Feasibility of Vitamin C in the Treatment of Post Viral Fatigue with Focus on Long COVID, Based on a Systematic Review of IV Vitamin C on Fatigue

Abstract

Fatigue is common not only in cancer patients but also after viral and other infections. Effective treatment options are still very rare. Therefore, the present knowledge on the pathophysiology of fatigue and the potential positive impact of treatment with vitamin C is illustrated. Additionally, the effectiveness of high-dose IV vitamin C in fatigue resulting from various diseases was assessed by a systematic literature review in order to assess the feasibility of vitamin C in post-viral, especially in long COVID, fatigue. Nine clinical studies with 720 participants were identified. Three of the four controlled trials observed a significant decrease in fatigue scores in the vitamin C group compared to the control group. Four of the five observational or before-and-after studies observed a significant reduction in pre–post levels of fatigue. Attendant symptoms of fatigue such as sleep disturbances, lack of concentration, depression, and pain were also frequently alleviated. Oxidative stress, inflammation, and circulatory disorders, which are important contributors to fatigue, are also discussed in long COVID fatigue. Thus, the antioxidant, anti-inflammatory, endothelial-restoring, and immunomodulatory effects of high-dose IV vitamin C might be a suitable treatment option.

Full text

nutrients
Review
Feasibility of Vitamin C in the Treatment of Post Viral Fatigue
with Focus on Long COVID, Based on a Systematic Review of
IV Vitamin C on Fatigue
Claudia Vollbracht 1,2, * and Karin Kraft 2


Citation: Vollbracht, C.; Kraft, K.
Feasibility of Vitamin C in the
Treatment of Post Viral Fatigue with
Focus on Long COVID, Based on a
Systematic Review of IV Vitamin C
on Fatigue. Nutrients 2021,13, 1154.
https://doi.org/10.3390/nu13041154
Academic Editor: Carol S. Johnston
Received: 2 March 2021
Accepted: 27 March 2021
Published: 31 March 2021
Publisher’s Note: MDPI stays neutral
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Copyright: © 2021 by the authors.
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This article is an open access article
distributed under the terms and
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Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Medical Science Department, Pascoe Pharmazeutische Präparate GmbH, 35383 Giessen, Germany
2Department of Internal Medicine, University Medicine Rostock, 18057 Rostock, Germany;
karin.kraft@med.uni-rostock.de
*Correspondence: claudia.vollbracht@pascoe.de
Abstract:
Fatigue is common not only in cancer patients but also after viral and other infections. Ef-
fective treatment options are still very rare. Therefore, the present knowledge on the pathophysiology
of fatigue and the potential positive impact of treatment with vitamin C is illustrated. Additionally,
the effectiveness of high-dose IV vitamin C in fatigue resulting from various diseases was assessed
by a systematic literature review in order to assess the feasibility of vitamin C in post-viral, espe-
cially in long COVID, fatigue. Nine clinical studies with 720 participants were identified. Three of
the four controlled trials observed a significant decrease in fatigue scores in the vitamin C group
compared to the control group. Four of the five observational or before-and-after studies observed
a significant reduction in pre–post levels of fatigue. Attendant symptoms of fatigue such as sleep
disturbances, lack of concentration, depression, and pain were also frequently alleviated. Oxidative
stress, inflammation, and circulatory disorders, which are important contributors to fatigue, are also
discussed in long COVID fatigue. Thus, the antioxidant, anti-inflammatory, endothelial-restoring,
and immunomodulatory effects of high-dose IV vitamin C might be a suitable treatment option.
Keywords: ascorbic acid; post-viral fatigue; lack of concentration; sleep disturbances; depression
1. Introduction
Fatigue often occurs as a symptom of severe diseases, such as cancer or autoimmune
diseases. Chronic fatigue syndrome (CFS) is defined as a separate clinical entity, although
the symptoms are very similar: besides intense fatigue, most patients with CFS report
attendant symptoms such as pain, cognitive dysfunction, and unrefreshing sleep [
1
,
2
].
Since fatigue is still difficult to treat, there is an urgent need for effective treatment options.
Fatigue is also currently coming into focus as a major symptom of long COVID.
Patient data from all over the world show that COVID-19 not only attacks people’s health
during the acute infection but also often results in post-infection problems, which are
summarized under the term long COVID [
3
]. SARS-CoV-2 positive persons can be grouped
into asymptomatic infection (no symptoms that are consistent with COVID-19), mild
or moderate (symptoms but SpO
2≥
94%), severe (SpO
2
< 94%, PaO
2
/FiO
2
< 300 mm
Hg, respiratory frequency > 30 breaths/min, or lung infiltrates > 50%), or critical illness
(respiratory failure, septic shock, and/or multiple organ dysfunction) [
4
]. Symptoms of
long COVID can overlap with the post–intensive care syndrome that has been described
in patients without COVID-19, but symptoms after COVID-19 have also been reported in
patients with milder illness, including outpatients. Obviously, COVID-19 is a multi-system
disease characterized by organ and vessel dysfunctions mainly caused by cytokine storm
and microembolism. Presumably, this also applies to the post-acute recovery phase. The
frequency, nature, and causes of long COVID are currently being investigated intensely.
Until the end of 2020, post-viral fatigue syndrome was listed under the WHO indica-
tion code G93.3 (CFS). As of January 2021, the WHO has defined new ICD-10 code numbers
Nutrients 2021,13, 1154. https://doi.org/10.3390/nu13041154 https://www.mdpi.com/journal/nutrients

Nutrients 2021,13, 1154 2 of 11
as part of the attention to COVID-19: U08.9 Personal history of COVID-19, unspecified;
and U09.9 Post-COVID-19 condition.
Post-viral fatigue is associated with various infectious diseases (SARS coronavirus,
Epstein–Barr virus, Ross River virus, enteroviruses, human herpesvirus-6, Ebola virus,
West Nile virus, Dengue virus, and parvovirus; bacteria such as Borrelia burgdorferi,Coxiella
burnetii, and Mycoplasma pneumoniae; and even parasites, such as Giardia lamblia), which
often show very different symptoms during the acute stage [
1
]. Post-viral fatigue syndrome
is rather similar to CFS. In this context, it is interesting to note that CFS often begins with
an infection during a period of increased physical activity or stress. This corresponds to
the current situation in which patients with long COVID are or were affected not only by
the infection but likely also by psychological and/or somatic stress during the lockdown.
In a recently published cohort study from Wuhan, which investigated 1733 patients af-
ter hospitalization for COVID-19 (half of them were younger than 57 years), even 6 months
after the acute infection, 63% of those who had recovered suffered from fatigue or muscle
weakness, 26% suffered from sleep disturbances, and 23% suffered from anxiety or depres-
sion. Patients who had been more severely ill during their hospital stay had more severely
impaired pulmonary diffusion capacities and abnormal chest imaging manifestations [
5
].
The US National Institute for Health Research started a dynamic review on persistent
COVID-19 symptoms in October 2020 and pointed out that not only hospitalized patients
but also those with milder courses can be affected [3].
A recent systematic review and meta-analysis identified more than 50 long-term
effects of COVID-19, with fatigue, anosmia, pulmonary dysfunction, abnormal chest X-
ray/CT, and neurological disorders being the most common. It was estimated that 80% of
individuals with a confirmed COVID-19 diagnosis continued to suffer from at least one
problem beyond two weeks following acute infection. Most of the symptoms were similar
to the symptomatology developed during the acute phase of COVID-19. The five most
common symptoms were fatigue (58%), headache (44%), attention deficit disorder (27%),
hair loss (25%), and dyspnea (24%) [6].
Although studies are still rather heterogeneous, it is already clear that post-viral
fatigue accompanied by sleep disturbances and cognitive deficits is one of the most common
complaints of long COVID.
The pathophysiology of COVID-19 is characterized by inflammation and oxidative
stress leading to vascular and organ damage, as well as to the suppression of adaptive
immune responses [
7
]. It can be assumed that the post-acute recovery phase is also
accompanied by oxidative stress, inflammation, and thus a deficiency of antioxidants such
as vitamin C. To date, post-infectious vitamin C plasma levels have not been evaluated.
However, a deficiency is most likely since infections are known to be associated with high
consumption of vitamin C, and deficiencies in acute infections are frequent [
8
], especially
for patients with pneumonia and COVID-19 [9–13].
A clinically relevant vitamin C deficiency is a disease-eliciting condition, as the water-
soluble vitamin is one of the body’s most important antioxidants and is involved as a
co-factor in more than 150 metabolic functions [
14
]. The term “vitamin C” encompasses
the terms ascorbic acid and ascorbate. The latter is the biologically active form that
is oxidized to dehydroascorbate when reactive oxygen species are neutralized. As an
enzymatic co-factor, it is particularly important for the synthesis of collagen and carnitine,
the bioavailability of tetrahydrobiopterin, and thus the formation of serotonin, dopamine,
and nitric oxide, the synthesis of noradrenaline, the biosynthesis of amidated peptides, the
degradation of the transcription factor HIF-1
α
, and the hypomethylation of DNA [
8
,
15
].
Fatigue, pain, cognitive disorders, and depression-like symptoms are known symptoms of
a vitamin C deficiency [16].
It is therefore clinically plausible that vitamin C administration could alleviate fatigue
(1) by treating vitamin C deficiency symptoms, including fatigue, and (2) by neuroprotective
and vasoprotective effects due to its antioxidant and anti-inflammatory properties.

Nutrients 2021,13, 1154 3 of 11
The aim of this publication is to provide a feasibility analysis of whether the use of
intravenous (IV) vitamin C in post-viral fatigue, particularly after COVID-19, should be
further investigated. For this purpose, the pathophysiological factors underlying fatigue
were investigated through a narrative review, and possible approaches for a therapeutic
benefit of vitamin C in this condition were elicited. In addition, a systematic review was
conducted to evaluate the study evidence on IV vitamin C in fatigue. The review focuses
on high-dose IV vitamin C because, in contrast to oral application, only the IV route results
in pharmacological plasma levels (>220
µ
M) [
17
,
18
]. Moreover, the high plasma levels
reached after IV application offer the advantage of rapid bioavailability in the tissues [
19
].
Studies with oral vitamin C administration are often of low quality because vitamin C blood
levels were rarely determined, and therefore, bioavailability and compliance could not be
verified. This bias can be avoided with IV administration, which has the advantage of 100%
bioavailability and compliance and additionally facilitates the circumvention of genetically
determined resorption differences, which are described for the vitamin C transporter in
patients with COVID-19 [20].
2. Materials and Methods
For the narrative feasibility analysis, the search terms “fatigue” and “review” as well
as “fatigue” and “oxidative stress” were used in the Medline database.
For the systematic review, the Medline and Cochrane Central databases were searched:
Medline with the mesh terms “fatigue” and “ascorbic acid” and Cochrane Central (PubMed,
Embase, ICTRP, CT.gov (accessed on 25 February 2021)) with “fatigue” and “vitamin C”.
The results were screened by the authors for clinical studies with IV vitamin C. Eligibility
criteria were the evaluation of fatigue by a score and the therapeutic use of IV vitamin
C > 1g. Studies detected via secondary literature were supplemented. As fatigue was
investigated in the context of the EORTC-Q30 in studies on quality of life in oncological
patients treated with high-dose vitamin C, these studies were added to the search result.
3. Results
The search in PubMed for the search terms "fatigue" and "ascorbic acid" resulted in 43
publications, the search in Cochrane Central resulted in 62 publications, 6 were identified
via publications that used EORTC Q30 questionnaires, and 8 were duplicates. Ninety-three
publications were excluded because they were not clinical studies (n= 31), were case
reports (n= 2), or they did not meet the eligibility criteria (because they used oral vitamin
C, often combined with several substances (n= 37), did not use vitamin C (n= 20), or were
study registrations without published results (n= 3)). From the 10 full-text publications,
one was discarded because there was no information as to how intensity of fatigue was
measured. (Figure 1).
From the nine identified clinical studies with 720 participants, three were random-
ized and controlled studies, one was a retrospective controlled cohort study, one was a
phase I study, one was a before-and-after study, and the remaining ones were prospective
observational studies.
For the evaluation of fatigue, four studies used EORTC QLQ-C30, three used a Likert
scale and, two used a numeric rating scale. The IV vitamin C doses administered ranged
from appr. 3.5 g to >75 g/day (three studies with >50 g, two studies with 10 g, three studies
with 7.5 g, and one with approximately 3.5 g).
Three of the four controlled trials observed a significant decrease in fatigue in the
vitamin C group compared to the control group (p< 0.005). In all observational before-
and-after studies, a reduction in fatigue was reported. In the four studies that performed
a statistical comparison of the pre–post values, the differences were significant (p< 0.01)
(Table 1).

Nutrients 2021,13, 1154 4 of 11
Table 1.
Clinical studies investigating intravenous vitamin C in conditions with fatigue. * p-value for pre vs. post; ** p-value for verum vs. control; bw: body weight; NRS: numeric
rating scale.
Reference
Study Type; Number of
Patients (n);
Underlying Disease
IV Vitamin C
Dose Additional
Interventions
Estimation of
Fatigue Impact on Fatigue and Related Parameters
Oncology
[21]
Single-center, phase II,
randomized clinical trial;
n= 97; extensively
pretreated patients with
advanced, refractory
non-small-cell lung cancer
1 g/kg bw, 3
times/week, 25
treatments in total
Vitamin C group
received
concurrently
modulated electro-
hyperthermia;
both groups
received best
supportive care
EORTC QLQ-C30
Fatigue (mean ±SD)
Verum group: pre: 46.48 ±17.52, post: 20.63 ±18.14
(* p< 0.0001)
Control group: pre: 39.93 ±20.59, post: 61.34 ±25.32
(* p< 0.0001)
(** p< 0.0001)
Physical function ↑(** p< 0.0001)
Cognitive function (** p= 0.1026)
Dyspnea ↓(** p< 0.0001)
Insomnia (** p= 0.0772
Pain ↓(p** p< 0.0001)
[22]
Single-center phase I
clinical trial; n= 17;
patients with refractory,
advanced solid tumors
(stage III-IV; colon,
pancreas, breast, etc.)
0.8–3 g/kg bw, 4
times/week for 4
weeks
None EORTC QLQ-C30
Fatigue ↓(pre: 49/ post 11)
Physical function ↑(pre 69/post 87)
Cognitive function ↑(pre 75/post 83)
Dyspnea ↓(pre 24/post 0)
Insomnia ↓(pre 31/post 17)
Pain ↓(pre 36/ post 0)
[23]
Multi-center, prospective
observational trial; n= 60;
patients with advanced
tumors (lung, breast,
stomach, colonm etc.)
Increasing
dosages up to 50 g
and more to
achieve plasma
levels of 350–400
mg/dL
2 times/week for
4 weeks
+/−
chemotherapy EORTC QLQ-C30
Fatigue (mean ±SD)
Pre: 42.4 ±28.7 post: 28.4 25.7 (* p< 0.01)
Physical function ↑(* p< 0.05)
Cognitive function ↑(* p< 0.01)
Dyspnea (not significant)
Insomnia ↓(* p< 0.01)
Pain ↓(* p< 0.05)
[24]
Single-center, prospective
before-and-after study;
n= 39, terminal cancer
patients (stomach, colon,
lungs, breast, gall
bladder, etc.)
10 g 2 times/week
for one week None EORTC QLQ-C30
Fatigue (mean ±SD)
Pre: 52 ±24, post: 40 ±19 (* p= 0.001)
Physical function ↑(* p= 0.037)
Cognitive function ↑(* p= 0.002)
Dyspnea (p= 0.051)
Insomnia ↓(* p= 0.029)
Pain ↓(* p= 0.013)

Nutrients 2021,13, 1154 5 of 11
Table 1. Cont.
Reference
Study Type; Number of
Patients (n);
Underlying Disease
IV Vitamin C
Dose Additional
Interventions
Estimation of
Fatigue Impact on Fatigue and Related Parameters
[25]
Multi-center, retrospective,
cohort study; n= 125,
patients with breast cancer
UICC IIa-IIIb
≥7.5 g at least
1 time/week for at
least 4 weeks
+/−
chemotherapy,
radiation
3-point Likert
scale
Fatigue (mean ±SD)
During adjuvant therapy (first 6 months after operation):
Verum: pre: 1.53 ±1.11, post: 0.71 ±0.89
Control: pre 1.68 ±1.004, post: 1.24 ±0.936 (** p= 0.004)
During after care (6–12 month after operation):
Verum: 0.34 ±0.58
Control: 0.64 ±0.718 (** p= 0.023)
Sleep disorders ↓(** p= 0.005)
Depression ↓(** p= 0.01)
Infection, allergies
[26]
Multi-center, prospective
observational trial; n= 67;
patients with herpes zoster
infection
7.5 or 15 g; on
average 8
infusions within
2–3 weeks
55.8% received
anti-infective drug
4-point Likert
scale
Fatigue improved in 78.2% of the patients;
Impaired concentration improved in 81.8% of the patients
[27]
Multi-center, prospective
observational trial; n= 71;
patients with respiratory
and cutaneous allergies
7.5 g; 2–3
times/week for
2–3 weeks in acute
and 11–12 weeks
in chronic states
35 % received
anti-allergic drugs
4-point Likert
scale
Sum score (0–12) of the 4 symptoms: fatigue, sleep disorders,
depression, and lack of mental concentration decreased from 5.93 to
1.09 (* p< 0.0001)
Fatigue improved in 93.5% of patients
Sleep disorders improved in 92.5%, depression in 95.5%, and
impaired concentration in 91.7%
Others
[28]
Single-center, randomized,
double-blind, controlled
clinical trial; n= 97;
patients under-going
laparoscopic colectomy
50 mg/ kg bw;
Single application
after induction of
anesthesia
Analgesics NRS (0–10)
No significant differences in fatigue score 2, 6, and 24 h post
operation
Pain ↓(** p< 0.05)
[29]
Multi-center, randomized,
double-blind, controlled
clinical trial; n= 147;
apparently healthy
full-time worker
10 g, single
application None NRS (0–10)
Fatigue (mean ±SD)
Verum: Pre: 5.64 ±2.02, after 2 h: 5.10 ±2.04, after 24 h: 4.97 ±2.33
Control: Pre: 5.54 ±2.07, after 2 h: 5.31 ±2.00, after 24 h: 5.66 ±2.16
(** p= 0.004)
Plasma vitamin C increased after 2 h, marker for oxidative stress
decreased in the verum group (** p< 0.001)

Nutrients 2021,13, 1154 6 of 11
Nutrients 2021, 13, x FOR PEER REVIEW 4 of 12
Figure 1. Documentation of study selection for the systematic review according to PRISMA guidelines.
From the nine identified clinical studies with 720 participants, three were random-
ized and controlled studies, one was a retrospective controlled cohort study, one was a
phase I study, one was a before-and-after study, and the remaining ones were prospective
observational studies.
For the evaluation of fatigue, four studies used EORTC QLQ-C30, three used a Likert
scale and, two used a numeric rating scale. The IV vitamin C doses administered ranged
from appr. 3.5 g to >75 g/day (three studies with >50 g, two studies with 10 g, three studies
with 7.5 g, and one with approximately 3.5 g).
Three of the four controlled trials observed a significant decrease in fatigue in the
vitamin C group compared to the control group (p < 0.005). In all observational before-
and-after studies, a reduction in fatigue was reported. In the four studies that performed
a statistical comparison of the pre–post values, the differences were significant (p < 0.01)
(Table 1).
Figure 1. Documentation of study selection for the systematic review according to PRISMA guidelines.
4. Discussion
Altogether, nine clinical studies with 720 participants were identified. In three of the
four controlled trials, a significant decrease in fatigue was detected in the high-dose vitamin
C group compared to the control group. Vitamin C had no effect on acute post-operative
fatigue. Four of the five observational or before-and-after studies performed a statistical
comparison of pre–post values and observed a significant reduction in fatigue. To date, the
effect of IV vitamin C on fatigue has been studied mainly in cancer patients. Additionally,
there is one study in herpes zoster [
26
], one in allergies [
27
], one post-operative [
28
], and
one in apparently healthy full-time employees [29].
Despite the different underlying diseases, high-dose vitamin C showed a significant
reduction in fatigue in almost all studies. The most recent study in patients with advanced
lung cancer [
21
] is particularly compelling: while fatigue continued to increase in the
control group despite the best supportive therapy, it decreased significantly in the group
with vitamin C plus hyperthermia. The oncology studies mostly used the EORCT QOL-C30,
which also examines physical and cognitive dysfunction, dyspnea, insomnia, and pain.
These complaints were also frequently alleviated by vitamin C. In cancer, very high doses of
vitamin C are tested because of its chemotherapeutic potential. Three of the five oncology
studies used doses >50 g [
21
–
23
]. In two studies, the dose was calculated based on body
weight (bw) and ranged between 0.8 and 3 g vitamin C per kg bw [
22
]. For a 75 kg person,
this means between 60 and 225 g of vitamin C per infusion. The two remaining studies
used much lower (by a factor of 10) doses per application, yet fatigue was significantly
reduced [
24
,
25
]. This means that very high doses do not seem to be necessary for improving

Nutrients 2021,13, 1154 7 of 11
quality of life such as reducing fatigue. In their review of vitamin C in cancer-associated
fatigue, Carr et al. [
30
] discussed the underlying mechanisms of action and concluded that
the rapid correction of deficiency states, the effect as a co-factor of enzymatic reactions,
and the anti-oxidative and anti-inflammatory effects are particularly important. All these
effects do not require extremely high doses of vitamin C. The only study that investigated
the effects of IV vitamin C in a viral disease (herpes zoster) also used a smaller amount
(7.5 g) but with a high frequency (every second or third day) [
26
]. Fatigue improved in
78.2%, and impaired concentration improved in 81.8% of the patients. The same dose was
used for the treatment of allergies, where fatigue is also a problem that affects the quality
of life [27].
While the change in fatigue was only evaluated after 3 or more weeks in most studies,
the study in apparently healthy full-time workers [
29
] reported an acute reduction in
fatigue. One of the oncological studies [
24
] evaluated fatigue after one week and detected
significant relief after this short treatment period.
The narrative feasibility analysis revealed that fatigue is most common in autoim-
mune diseases, intestinal bowel diseases, neurological diseases, and cancer [
31
–
34
]. Shared
features of these diseases are inflammation and oxidative stress, which reinforce each
other. Oxidative stress seems to be not only a convincing contributor but also a promising
biomarker of the treatment of fatigue [
35
–
39
]. In cancer patients, an exercise interven-
tion upon cessation of radiation or chemotherapy resulted in a reduction in fatigue [
35
].
The improvement was accompanied by a significant decrease in markers of oxidative
stress. Changes in total and affective fatigue exhibited significant correlations with changes
in plasma 8-hydroxy-deoxyguanosine over time, while behavioral and sensory fatigue
changes were significantly correlated with protein carbonyls. Increases in antioxidant
capacity were significantly correlated with reductions in affective, sensory, and cognitive fa-
tigue [
35
]. Fatigue in patients with systemic lupus erythematosus with low disease activity
is associated with increased markers of oxidative stress (F(2)-isoprostane). In a multivariate
model, F(2)-isoprostane was a significant predictor of fatigue severity after adjustment
for age, body mass index, pain, and depression [
39
]. Oxidative stress, impaired sleep
homeostasis, mitochondrial dysfunction, immune activation, and (neuro-)inflammation
can aggravate each other in a vicious pathophysiological loop in CFS [
37
]. Even in the
pathophysiology of idiopathic CFS, oxidative stress seems to be a key contributor [
36
].
Compared to healthy controls, patients with idiopathic CFS have significantly elevated
markers of oxidative stress (including reactive oxygen species, malondialdehyde, and F2-
isoprostane) and reduced levels of antioxidant parameters, which include total antioxidant
activity and catalase, superoxide dismutase, SOD, and GSH activity [36].
Fatigue is also very well known in cancer: not only does it accompany chemother-
apy and radiation, which contribute to oxidative stress, but it can also persist long after
completion of oncological treatment [34,40].
Inflammation and oxidative stress interfere with neurotransmitter metabolism, result-
ing in increased glutamatergic and decreased monoaminergic neurotransmission (serotonin,
noradrenaline, and dopamine) via differing routes. These negatively affect neurotransmit-
ter functioning in various cerebral areas that are involved in fatigue [
41
]. In this context,
it is important to consider that oxidative stress not only reduces the bioavailability of
neurotransmitters due to increased degradation, decreased formation, and distribution
but also results in a decrease in antioxidants. Vitamin C is one of the most important
endogenous antioxidants and is reduced in many chronic inflammatory diseases such
as rheumatoid arthritis, inflammatory bowel diseases, and cancer [
42
–
45
]. Furthermore,
together with vitamin C, vitamin B6, B12, and folic acid are important enzymatic cofactors
of the synthesis of serotonin, dopamine, and noradrenaline.
Oxidative stress is also a major influencing factor for endothelial dysfunction and
circulatory disorders. High-dose IV vitamin C combats overwhelming oxidative stress
and restores endothelial and organ function [
46
]. In the case of COVID-19, oxidative stress
not only triggers organ damage but also causes immune thrombosis via the formation

Nutrients 2021,13, 1154 8 of 11
of neutrophil extracellular traps (NETs). This results in embolisms and dysfunction of
microcirculation [
7
,
47
]. The situation is aggravated by the fact that SARS-CoV-2 also
penetrates endothelial cells via ACE receptors and triggers a chain reaction of endothelial
damage, infiltration of neutrophils, and resulting NETs [
48
]. As for vitamin C, it is essential
for the phagocytosis of consumed neutrophils by macrophages. If this clearance does
not take place, necrosis of the neutrophils occurs, leading to NETs and thus to circulatory
disorders [
8
,
47
]. Therefore, an early application of high-dose vitamin C is proposed to
possibly prevent the development of severe COVID-19 courses [
7
,
47
]. Indeed, in a first pilot
study in COVID-19 patients requiring intensive care, high-dose IV vitamin C significantly
improved oxygenation, reduced organ-damaging cytokine storm (IL-6), and showed a
trend towards reduced mortality in severely ill patients [
49
]. A significant reduction in
mortality and improvement of oxygen status by high-dose vitamin C was observed in a
recent retrospective cohort study [
50
]. From these findings, it can be hypothesized that
vitamin C administration may also be associated with a therapeutic post-viral benefit in
the case of persistent symptoms. Randomized controlled trials, such as LOVIT-COVID
(NCT04401150) or EVICT-CORONA-ALI (NCT04344184), are still ongoing.
A recent review of long COVID described abnormal chest X-rays/CT in 34% of the
patients 6 months after infection. Markers reported to be elevated were D-dimer, NT-
proBNP, C-reactive protein, serum ferritin, procalcitonin, and IL-6 [
6
], which implies
involvement in circulatory disorders, cardiac insufficiency, and inflammatory reactions.
Another cause of persistent symptoms could be the induction of immune responses to
self-epitopes during acute severe COVID-19. First observations point to IgG autoantibodies
that are widely associated with myopathies, vasculitis, and antiphospholipid syndromes
in SARS-CoV-2 infected subjects [
51
]. The observation of autoimmune antibodies is in-
teresting, as fatigue is a known major problem in autoimmune diseases such as multiple
sclerosis [
37
,
52
], rheumatoid arthritis [
33
,
53
], diabetes mellitus type 1 [
54
], systemic lupus
erythematosus [39], and inflammatory bowel diseases [55].
Inflammation results in an overlap of fatigue, disturbed sleep, cognitive deficits, pain,
and depression-like symptoms [
41
], the very pattern of symptoms observed in long COVID.
These factors, which accompany and probably promote fatigue in long COVID, were
alleviated in the clinical studies on IV vitamin C.
Therefore, the effects of IV vitamin C on post-viral COVID-19 fatigue should be
investigated in clinical trials.
5. Conclusions
Oxidative stress and inflammation can cause and maintain fatigue, cognitive impair-
ment, depression, and sleep disturbances. They disrupt the formation and functioning
of important neurotransmitters and of blood circulation. Vitamin C is one of the most
effective physiological antioxidants, showing anti-inflammatory effects, especially if ap-
plied intravenously in pharmacological doses. It restores endothelial function, and it is an
enzymatic co-factor in the synthesis of various neurotransmitters.
High-dose IV vitamin C has been investigated in four controlled and five observational
or before-and-after studies in patients with cancer, allergies, and herpes zoster infections.
The results show a reduction in fatigue and attendant symptoms such as sleep disturbances,
depressive symptoms, pain, and cognitive disorders.
COVID-19 is a multisystem disease in which oxidative stress is partly responsible for
excessive inflammation and circulatory disorders such as immune thrombosis. Vitamin
C deficiency has been demonstrated in COVID-19 and other acute severe infections and
should also be investigated in long COVID. Furthermore, the effects of high-dose IV
vitamin C on long COVID-associated fatigue should be investigated in clinical trials.

Nutrients 2021,13, 1154 9 of 11
Author Contributions:
Conceptualization, C.V. and K.K.; methodology, C.V.; validation, C.V., and
K.K.; formal analysis, C.V.; investigation, C.V.; data curation, C.V.; writing—original draft preparation,
C.V.; writing—review and editing, C.V. and K.K.; visualization, C.V.; supervision, K.K.; project
administration, C.V.; funding acquisition, C.V. All authors have read and agreed to the published
version of the manuscript.
Funding:
Charge for the open-access journal was sponsored by Pascoe Pharmazeutische Praeparate
GmbH, Germany.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Not applicable.
Conflicts of Interest:
K.K. declare that she has no competing interests. C.V. is employed part time at
Pascoe Pharmazeutische Praeparate GmbH (Giessen, Germany).
References
1.
Komaroff, A.L.; Bateman, L. Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front. Med.
(Lausanne) 2020,7, 606824. [CrossRef]
2.
Bleijenberg, G.; van der Meer, J.W.M. Chapter 442: Chronic Fatigue Syndrome. In Harrison’s Principles of Internal Medicine, 20e;
McGraw-Hill Education: New York, NY, USA, 2018.
3.
NIHR. Living with Covid19. Available online: https://evidence.nihr.ac.uk/themedreview/living-with-covid19/ (accessed on 25
February 2021).
4.
NIH. COVID-19 Treatment Guidlines: Clinical Spectrum of SARS-CoV-2 Infection. Available online: https://www.covid1
9treatmentguidelines.nih.gov/overview/clinical-spectrum/ (accessed on 15 March 2021).
5.
Huang, C.; Huang, L.; Wang, Y.; Li, X.; Ren, L.; Gu, X.; Kang, L.; Guo, L.; Liu, M.; Zhou, X.; et al. 6-month consequences of
COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021,397, 220–232. [CrossRef]
6.
Lopez-Leon, S.; Wegman-Ostrosky, T.; Perelman, C.; Sepulveda, R.; Rebolledo, P.A.; Cuapio, A.; Villapol, S. More than 50
Long-term effects of COVID-19: A systematic review and meta-analysis. medRxiv 2021. [CrossRef]
7.
Schonrich, G.; Raftery, M.J.; Samstag, Y. Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps
(NETs), and T cell suppression. Adv. Biol. Regul. 2020,77, 100741. [CrossRef]
8. Carr, A.C.; Maggini, S. Vitamin C and Immune Function. Nutrients 2017,9, 1211. [CrossRef]
9.
Chiscano-Camon, L.; Ruiz-Rodriguez, J.C.; Ruiz-Sanmartin, A.; Roca, O.; Ferrer, R. Vitamin C levels in patients with SARS-CoV-2-
associated acute respiratory distress syndrome. Crit. Care 2020,24, 522. [CrossRef]
10.
Carr, A.C.; Spencer, E.; Dixon, L.; Chambers, S.T. Patients with Community Acquired Pneumonia Exhibit Depleted Vitamin C
Status and Elevated Oxidative Stress. Nutrients 2020,12, 1318. [CrossRef]
11.
Xing, Y.; Zhao, B.; Yin, L.; Guo, M.; Shi, H.; Zhu, Z.; Zhang, L.; He, J.; Ling, Y.; Gao, M.; et al. Vitamin C supplementation is
necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandem mass spectrometry
finding. J. Pharm Biomed. Anal. 2021,196, 113927. [CrossRef]
12.
Pincemail, J.; Cavalier, E.; Charlier, C.; Cheramy-Bien, J.P.; Brevers, E.; Courtois, A.; Fadeur, M.; Meziane, S.; Goff, C.L.; Misset,
B.; et al. Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. Pilot Study
Antioxid. 2021,10, 257. [CrossRef]
13.
Arvinte, C.; Singh, M.; Marik, P.E. Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients
of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study. Med. Drug Discov.
2020
,8, 100064.
[CrossRef]
14.
Blaszczak, W.; Barczak, W.; Masternak, J.; Kopczynski, P.; Zhitkovich, A.; Rubis, B. Vitamin C as a Modulator of the Response to
Cancer Therapy. Molecules 2019,24, 453. [CrossRef] [PubMed]
15.
Dattola, A.; Silvestri, M.; Bennardo, L.; Passante, M.; Scali, E.; Patruno, C.; Nistico, S.P. Role of Vitamins in Skin Health: A
Systematic Review. Curr. Nutr. Rep. 2020,9, 226–235. [CrossRef] [PubMed]
16.
Institute of Medicine (US). Panel on Dietary Antioxidants and Related Compounds. In Dietary Reference Intakes for Vitamin C,
Vitamin E, Selenium, and Carotenoids; National Academies Press: Washington, DC, USA, 2000.
17.
Levine, M.; Padayatty, S.J.; Espey, M.G. Vitamin C: Concentration-function approach yields pharmacology and therapeutic
discoveries. Adv. Nutr. 2011,2, 78–88. [CrossRef]
18.
Padayatty, S.J.; Sun, H.; Wang, Y.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Wesley, R.A.; Levine, M. Vitamin C pharmacokinetics:
Implications for oral and intravenous use. Ann. Intern. Med. 2004,140, 533–537. [CrossRef]
19.
Kuiper, C.; Vissers, M.C.; Hicks, K.O. Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue. Free
Radic. Biol. Med. 2014,77, 340–352. [CrossRef]

Nutrients 2021,13, 1154 10 of 11
20.
Patterson, T.; Isales, C.M.; Fulzele, S. Low level of Vitamin C and dysregulation of Vitamin C transporter might be involved in the
severity of COVID-19 Infection. Aging Dis. 2021,12, 14–26. [CrossRef]
21.
Ou, J.; Zhu, X.; Chen, P.; Du, Y.; Lu, Y.; Peng, X.; Bao, S.; Wang, J.; Zhang, X.; Zhang, T.; et al. A randomized phase II trial of best
supportive care with or without hyperthermia and vitamin C for heavily pretreated, advanced, refractory non-small-cell lung
cancer. J. Adv. Res. 2020,24, 175–182. [CrossRef]
22.
Stephenson, C.M.; Levin, R.D.; Spector, T.; Lis, C.G. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics
of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother. Pharm.
2013
,72, 139–146. [CrossRef]
23.
Takahashi, H.; Mizuno, H.; Yanagisawa, A. High-dose intravenous vitamin C improves quality of life in cancer patients. Pers.
Med. Universe 2012,1, 49–53. [CrossRef]
24.
Yeom, C.H.; Jung, G.C.; Song, K.J. Changes of terminal cancer patients’ health-related quality of life after high dose vitamin C
administration. J. Korean Med. Sci. 2007,22, 7–11. [CrossRef] [PubMed]
25.
Vollbracht, C.; Schneider, B.; Leendert, V.; Weiss, G.; Auerbach, L.; Beuth, J. Intravenous vitamin C administration improves
quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: Results of a retrospective, multicentre,
epidemiological cohort study in Germany. In Vivo 2011,25, 983–990.
26.
Schencking, M.; Vollbracht, C.; Weiss, G.; Lebert, J.; Biller, A.; Goyvaerts, B.; Kraft, K. Intravenous vitamin C in the treatment of
shingles: Results of a multicenter prospective cohort study. Med. Sci. Monit. 2012,18, CR215. [CrossRef] [PubMed]
27.
Vollbracht, C.; Raithel, M.; Krick, B.; Kraft, K.; Hagel, A.F. Intravenous vitamin C in the treatment of allergies: An interim
subgroup analysis of a long-term observational study. J. Int. Med. Res. 2018,46, 3640–3655. [CrossRef]
28.
Jeon, Y.; Park, J.S.; Moon, S.; Yeo, J. Effect of Intravenous High Dose Vitamin C on Postoperative Pain and Morphine Use after
Laparoscopic Colectomy: A Randomized Controlled Trial. Pain Res. Manag. 2016,2016, 9147279. [CrossRef]
29.
Suh, S.Y.; Bae, W.K.; Ahn, H.Y.; Choi, S.E.; Jung, G.C.; Yeom, C.H. Intravenous Vitamin C Administration Reduces Fatigue in
Office Workers: A Double-blind Randomized Controlled Trial. Nutr. J. 2012,11, 7. [CrossRef] [PubMed]
30.
Carr, A.C.; Vissers, M.C.; Cook, J.S. The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality
of life. Front. Oncol. 2014,4, 283. [CrossRef] [PubMed]
31. Finsterer, J.; Mahjoub, S.Z. Fatigue in healthy and diseased individuals. Am. J. Hosp. Palliat Care 2014,31, 562–575. [CrossRef]
32.
Borren, N.Z.; van der Woude, C.J.; Ananthakrishnan, A.N. Fatigue in IBD: Epidemiology, pathophysiology and management.
Nat. Rev. Gastroenterol. Hepatol. 2019,16, 247–259. [CrossRef]
33.
Elera-Fitzcarrald, C.; Rocha, J.; Burgos, P.I.; Ugarte-Gil, M.F.; Petri, M.; Alarcon, G.S. Measures of Fatigue in Patients With
Rheumatic Diseases: A Critical Review. Arthritis Care Res. 2020,72 (Suppl. 10), 369–409. [CrossRef]
34.
Mohandas, H.; Jaganathan, S.K.; Mani, M.P.; Ayyar, M.; Rohini Thevi, G.V. Cancer-related fatigue treatment: An overview. J.
Cancer Res. Ther. 2017,13, 916–929. [CrossRef]
35.
Repka, C.P.; Hayward, R. Effects of an Exercise Intervention on Cancer-Related Fatigue and Its Relationship to Markers of
Oxidative Stress. Integr. Cancer Ther. 2018,17, 503–510. [CrossRef]
36.
Lee, J.S.; Kim, H.G.; Lee, D.S.; Son, C.G. Oxidative Stress is a Convincing Contributor to Idiopathic Chronic Fatigue. Sci. Rep.
2018,8, 12890. [CrossRef]
37.
Morris, G.; Stubbs, B.; Kohler, C.A.; Walder, K.; Slyepchenko, A.; Berk, M.; Carvalho, A.F. The putative role of oxidative stress and
inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome,
bipolar disorder and multiple sclerosis. Sleep Med. Rev. 2018,41, 255–265. [CrossRef]
38.
Fukuda, S.; Nojima, J.; Motoki, Y.; Yamaguti, K.; Nakatomi, Y.; Okawa, N.; Fujiwara, K.; Watanabe, Y.; Kuratsune, H. A potential
biomarker for fatigue: Oxidative stress and anti-oxidative activity. Biol. Psychol. 2016,118, 88–93. [CrossRef] [PubMed]
39.
Segal, B.M.; Thomas, W.; Zhu, X.; Diebes, A.; McElvain, G.; Baechler, E.; Gross, M. Oxidative stress and fatigue in systemic lupus
erythematosus. Lupus 2012,21, 984–992. [CrossRef]
40.
Pearson, E.J.M.; Morris, M.E.; di Stefano, M.; McKinstry, C.E. Interventions for cancer-related fatigue: A scoping review. Eur. J.
Cancer Care 2018,27. [CrossRef]
41.
Korte, S.M.; Straub, R.H. Fatigue in inflammatory rheumatic disorders: Pathophysiological mechanisms. Rheumatology
2019
,58,
v35–v50. [CrossRef]
42.
Lunec, J.; Blake, D.R. The determination of dehydroascorbic acid and ascorbic acid in the serum and synovial fluid of patients
with rheumatoid arthritis (RA). Free Radic. Res. Commun. 1985,1, 31–39. [CrossRef] [PubMed]
43.
Jaswal, S.; Mehta, H.C.; Sood, A.K.; Kaur, J. Antioxidant status in rheumatoid arthritis and role of antioxidant therapy. Clin. Chim.
Acta 2003,338, 123–129. [CrossRef]
44.
Carr, A.C.; Cook, J. Intravenous Vitamin C for Cancer Therapy-Identifying the Current Gaps in Our Knowledge. Front. Physiol.
2018,9, 1182. [CrossRef]
45.
Subramanian, V.S.; Sabui, S.; Subramenium, G.A.; Marchant, J.S.; Said, H.M. Tumor necrosis factor alpha reduces intestinal
vitamin C uptake: A role for NF-kappaB-mediated signaling. Am. J. Physiol. Gastrointest. Liver Physiol.
2018
,315, G241–G248.
[CrossRef]
46.
Spoelstra-de Man, A.M.E.; Elbers, P.W.G.; Oudemans-Van Straaten, H.M. Vitamin C: Should we supplement? Curr. Opin Crit.
Care 2018,24, 248–255. [CrossRef]
47.
Holford, P.; Carr, A.C.; Jovic, T.H.; Ali, S.R.; Whitaker, I.S.; Marik, P.E.; Smith, A.D. Vitamin C-An Adjunctive Therapy for
Respiratory Infection, Sepsis and COVID-19. Nutrients 2020,12, 3760. [CrossRef]

Nutrients 2021,13, 1154 11 of 11
48.
Leppkes, M.; Knopf, J.; Naschberger, E.; Lindemann, A.; Singh, J.; Herrmann, I.; Sturzl, M.; Staats, L.; Mahajan, A.; Schauer, C.;
et al. Vascular occlusion by neutrophil extracellular traps in COVID-19. EBioMedicine 2020,58, 102925. [CrossRef]
49.
Zhang, J.; Rao, X.; Li, Y.; Zhu, Y.; Liu, F.; Guo, G.; Luo, G.; Meng, Z.; De Backer, D.; Xiang, H.; et al. Pilot trial of high-dose vitamin
C in critically ill COVID-19 patients. Ann. Intensive Care 2021,11, 5. [CrossRef]
50.
Gao, D.; Xu, M.; Wang, G.; Lv, J.; Ma, X.; Guo, Y.; Zhang, D.; Yang, H.; Jiang, W.; Deng, F.; et al. The efficiency and safety of
high-dose vitamin C in patients with COVID-19: A retrospective cohort study. Aging 2021,13. [CrossRef]
51.
Bhadelia, N.; Belkina, A.C.; Olson, A.; Winters, T.; Urick, P.; Lin, N.; Rifkin, I.; Kataria, Y.; Yuen, R.R.; Sagar, M.; et al. Distinct
Autoimmune Antibody Signatures Between Hospitalized Acute COVID-19 Patients, SARS-CoV-2 Convalescent Individuals, and
Unexposed Pre-Pandemic Controls. medRxiv 2021. [CrossRef]
52. Rottoli, M.; La Gioia, S.; Frigeni, B.; Barcella, V. Pathophysiology, assessment and management of multiple sclerosis fatigue: An
update. Expert Rev. Neurother. 2017,17, 373–379. [CrossRef]
53.
Cramp, F. The role of non-pharmacological interventions in the management of rheumatoid-arthritis-related fatigue. Rheumatology
2019,58, v22–v28. [CrossRef]
54.
Griggs, S.; Morris, N.S. Fatigue Among Adults With Type 1 Diabetes Mellitus and Implications for Self-Management: An
Integrative Review. Diabetes Educ. 2018,44, 325–339. [CrossRef] [PubMed]
55.
Nocerino, A.; Nguyen, A.; Agrawal, M.; Mone, A.; Lakhani, K.; Swaminath, A. Fatigue in Inflammatory Bowel Diseases: Etiologies
and Management. Adv. Ther. 2020,37, 97–112. [CrossRef] [PubMed]