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Vitamin C Intervention for Critical COVID-19
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This entry is adapted from the peer-reviewed paper 10.3390/life11111166

Coronaviruses are single-stranded ribonucleic acid viruses comprising a lipid bilayer containing crown-like spikes (Latin, Corona = Crown) on their outer surface.

vitamin C SARS-CoV2 COVID-19 clinical trials randomised controlled trials

1. Introduction

Coronaviruses are single-stranded ribonucleic acid viruses comprising a lipid bilayer containing crown-like spikes (Latin, Corona = Crown) on their outer surface [1]. Infection with these viruses can affect both the upper and lower respiratory tract and can cause diseases ranging from a mild form, or common cold, to pneumonia [2]. In early December 2019, there were reports of infections with pneumonia-like symptoms of unidentified causes in China [3]. The infections were subsequently identified as being caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the resultant disease being named coronavirus disease (COVID-19) in February 2020 [4]. Globally, as of August 2021, there have been over 200 million confirmed cases of COVID-19, including nearly 4.5 million deaths, reported [5]. Initial data indicated that the majority of patients were aged over 40 years, and that the risk of death increased with age [1]. Since then, numerous other risk factors have been identified, including specific underlying health conditions [6]. Currently, there is a global research effort to try and identify therapies that may help in the treatment of COVID-19.
Vitamin C is an essential nutrient that has important roles in immune function, including antioxidant, anti-inflammatory, antithrombotic, and immuno-modulatory functions [7][8]. Vitamin C deficiency, defined as a plasma concentrations of ≤11 µmol/L, is more common in the elderly, male gender, people with comorbidities, and low socioeconomic status [9]. These are also risk factors for COVID-19 infection [6]. Severe respiratory infections, such as pneumonia, are common clinical conditions that lead to a high requirement for vitamin C, thus providing grounds for active vitamin C replacement in patients who suffer from severe respiratory infections [10]. Although a vitamin C intake of 200 mg daily in healthy volunteers produces a saturating plasma concentration of 70 to 90 µmol/L [11][12], at least ten-fold higher doses (i.e., 2–3 g/day) are required to saturate the plasma of critically ill patients [13][14][15]. Critically ill patients are defined as patients at high risk for actual or potential life-threatening injuries and illnesses, requiring at least organ support and are continuously monitored in the intensive care unit (ICU). Vitamin C is generally administered parenterally to critically ill patients as it provides significantly higher circulating concentrations than enteral vitamin C [16].
Vitamin C administration in patients with pneumonia, sepsis and acute respiratory distress syndrome (ARDS) has shown potential benefits such as reducing duration of hospital and ICU stay and mortality [8]. Pneumonia, sepsis and ARDS are common complications of patients with severe COVID-19 and in March 2020, the World Health Organization highlighted vitamin C as a potential adjunctive therapy with biologic plausibility for patients with critical COVID-19 [17].

2. Vitamin C Status in Patients with COVID-19

Significant evidence indicates that patients with severe respiratory infections have depleted vitamin C status, with the prevalence of deficiency increasing with the severity of the condition [18][19][20]. The vitamin C status of patients with COVID-19 has been reported in several small observational studies (Table 1) [21][22][23][24][25][26]. Plasma concentrations of vitamin C in most of these patients were reported to be very low with 70–80% of the patients having hypovitaminosis C (plasma concentration <23 µmol/L) [22][24]. The low concentrations were despite patients receiving on average 124 mg/day vitamin C in their enteral or parenteral nutrition [26]. Interestingly, markers of oxidative stress were elevated in the COVID-19 patients relative to controls and there was an inverse correlation between oxidative stress markers and vitamin C status in the patients [25]. Thus, vitamin C supplementation appears warranted in these patients to address their hypovitaminosis C and restore adequate plasma vitamin C status [21]. It should be noted that short-term (i.e., 2–4 day) intervention with intravenous vitamin C may not be of sufficient duration to provide lasting benefit as 15–25% of patients can return to hypovitaminosis C status following cessation of intervention [15][27].
Table 1. Vitamin C status in patients with COVID-19.
Table
Population
Location		 Method Findings Reference
18 patients with ARDS 1
Barcelona, Spain.		 Plasma
HPLC-PDA 2		 17 patients had <8 µM vitamin C
1 patient had 14 µM vitamin C		 [23]
21 ICU 3 patients
Thornton, Colorado, USA		 Serum Total cohort (n = 21) had 22 µM vitamin C
(45% were deficient, 70% were hypovitaminosis C)
Survivors (n = 11) had 29 µM vitamin C
Non-Survivors (n = 10) had 15 µM vitamin C		 [22]
31 hospitalised patients
51 healthy controlsShanghai, China		 Plasma
UHPLC-MS 4		 6 patients (no IVC 5) had 11 µM vitamin C
25 patients given 100 mg/kg/day IVC had 76 µM
51 healthy controls had 52 µM vitamin C		 [21]
50 symptomatic patients
21 healthy controls
Jigwa, Nigeria		 Serum
Colourimetric		 Patients had 19 µM vitamin C
Controls had 25 µM vitamin C		 [25]
9 ICU patients with severe pneumonia
Liège, Belgium		   Patients had 22 µM vitamin C
(reference range: 35–86 µM)		 [26]
67 patients with ARDS
Barcelona, Spain		 Plasma
HPLC		 Mean vitamin C concentration was 8 ± 3 µM
55 patients (82%) had values <23 µM
12 patients (18%) had values <6 µM		 [24]

1 ARDS: acute respiratory distress syndrome, 2 PDA: photo diode array, 3 ICU: intensive care unit, 4 UHPLC-MS: ultra-high-performance liquid chromatography-mass spectrometry, 5 IVC: intravenous vitamin C. Note: vitamin C concentrations <11 µM are considered deficient, and <23 µM are considered hypovitaminosis C.

3. Randomised Controlled Trials with Intravenous Vitamin C

The first published randomised placebo-controlled trial was carried out in Wuhan, China, and administered IVC at a dose of 12 g/12 h at a late stage (10–17 days after the onset of the first symptoms) for seven days (Table 2) [28]. This trial reported a 70% reduced ICU and hospital mortality in patients with sequential organ failure assessment (SOFA) scores ≥3 who received IVC relative to those who received placebo (4 vs. 10 days, p = 0.03). There was no difference in invasive ventilation-free days of the intervention vs. placebo group overall (26.5 vs. 10.5 days, p = 0.56), however, this trial was halted early due to diminishing patient numbers. Nevertheless, increased peripheral capillary oxygen saturation/pulmonary function was observed in the IVC group relative to placebo (PaO2/FiO2; 229 vs. 151 mmHg, p = 0.01). Furthermore, the study group also had a lower inflammation marker (interleukin-6, IL-6) than the placebo group (19 vs. 158 pg/mL, p = 0.04). Patients with worse organ dysfunction may have more severe vitamin C deficiency [29], which could contribute to the benefit of intervention being more significant in the more severe COVID-19 patients with higher baseline SOFA scores in this study.
Table 2. Randomised controlled trials investigating the effect of intravenous vitamin C (IVC) in patients with COVID-19.
Table
Population
Mean Age
Location		 Intervention
Duration		 Findings (IVC vs. Control) Reference
54 patients with
COVID-19-pneumonia
and multiple organ injury
Age = 67 ± 13 years
Wuhan, Hubei, China		 IVC 1 24 g/day (n = 27)
or placebo (n= 29)
for 7 days		 Higher PaO2/FiO2 2 (229 vs. 151 mmHg, p = 0.01)
Lower Interleukin-6 (19 vs. 158 pg/mL, p = 0.04)
Lower ICU 3 and hospital mortality in patients with SOFA 4 scores ≥3 (4 vs. 10 days, p = 0.03)
No difference in ventilation-free days (26.5 vs. 10.5 days, p = 0.56)		 [28]
150 patients with severe COVID-19
Age = 52–53 years
Karachi, Pakistan		 IVC 50 mg/kg/day
+ standard therapy
or standard therapy
(75 per group)		 Patients became symptom-free earlier
(7.1 ± 1.8 vs. 9.6 ± 2.1 days, p < 0.0001)
Patients spent fewer days in the hospital
(8.1 ± 1.8 vs. 10.7 ± 2.2 days, p < 0.0001)
No difference in need for mechanical ventilation (16% vs. 20%, p = 0.4)
No difference in mortality (9.3% vs. 14.6%, p = 0.3)		 [30]
60 patients with COVID-19
Age = 57–61 years
Tehran, Iran		 IVC 6 g/day
+ standard therapy
or standard therapy
(30 per group)
for 5 days		 Lower body temperature on 3rd day
of hospitalisation (p = 0.001)
Improvement in oxygen saturation on 3rd day
of hospitalisation (p = 0.014)
No differences in length of ICU stay or mortality		 [31]

1 IVC: intravenous vitamin C, 2 PaO2/FiO2: ratio of partial pressure of oxygen to fraction of inspired oxygen, 3 ICU: intensive care unit, 4 SOFA: sequential organ failure assessment.

An open label RCT of 150 critical COVID-19 patients in Karachi, Pakistan, administered IVC at 50 mg/kg/day (3.5 g for 70 kg person) along with standard care or standard therapy alone and reported that the IVC group became symptom-free earlier (7.1 vs. 9.6 days, p < 0.0001), and spent fewer days in the hospital (8.1 vs. 10.7 days, p < 0.0001; Table 2) [30]. However, there were non-significant reductions in need for mechanical ventilation and mortality. A similar open label RCT in Tehran, Iran, randomised 60 patients with COVID-19 to 6 g/day IVC for five days or standard care [31]. Body temperature was reduced (p = 0.001) and oxygenation (SpO2) increased (p = 0.014) after three days of receiving the treatment. There were, however, no differences in ICU length of stay or mortality.

References

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Patrick Holford
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