and women followed over 20 years found that people in
the top quartiles of baseline plasma vitamin C concentrations had a 30% lower risk of pneumonia [21].
Furthermore, meta-analysis has indicated a reduction in the risk of pneumonia with oral vitamin C
supplementation, particularly in individuals with low dietary intakes [22].
Post-mortem investigations of severe COVID-19 have demonstrated a secondary organising
pneumonia phenomenon [23]; therefore, studies investigating vitamin C in relation to pneumonia
may be relevant [18,24–27] (Table 1). The most recent study, from New Zealand, reported that
patients with pneumonia had depleted vitamin C levels compared with healthy controls (23 µmol/L
vs. 56 µmol/L, p < 0.001). The pneumonia cohort comprised 62% with hypovitaminosis C and 22%
with vitamin C ≤ 11 µmol/L, compared with 8% hypovitaminosis C and no cases with ≤11µmol/L
in the healthy controls [24]. The more severely ill patients in the ICU had mean vitamin C levels of
11 µmol/L. Similar findings have been reported in other studies of critically ill septic patients [28–33]
(Table 1). A New Zealand study of patients with sepsis found that 40% had vitamin C ≤ 11 µmol/L
and the majority of the patients had hypovitaminosis C (serum level < 23 µmol/L), despite receiving
recommended enteral and parenteral intakes of the vitamin [29].
Nutrients 2020, 12, 3760
3 of 17
Table 1. Vitamin C status of patients with pneumonia, sepsis and severe COVID-19.
Study Type
Cohort
Vitamin C (µmol/L)
(% Deficient, %
Hypovitaminosis C)
Healthy volunteers (n = 50)
56 ± 2 a (0% b , 8% c )
Community-acquired pneumonia
(n = 50)
23 ± 3 (22%, 62%)
Refs.
Pneumonia
Case control
Case control
[24]
Healthy volunteers (n = 20)
66 ± 3
Pneumonia cases (n = 11)
31 ± 9
Healthy participants (n = 28)
49 ± 1
[25]
Lobular pneumonia (n = 35):
Case control
Acute—did not survive (n = 7)
17 ± 1
Acute—survived (n = 15)
24 ± 1
Convalescent cases (n = 13)
34 ± 1
[26]
Pneumonia/bronchitis (n = 29):
Intervention (placebo group)
Week 0
24 ± 5 (40%) b
Week 2
19 ± 3 (37%)
Week 4
24 ± 6 (25%)
[18]
Pneumonia cases (n = 70):
Intervention (control group)
Day 0
41
Day 5–10
23–24
Day 15–20
32–35
Day 30
39
[27]
Sepsis
Sepsis with ARDS (n = 83):
Intervention (baseline)
Day 0
22 (11–37) d
Day 2
23 (9–37)
Day 4
26 (9–41)
[28]
Day 7
29 (12–39)
Observational
Septic shock patients (n = 24)
15 ± 2 (38% b , 88% c )
[29]
Intervention (baseline)
Severe sepsis patients (n = 24)
18 ± 2
[30]
Healthy controls (n = 6)
48 ± 6
Severe sepsis (n = 19)
14 ± 3
Septic shock (n = 37)
14 ± 3
Case control
Case control
Case control
Healthy controls (n = 14)
76 ± 6
Septic encephalopathy (n = 11)
19 ± 11
Healthy controls (n = 34)
62 (55–72) d
ICU (injury, surgery, sepsis) (n = 62)
11 (8–22)
Critically ill COVID-19 (n = 21)
22 ± 4 (45%b , 70% c ) e
Survivors (n = 11)
29 ± 7 (40%, 50%)
[31]
[32]
[33]
Severe COVID-19
Observational
Non-survivors (n = 10)
Observational
COVID-associated ARDS (n = 18)
[34]
15 ± 2 (50%, 90%)
17 with
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![I’m working on a english writing question and need guidance to help me learn.
write your opinion about the overall themenutrients
Review
Vitamin C—An Adjunctive Therapy for Respiratory
Infection, Sepsis and COVID-19
Patrick Holford 1, *, Anitra C. Carr 2 , Thomas H. Jovic 3,4 , Stephen R. Ali 3,4 , Iain S. Whitaker 3,4 ,
Paul E. Marik 5 and A. David Smith 6
1
2
3
4
5
6
*
Institute for Optimum Nutrition, Ambassador House, Richmond TW9 1SQ, UK
Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago,
Christchurch 8140, New Zealand; anitra.carr@otago.ac.nz
Reconstructive Surgery & Regenerative Medicine Research Group, Institute of Life Sciences,
Swansea University Medical School, Swansea University, Swansea SA2 8PY, UK;
Thomas.Jovic@wales.nhs.uk (T.H.J.); Stephen.Ali@wales.nhs.uk (S.R.A.);
Iain.Whitaker@wales.nhs.uk (I.S.W.)
Welsh Centre for Burns & Plastic Surgery, Morriston Hospital, Swansea SA6 6NL, UK
Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School,
Norfolk, VA 23507, USA; marikpe@evms.edu
Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK; david.smith@pharm.ox.ac.uk
Correspondence: pat@patrickholford.com; Tel.: +44-(0)-7944-689108
Received: 19 October 2020; Accepted: 3 December 2020; Published: 7 December 2020
Abstract: There are limited proven therapies for COVID-19.
Vitamin C’s antioxidant,
anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for
the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical
care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections,
including COVID-19, and the mechanisms of action in infectious disease, including support of the
stress response, its role in preventing and treating colds and pneumonia, and its role in treating
sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2–8 g/day) may reduce the
incidence and duration of respiratory infections and intravenous vitamin C (6–24 g/day) has been
shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical
ventilation for severe respiratory infections. Further trials are urgently warranted. Given the
favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in
respiratory infections, it may be worthwhile testing patients’ vitamin C status and treating them
accordingly with intravenous administration within ICUs and oral administration in hospitalised
persons with COVID-19.
Keywords: COVID-19; SARS-CoV-2; coronavirus; vitamin C; ascorbate; colds; pneumonia; sepsis;
immunonutrition; supplementation
1. Introduction
Vitamin C, ascorbic acid, is an essential water-soluble nutrient. It is synthesised in plants
from fructose and in almost all animals from glucose. It is not synthesised by primates, most bats,
guinea pigs, and a small number of birds and fish since the final enzyme, gulonolactone oxidase
(GULO), required for ascorbic acid synthesis is missing due to gene mutations that occurred prior to
the evolution of Homo sapiens [1]. All these species are therefore dependent on vitamin C in their
food. Primates are dependent on an adequate supply provided by fruits and vegetation intake ranging
from 4.5 g/day for gorillas [2] to 600 mg/day for smaller monkeys (7.5 kg—a tenth of human size) [3].
Nutrients 2020, 12, 3760; doi:10.3390/nu12123760
www.mdpi.com/journal/nutrients
Nutrients 2020, 12, 3760
2 of 17
The EU Average Requirement of 90 mg/day for men and 80 mg/day for women is to maintain a
normal plasma level of 50 µmol/L [4], which is the mean plasma level in UK adults [5]. This is sufficient
to prevent scurvy but may be inadequate when a person is under viral exposure and physiological
stress. An expert panel in cooperation with the Swiss Society of Nutrition recommended that everyone
supplement with 200 mg “to fill the nutrient gap for the general population and especially for the
adults age 65 and older. This supplement is targeted to strengthen the immune system” [6]. The Linus
Pauling Institute recommends 400 mg for older adults (>50 years old) [7].
Pharmacokinetic studies in healthy volunteers support a 200 mg daily dose to produce a plasma
level of circa 70 to 90 µmol/L [8,9]. Complete plasma saturation occurs between 1 g daily and 3 g every
four hours, being the highest tolerated oral dose, giving a predicted peak plasma concentration of circa
220 µmol/L [10]. The same dose given intravenously raises plasma vitamin C levels approximately
ten-fold. Higher intakes of vitamin C are likely to be needed during viral infections with 2–3 g/day
required to maintain normal plasma levels between 60 and 80 µmol/L [11,12]. Whether higher plasma
levels have additional benefit is yet to be determined, but would be consistent with the results of the
clinical trials discussed in this review.
2. Vitamin C Deficiency in Pneumonia, Sepsis and COVID-19
Human plasma vitamin C levels decline rapidly under conditions of physiological stress including
infection, trauma, and surgery, not uncommonly resulting in overt vitamin C deficiency in hospitalised
patients, defined as a plasma level of vitamin C ≤ 11 µmol/L [13–18]. Two studies in hospitals in
Paris reported that 17 to 44% of patients had vitamin C plasma levels less than ≤ 11 µmol/L [14,15].
In a Canadian university hospital, it was found that 19% of patients had vitamin C plasma levels
≤ 11 µmol/L [16]. In a study of surgical patients in Australia, it was found that 21% had vitamin C
plasma levels ≤ 11 µmol/L [17]. A survey of elderly Scottish patients hospitalised as a consequence of
acute respiratory infections reported that 35% of patients had vitamin C plasma levels ≤ 11 µmol/L [18].
The UK’s National Diet and Nutrition Survey, based on a cross section of the UK population,
reports that 4% of 65+ year olds and 40% of those institutionalised in care homes have vitamin C
levels ≤ 11 µmol/L [5,19], indicating the way in which older people with low vitamin C status may be
especially susceptible to critical infection.
The vitamin C-deficiency disease scurvy has long been associated with pneumonia which led
to the view that vitamin C may influence susceptibility to respiratory infections [20]. In other
words, people deficient in vitamin C may be more susceptible to severe respiratory infections such as
pneumonia. A prospective study of 19,357 men and women followed over 20 years found that people in
the top quartiles of baseline plasma vitamin C concentrations had a 30% lower risk of pneumonia [21].
Furthermore, meta-analysis has indicated a reduction in the risk of pneumonia with oral vitamin C
supplementation, particularly in individuals with low dietary intakes [22].
Post-mortem investigations of severe COVID-19 have demonstrated a secondary organising
pneumonia phenomenon [23]; therefore, studies investigating vitamin C in relation to pneumonia
may be relevant [18,24–27] (Table 1). The most recent study, from New Zealand, reported that
patients with pneumonia had depleted vitamin C levels compared with healthy controls (23 µmol/L
vs. 56 µmol/L, p < 0.001). The pneumonia cohort comprised 62% with hypovitaminosis C and 22%
with vitamin C ≤ 11 µmol/L, compared with 8% hypovitaminosis C and no cases with ≤11µmol/L
in the healthy controls [24]. The more severely ill patients in the ICU had mean vitamin C levels of
11 µmol/L. Similar findings have been reported in other studies of critically ill septic patients [28–33]
(Table 1). A New Zealand study of patients with sepsis found that 40% had vitamin C ≤ 11 µmol/L
and the majority of the patients had hypovitaminosis C (serum level < 23 µmol/L), despite receiving
recommended enteral and parenteral intakes of the vitamin [29].
Nutrients 2020, 12, 3760
3 of 17
Table 1. Vitamin C status of patients with pneumonia, sepsis and severe COVID-19.
Study Type
Cohort
Vitamin C (µmol/L)
(% Deficient, %
Hypovitaminosis C)
Healthy volunteers (n = 50)
56 ± 2 a (0% b , 8% c )
Community-acquired pneumonia
(n = 50)
23 ± 3 (22%, 62%)
Refs.
Pneumonia
Case control
Case control
[24]
Healthy volunteers (n = 20)
66 ± 3
Pneumonia cases (n = 11)
31 ± 9
Healthy participants (n = 28)
49 ± 1
[25]
Lobular pneumonia (n = 35):
Case control
Acute—did not survive (n = 7)
17 ± 1
Acute—survived (n = 15)
24 ± 1
Convalescent cases (n = 13)
34 ± 1
[26]
Pneumonia/bronchitis (n = 29):
Intervention (placebo group)
Week 0
24 ± 5 (40%) b
Week 2
19 ± 3 (37%)
Week 4
24 ± 6 (25%)
[18]
Pneumonia cases (n = 70):
Intervention (control group)
Day 0
41
Day 5–10
23–24
Day 15–20
32–35
Day 30
39
[27]
Sepsis
Sepsis with ARDS (n = 83):
Intervention (baseline)
Day 0
22 (11–37) d
Day 2
23 (9–37)
Day 4
26 (9–41)
[28]
Day 7
29 (12–39)
Observational
Septic shock patients (n = 24)
15 ± 2 (38% b , 88% c )
[29]
Intervention (baseline)
Severe sepsis patients (n = 24)
18 ± 2
[30]
Healthy controls (n = 6)
48 ± 6
Severe sepsis (n = 19)
14 ± 3
Septic shock (n = 37)
14 ± 3
Case control
Case control
Case control
Healthy controls (n = 14)
76 ± 6
Septic encephalopathy (n = 11)
19 ± 11
Healthy controls (n = 34)
62 (55–72) d
ICU (injury, surgery, sepsis) (n = 62)
11 (8–22)
Critically ill COVID-19 (n = 21)
22 ± 4 (45%b , 70% c ) e
Survivors (n = 11)
29 ± 7 (40%, 50%)
[31]
[32]
[33]
Severe COVID-19
Observational
Non-survivors (n = 10)
Observational
COVID-associated ARDS (n = 18)
[34]
15 ± 2 (50%, 90%)
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