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Rationale for ozone-therapy as an adjuvant therapy in COVID-19


Abstract and Figures

Coronavirus disease 2019 (COVID-19) is the respiratory disease caused by the novel severe acute respiratory syndrome-coronavirus-2 and is characterized by clinical manifestations ranging from mild, flu-like symptoms to severe respiratory insufficiency and multi-organ failure. Patients with more severe symptoms may require intensive care treatments and face a high mortality risk. Also, thrombotic complications such as pulmonary embolisms and disseminated intravascular coagulation are frequent in these patients. Indeed, COVID-19 is characterized by an abnormal inflammatory response resembling a cytokine storm, which is associated to endothelial dysfunction and microvascular complications. To date, no specific treatments are available for COVID-19 and its life-threatening complication. Immunomodulatory drugs, such as hydroxychloroquine and interleukin-6 inhibitors, as well as antithrombotic drugs such as heparin and low molecular weight heparin, are currently being administered with some benefit. Ozone therapy consists in the administration of a mixture of ozone and oxygen, called medical ozone, which has been used for over a century as an unconventional medicine practice for several diseases. Medical ozone rationale in COVID-19 is the possibility of contrasting endothelial dysfunction, modulating the immune response and acting as a virustatic agent. Thus, medical ozone could help to decrease lung inflammation, slow down viral growth, regulate lung circulation and oxygenation and prevent microvascular thrombosis. Ozone-therapy could be considered a feasible, cost-effective and easy to administer adjuvant therapy while waiting for the synthesis of a therapy or the development of the vaccine.
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Coronavirus disease 2019 (COVID-19) is a disease caused
by the novel severe acute respiratory syndrome (SARS)-
coronavirus-2 (SARS-CoV-2), a virus belonging to the same
family of the viruses causing SARS and middle-eastern
respiratory syndrome (MERS), which was rst reported in
Wuhan in December 2019, in the province of Hubei, China.1
COVID-19 shows a wide spectrum of clinical manifestations,
ranging from mild, u-like symptoms to severe interstitial
Patients with more severe symptoms may require intensive
care treatment due to acute respiratory failure, needing
mechanical ventilation and high positive end-expiratory
pressure, and face high mortality risk.2 COVID-19 can
cause an abnormal inammatory response, which indeed
resembles a “cytokine storm” characterized by increased
plasma concentrations of C-reactive proteins, ferritin, pro-
inammatory cytokines (interleukin (IL)-1β, IL-6, IL-12,
tumor necrosis factor, interferon-γ) and decreased numbers of
CD16+ and CD56+ lymphocytes.3 This inammatory pattern is
different from that of severe SARS patients4 and it is similar
to that at the basis of adaptive immunity.5 Immunomodulatory
agents such as anti-rheumatoid arthritis drugs (chloroquine,
hydroxychloroquine and tocilizumab, a humanized monoclonal
antibody targeting IL-6) are currently prescribed as an adjuvant
treatment of COVID-19, in addition to antiviral drugs.6
Immune activation is associated to endothelial dysfunction
and microvascular complications,7 with signicant septal
capillary injury, characterized by mural and luminal
brin deposition, permeation of the interalveolar septa by
neutrophils and signicant deposits of terminal complement
components consistent with sustained, systemic activation
of the alternative and lectin-based complement pathways,
associated with procoagulant state.8 COVID-19 can also
determine thrombotic complications: 1.4% of dead patients
meet the International Society on Thrombosis and Haemostasis
criteria for disseminated intravascular coagulation, as proven
by the increased levels of D-dimer and brinogen, with lower
anti-thrombin levels and spontaneous increase of the length
of international normalized ratio,9 while only 0.6% of patients
who survive meet these criteria10; pulmonary congestion with
microvascular thrombosis and occlusion is the most relevant
aspect on pathology.3 Pathological ndings include “spotty
lungs,” where hyperemic/hemorrhagic areas co-exist with
areas of normal lung. There is also vascular hypertrophy,
with enlarged (up to 20 times) and tubular pulmonary vessels,
with microthrombi, followed by reduction of caliber. In the
alveoli, there are typical ndings of diffuse alveolar damage,
with desquamation of pneumocytes, formation of hyaline
membranes and brotic exudate.11 To suggest the systemic
origin of the coagulative disorder, there is increasing evidence
of central line thrombosis and vascular occlusive events (e.g.,
ischemic limbs).12 Moreover, there is increasing evidence of
Rationale for ozone-therapy as an adjuvant therapy in
COVID-19: a narrative review
Giovanni Tommaso Ranaldi1, Emanuele Rocco Villani2, *, Laura Franza3
1 Unità Operativa Semplice Dipartimentale Farmacologia Clinica e Sperimentazione Clinica, Azienda Sanitaria, Potenza, Italy
2 Department of Geriatrics, Università Cattolica del Sacro Cuore, Rome, Italy
3 Department of Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli” IRCCS, Rome, Italy
*Correspondence to: Emanuele Rocco Villani, MD,
orcid: 0000-0001-8813-2419 (Emanuele Rocco Villani)
Coronavirus disease 2019 (COVID-19) is the respiratory disease caused by the novel severe acute respiratory syndrome-coronavirus-2 and
is characterized by clinical manifestations ranging from mild, u-like symptoms to severe respiratory insufciency and multi-organ failure.
Patients with more severe symptoms may require intensive care treatments and face a high mortality risk. Also, thrombotic complications
such as pulmonary embolisms and disseminated intravascular coagulation are frequent in these patients. Indeed, COVID-19 is character-
ized by an abnormal inammatory response resembling a cytokine storm, which is associated to endothelial dysfunction and microvascular
complications. To date, no specic treatments are available for COVID-19 and its life-threatening complication. Immunomodulatory drugs,
such as hydroxychloroquine and interleukin-6 inhibitors, as well as antithrombotic drugs such as heparin and low molecular weight heparin,
are currently being administered with some benet. Ozone therapy consists in the administration of a mixture of ozone and oxygen, called
medical ozone, which has been used for over a century as an unconventional medicine practice for several diseases. Medical ozone rationale
in COVID-19 is the possibility of contrasting endothelial dysfunction, modulating the immune response and acting as a virustatic agent.
Thus, medical ozone could help to decrease lung inammation, slow down viral growth, regulate lung circulation and oxygenation and pre-
vent microvascular thrombosis. Ozone-therapy could be considered a feasible, cost-effective and easy to administer adjuvant therapy while
waiting for the synthesis of a therapy or the development of the vaccine.
Key words: COVID-19; cytokine storm; endothelial dysfunction; immunomodulation; medical ozone; ozone therapy; ozone; SARS-COV-2;
doi: 10.4103/2045-9912.289462
How to cite this article: Ranaldi GT, Villani ER, Franza L. Rationale for ozone-therapy as an adjuvant therapy in COVID-19: a narrative
review. Med Gas Res. 2020;10(3):134-138.
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Medical Gas Research ¦ September ¦ Volume 10 ¦ Issue 3 135
Ranaldi et al. / Med Gas Res
other SARS-CoV2-related vasculitis such as skin purpura8
and cerebrovascular accidents.13
The use of heparin has, indeed, proven useful in these
patients: high-dose heparin is being used with success
in patients who develop moderate to severe forms of
COVID-19.14 Other treatments being investigated include
debrotide, a mixture of single-stranded oligonucleotides
showing anti-clotting properties and used to treat veno-
occlusive disease (NCT04335201), and tissue-plasminogen
activators.15 Yet, even though these approaches seem to work,
they are symptomatic treatments and do not act on the causes
of the endothelial dysfunction.
In this scenario, it is imperative to nd new therapeutic
options. An interesting option could be ozone therapy. In the
present short review, we describe potential benets of ozone
therapy in COVID-19. A literature search was conducted on
PubMed and Embase including “ozone,” “medical ozone,”
“endothelial dysfunction,” “cytokine storm,” “shock,” and
“ARDS” as search terms. An additional search was conducted
on including “ozone,” “COVID-19,”
“SARS-CoV-2” and “oxygen therapy.”
Ozone is an allotropic form of oxygen, with a molecule made
up by three oxygen atoms. Ozone is a powerful oxidant, di-
rectly acting on the cells through lipidic peroxidation, amino
acids oxidations and DNA irreversible damage, leading to cell
death.16 Being one of the strongest oxidants, it is extremely tox-
ic. Ozone therapy consists in the preparation of an extemporary
mixture of ozone (5% maximum concentration) and oxygen
(95% minimum concentration), so-called medical ozone (MO).
MO has several actions and has been applied on a wide range
of pathologies as an unconventional medicine practice.17 MO
can be administered systemically by adding it to a sample of
patient’s blood which is then reinfused (auto-hemo-infusion)
or by adding it to saline solution. It can also be administered
locally, by subcutaneous/intramuscular injection, by inhalation
or by exposing the skin or other bodily cavities (i.e., rectal,
nasal) to an air mixture containing MO.18 The biological effects
of ozone are mainly mediated by antioxidant systems.19 The
anti-inammatory, immuno-modulator and virustatic effects
of ozone as well as its direct effect on coagulation and micro-
circulation improvement are particularly important.
Biochemical reactions
MO reacts within biological liquids especially in the blood
with a wide range of substrates, involved in several metabolic
pathways. These complex reactions occur very quickly, and
MO’s half-life lasts only milliseconds. MO mainly reacts with
polyunsaturated fatty acids, bound to albumin and present in
most lipids and phospholipids, as well as with antioxidants,
proteins and carbohydrates.20 Most of MO is involved in the
reaction of “addition of polyunsaturated fatty acids to double
carbon bonds,” known as “Criegée reaction.”20 This reaction
involves the formation of a primary ozonide, which splits into
a lipid peroxidation product whose structure is α-hydroxy-
hydroperoxide and its aldehyde. Lipid peroxidation products
oxidizing power is lower than other peroxides and in an aque-
ous solution it is degraded into hydrogen peroxide, a reactive
oxygen species. Among the aldehydes that are formed in this
process, the most active is the 4-hydroxy-2,3 trans-nonenal,
fundamental in cellular signal-transduction, by upregulating
the antioxidant system in a controlled way on numerous cells
of the organism.21 This cascade of reactions ends with the ex-
haustion of MO. In other words, ozone is an unstable molecule
and causes oxidative reactions but, if administered properly
(i.e., MO), it generates a “controlled and transient oxidative
stress,” which stimulates the cell’s antioxidant system. This
is the paradox that a molecule having oxidizing activity can
be the basis of a complex antioxidant mechanism with several
metabolic effects, as summarized in Figure 1.22
Figure 1: Biological effects of oxygen-ozone.
Note: LOP: Lipid peroxidation product; NO: nitric oxide; O3: ozone; ROS: reactive
oxygen species. Adapted from Bocci et al.22
Anti-inflammatory and immunomodulatory effects
The anti-inammatory and immunomodulatory effect of MO
is expressed through the activation or inhibition of different
molecular pathways, involved in systemic inammation.
For instance, MO inhibits the nuclear factor-kappaB (NF-
κB) pathway, whose activation promotes the transcription
of proinammatory cytokine genes such as tumor necrosis
factor-α, IL-1β, IL-8.23 The underlying reasons for the anti-
inammatory efcacy of MO therapy can therefore be found
in a systemic reduction of inammatory parameters such as
IL-1.24 On the other hand, MO stimulates the activation of
the nuclear factor erythroid 2-related factor 2 pathway,25 an
intracellular transcription factor, binding to the anti-oxidant
response elements nuclear regions encoding for antioxidants
enzymes such as superoxide dismutase, catalase and heme
oxygenase-1. Heme oxygenase-1 is a microsomal enzyme
that catalyzes the degradation of haeme and produces carbon
monoxide, which is another inhibitor of the NF-κB pathway.26
Moreover, heme oxygenase-1 directly activates anti-inamma-
tory cytokines,25 and increases the number of progenitor cells
of the endothelium.27,28 Given the above-mentioned reasons,
one might wonder if ozone can have an immunosuppressant
effect. On the contrary, ozone application in addition to an-
tibiotic therapy can have protective effects on septic injuries
of lungs, by lowering the lipopolysaccharide-induced NF-κB
hyperexpression.16,29 Yet, even though a few studies have been
carried out to evaluate effects of ozone on sepsis, no clear
benets have been found.30-32
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Effects on microcirculation
MO is mostly applied where microcirculation is impaired,
as in peripheral arteriopathies (i.e., diabetic foot or systemic
sclerosis).33 Ozone therapy improves blood ow in poorly
perfused territories, promoting revascularization, vascular
compliance, rheology and blood-tissues gas exchanges. Re-
vascularization can be assessed by video capillaroscopy with
optical probe, with the restoration of the three-dimensional
capillary bed framework,28 if the capillary damage has not
already caused a severe capillary loss.32 Revascularization
depends on a non-chaotic neo-angiogenesis, favored by an
appropriate synthesis of vascular endothelial growth factor,
due to an increased production of hydrogen peroxide.34 In ad-
dition, MO induces nitric oxide synthase with the consequent
formation of nitric oxide and other reactive nitrogen species.
Reactive nitrogen species play a central role as modulators of
the physiological signals of the cardiovascular system and in
particular of vasodilator mechanisms; nitric oxide also acts as
a neuromodulator, and inhibitor of platelet aggregation, vas-
cular adhesion of leukocytes and the proliferation of smooth
muscle cells.35 At an erythrocyte level, the molecular pathways
determined by MO lead to an increase in the concentration
of 2,3-diphosphoglicerate, which determines a right shift in
the dissociation curve of oxyhemoglobin and, therefore, an
increased exchange of oxygen to the peripheral tissues. In ad-
dition, the temporary lipid peroxidation action makes the red
blood cell membrane more deformable. Thus, in the smaller
capillaries, the red cells, instead of moving in disorder, align
themselves and proceed along the axis of the vessel, arranging
in a pile (Fahraeus-Lindquist effect) and facilitating metabolic
exchanges.36 MO has a benecial action in the granulation
and healing processes through lowering production of tissue
plasminogen activation factor and inducing greater quantities
of its inhibitors, favoring the processes of brinolysis to those
of deposition of brin.37
The net result of MO in the damage of microcirculation is to
favor the regeneration of the microcirculation and the gaseous
exchanges (through the increase of the blood ow, decrease
of the blood viscosity and of the platelet aggregation, of the
erythrocyte deformability and of the release of oxygen) and,
at the same time, to reduce thrombotic and brotic processes.
Virustatic effects
Ozone directly inactivates some viruses. To successfully pen-
etrate cells, various viruses (e.g., hepatitis A, human immuno-
deciency virus, Ebola) require that membrane glycoproteins
have sulfhydryl groups in the reduced form. The Ebola virus
has regions on the envelope rich in cysteine, whose altera-
tion blocks the growth properties of the virus.38 Ozone can
permanently oxidize the thiol residues of cysteine in vitro.39
Virustatic ozone against Ebola has also been tested in vivo,
with encouraging results but on a limited sample.40
MO could play a benecial role in the patient suffering from
COVID-19 on various levels. To foster the use of ozone
therapy in COVID-19 there is the similarity between the
microvascular damage in the peripheral arterial diseases41
and in the diabetic retinopathy42 with the microvascular
(arterioles, precapillary arterioles, capillaries, postcapillary
venules, and venules) damage at lung level in COVID-19.
The latter is evidenced by CT imaging of tubular and en-
larged pulmonary vessels followed by a sudden reduction of
their caliber43 and by pathological ndings of microthrombi
and capillary aneurisms. All these diseases share vascular
features of microhemorrhages, microthrombi, microaneu-
rysms, pericapillary and tissue edema, as demonstrated both
by video capillaroscopy with optical probe and by autopsy
ndings. The action of MO on microcirculation in terms of
organized neo-angiogenesis, increase in blood ow, decrease
in blood viscosity and platelet aggregation, and increase in
red blood cells deformability and gas exchanges was previ-
ously discussed. Overall, MO therapy has given excellent
benets in diabetic foot, trophic or pressure ulcers, systemic
sclerosis.17,33,34 Positive responses in terms of reduction of
ischemic-hemorrhagic damage of the microcirculation could
be obtained in COVID-19 pneumonia and on other paren-
chyma by an early MO auto-hemo-infusion. These positive
responses could be mediated both by increasing the produc-
tion of surfactant and the elasticity of the alveoli and by a
reduction of endothelial damage, through platelet adhesion
reduction and through blockage of the coagulation cascade
preventing microthrombi formation.44 In addition, this effect
would also occur at a peripheral level, by reducing formation
of deep venous thrombi and consequent pulmonary embolism.
Both micro and macrothrombi lead to the formation of pul-
monary shunt and pulmonary hypertension, that are typical
features of hypoxemia refractory to ventilatory therapy.45 To
our knowledge, no studies have been published regarding the
development of pulmonary hypertension in COVID-19 or its
severity in those with a history of pulmonary hypertension.
In the authors’ opinion, MO should not be administered in a
context of advanced microvascular lung damage with massive
capillary loss, similar to what occurs in systemic sclerosis
with pulmonary hypertension46; in this context ozone could
determine a worsening of lung damage, inammation and
edema in patients with pulmonary hypertension,47 or it could
have no effect due to the capillary loss. Yet, an anti-hypoxemic
action was observed by the MO auto-hemo-infusion in pa-
tients suffering from chronic obstructive bronchitis.48 Further-
more, in an animal model with a healthy lung, ozone seems to
have a protective action on the genesis of pulmonary edema,
thanks to the ability to stimulate the pulmonary sympathetic
nervous system, and block microvascular responses to acetyl-
choline and substance P at a lung level.49 Interestingly, when
applied to the patient with severe respiratory insufciency,
requiring mechanical ventilation with long-term elevated
positive end-expiratory pressure (as in severe COVID-19
pneumonia), inhaled ozone improved gas exchanges in the
lung, increased surfactant production and lung compliance
in a small sample of patients.44
Another potential benet of MO auto-hemo-infusion could
be on the “cytokine storm” in the pathogenesis of respiratory
failure, disseminated intravascular coagulation and multi-
organ failure in COVID-19. The protective immunomodula-
tory effects of ozone in septic lung injury have already been
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Ranaldi et al. / Med Gas Res
discussed previously. “Cytokine storm” hemodynamic conse-
quences are similar to those of toxic shock.50 In toxic shock,
as in septic shock, microcirculatory abnormalities are cardinal
features, being dissociated from that of systemic hemody-
namic and more severe among non-survivors.51 Therefore,
microcirculatory alterations may persist despite correction of
systemic hemodynamic variables with vasopressors drugs.52
Ozone preconditioning has been demonstrated to be as potent
as dexamethasone in reducing tumor necrosis factor-α level
during lipopolysaccharide-induced endotoxic shock and
oxidative stress in a murine model.31 In addition to primary
“cytokine storm,” a superinfection and a secondary septic
shock are prevalent among patients with COVID-19.31,53
Ozone has both a direct bactericidal action, through lipid
peroxidation product and reactive oxygen species,54 and an
indirect one, through an increase in neutrophilic chemotaxis
and myeloperoxidase activity.55 Thus, MO could both reduce
the microcirculatory alterations induced by the “cytokine
storm” and the occurrence of bacterial superinfections and
septic shock.
Like in the case of Ebola virus, another potential action
of ozone is the inactivation of the spike protein that coro-
naviruses need to infect guest cells. The spike protein is
rich in cysteine residues, permanently oxidized by ozone,
and these residues are preserved during the evolution of the
viral strains.56 Therefore, SARS-CoV-2 could potentially be
inactivated by ozone-mediated oxidation during the viremic
phase (if administered early via auto-hemo-infusion) and at
the level of the colonized nasopharyngeal mucosa of healthy
carriers through topic formulations.57
Only one clinical trial about ozone therapy in patients
affected by severe COVID-19 related pneumonia has been
conducted to date (NCT04370223). Preliminary data showed
that the patients treated with MO presented both shorter time
to clinical improvement and a signicantly higher proportion
of patients achieving 14-day clinical improvement compared
to those receiving supportive care.58 Yet, it was a single-center
study enrolling few patients and larger randomized clini-
cal trials are needed. On the other hand, three trials about
hyperbaric oxygen therapy have already been conducted
(NCT04370223, NCT04343183, and NCT04332081). This
preliminary data suggest potential benet of hyperbaric
oxygen therapy in COVID-19.59 This nding is also of in-
terests because, in a murine model of pulmonary damage,
a combination of hyperbaric oxygen therapy and MO was
demonstrated to be more effective than hyperbaric oxygen
therapy regarding serum IL-1β, lung glutathione storages
and histologic outcome.29
Regarding MO systemic therapy, there are some contraindi-
cations and warnings. First, MO should not be administered
directly in the blood and should not be mixed in solution
with other drugs but saline solution, because of its oxidizing
effect. Second, there are no studies about ozone-therapy and
pregnancy; hence it should be avoided in this case. Another
absolute contraindication is glucose-6-phosphate dehydroge-
nase deciency in systemic administration,60 the same warning
concerning antimalarials.61 Potentially, MO administration in
patients suffering from hyperthyroidism could be harmful for
the lungs, as shown in murine models.62
The adjuvant use of ozone-therapy in COVID-19 through auto-
hemo-infusion could better oxygenate the tissues, decrease
lung inammation and regulate the immune response, avoiding
the “cytokine storm,” slow down viral growth, regulate lung
microcirculation and avoid or slow down vascular hypertrophy
and the consequent hyperemia, especially in the initial stages,
by contrasting endothelial damage, in analogy with what hap-
pens in peripheral arterial pathologies. An association with
other currently available treatments is mandatory, to avoid or
limit the use of intubation and, ultimately, allowing a shorten-
ing of healing times with the possibility of greater replacement
in the intensive care, to date the real limiting factor.
If auto-hemo-infusion is not administrable, MO could be
delivered through dilution in saline solution or rectal infu-
sion. Endonasal application could be administered to inac-
tivate colonizing SARS-CoV2 in the asymptomatic carriers.
Furthermore, since there are no major side effects and it can
be synergistic with other therapies, it is a candidate to be
an essential therapy in home care, given its easy execution
and low cost. Ozone-therapy could be considered a feasible,
cost-effective and easy to administer adjuvant therapy while
waiting for the synthesis of a therapy or the development of
the vaccine.
Author contributions
Manuscript concepts and preparation: GTR; search strategy and manu-
script editing: GTR, ERV; manuscript review: ERV, LF. All authors
read and approved the nal version of manuscript for publication.
Conflicts of interest
The authors declare no conicts of interest.
Financial support
The authors declare they did not receive nancial support for the
present review.
Copyright license agreement
The Copyright License Agreement has been signed by all authors
before publication.
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Externally peer reviewed.
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Received: May 10, 2020
Accepted: May 11, 2020
Published Online: July 13, 2020
[Downloaded free from on Sunday, November 8, 2020, IP:]
... It can reactivate the intra-and extracellular antioxidant system, thereby reversing chronic oxidative stress in various inflammatory, degenerative processes, etc. During ozone treatment, cells throughout the body receive gradual and subtle impulses of LOP, significant long-term messengers that play a crucial role in up-regulating antioxidant enzymes in multiple cell types while rebalancing the oxidant/antioxidant system [46,47]. ...
... Severe oxidative stress, triggered by high concentrations of ozone, along with proinflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), activate NF-κB, a key regulator of the inflammatory response and muscle atrophy. This contributes to an increased inflammatory response and tissue damage, including the release of other inflammatory factors that enhance the migration of eosinophils and neutrophils [9,13,17,47,49]. ...
Introduction. Oxygen-ozone therapy stands as a medically endorsed practice confirmed by numerous international clinical studies. Various authors have illustrated the beneficial clinical outcomes of ozone therapy in terms of its capacity to regulate redox balance, cellular inflammatory responses, and adaptation to ischemia/reperfusion processes. Ozone therapy extends to encompass a range of viral infections, inflammatory disorders, and degenerative ailments, used as both monotherapy and as an adjunct to unified conventional therapies. Material and methods. Narrative literature review study. Bibliographic search was conducted using the PubMed, Hinari, and SpringerLink databases, as well as the National Center of Biotechnology Information and Medline. Articles published between 1990 and 2022 were selected using various combinations of keywords, including “ozone”, “ozone therapy”, “mechanisms of ozone action”, “biological effects of ozone”, “antioxidant effect”, “anti-inflammatory effect” and “immunomodulatory effect.” Information regarding ozone’s mechanisms of action was identified and processed. Following the database information processing and search criteria, a total of 475 full-text articles were found. The final bibliography consists of 52 relevant sources that were deemed representative of the materials published on the topic of this synthesis article. Results. The effects of ozone on oxygen metabolism are explained by changes in the rheological properties of blood, including inhibition of erythrocyte aggregation and stimulation of 2,3-diphosphoglycerate in erythrocytes, favoring the transport and delivery of oxygen to tissues while facilitating the substantial elimination of nitric oxide and increasing blood flow. Intracellular triatomic oxygen enhances the oxidative carboxylation of pyruvate, stimulating ATP production, which also contributes to reducing peripheral vascular resistance. Conclusions. Ozone generates a moderate oxidative stress. Yet, it can set off several beneficial biochemical mechanisms that reactivate both the intra- and extracellular antioxidant systems and reverse chronic oxidative stress in various inflammatory and degenerative processes. Ozone induces a mild activation of the immune system by triggering neutrophil activation and stimulating the synthesis of certain cytokines (IL-2, TNF-α, IL-6, and IFN-γ), thereby initiating a complete cascade of immune responses. Ozone therapy yields the following biological reactions: optimization of blood circulation and oxygen delivery to ischemic tissue, regulation of cellular antioxidant enzymes, initiation of a slight immune system activation, and enhancing the release of growth factors.
... The numerous papers describing the ability of oxygen-ozone to counteract SARS-CoV2 infections in progressing to more severe forms of COVID-19 [39][40][41][42][43][44][45] suggest that ozone is able to treat COVID-19 [46] and that the mechanism by which ozone targets SARS-CoV2 infection is of a hormetic nature [46] (Table 1). Ozone does not actually directly elicit a pro-inflammatory response, in order to help innate immune cells in the virus clearance. ...
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An increasing body of evidence in the literature is reporting the feasibility of using medical ozone as a possible alternative and adjuvant treatment for COVID-19 patients, significantly reducing hospitalization time, pro-inflammatory indicators, and coagulation markers and improving blood oxygenation parameters. In addition to the well-described ability of medical ozone in counteracting oxidative stress through the upregulation of the main anti-oxidant and scavenging enzymes, oxygen–ozone (O2–O3) therapy has also proved effective in reducing chronic inflammation and the occurrence of immune thrombosis, two key players involved in COVID-19 exacerbation and severity. As chronic inflammation and oxidative stress are also reported to be among the main drivers of the long sequelae of SARS-CoV2 infection, a rising number of studies is investigating the potential of O2–O3 therapy to reduce and/or prevent the wide range of post-COVID (or PASC)-related disorders. This narrative review aims to describe the molecular mechanisms through which medical ozone acts, to summarize the clinical evidence on the use of O2–O3 therapy as an alternative and adjuvant COVID-19 treatment, and to discuss the emerging potential of this approach in the context of PASC symptoms, thus offering new insights into effective and safe nonantiviral therapies for the fighting of this devastating pandemic.
... Medical ozone is an ozone/oxygen mixture which has showed its effectiveness in a number of diseases having an oxidative etiology [6][7][8]. Experimental and clinical trials have evidenced its therapeutic actions on targets that are coincident with molecules/processes recognized as pathological in SARS-CoV-2. Therefore, taking the background described above into account, the aim of this study was to establish a relevant analysis of the pharmacological mechanism of action demonstrated by ozone in previous investigations. ...
Introduction: Medical ozone has been used with safety and efficacy in different diseases of oxidative etiology, for the most part involving autoimmune diseases. Methods: An analysis of the pharmacological mechanism of action of ozone was carried out to explain its clinical effectiveness and its positive response in clinical patients to COVID-19. This was done in the context of the different therapeutic targets that have been demonstrated for ozone in other diseases (autoimmune and hypoxia status). Results: Based on the intestine/lung functional axis, the necessity of rectal insufflation as route of application with the aim of attaining improved results using medical ozone against COVID 19 is demonstrated. It was possible to identify at least nine adverse events/molecules which were targets of regulation through medical ozone in other diseases, including innate immune response, nuclear transcription factor NF-kB, “cytokine storm”, inflammation, severe acute respiratory syndrome and coagulopathy. Some of them lead to multi organ failure. Finally, a brief analysis is undertaken to show the regulatory effects of ozone versus the comorbidities contributing to virus lethality, including hyperglycemia and its vascular complications. Conclusions: Medical ozone is effective against COVID-19/SARS-CoV-2: due to the multiple targets it is able to regulate and thereby achieve a positive patient response.
... Some antibiotics, such as rifaximin, can instead be used to target a larger number of pathogens, improving conditions such as IBS, SIBO and preventing encephalopathy in patients suffering from liver disease [30]. Ozone, for instance, also seems to have a similar capacity to reduce inflammation in the gut, also through microbiota modulation [31,32]. ...
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How can the knowledge of probiotics and their mechanisms of action be translated into clinical practice when treating patients with diverticular disease and acute diverticulitis? Changes in microbiota composition have been observed in patients who were developing acute diverticulitis, with a reduction of taxa with anti-inflammatory activity, such as Clostridium cluster IV, Lactobacilli and Bacteroides. Recent observations supported that a dysbiosis characterised by decreased presence of anti-inflammatory bacterial species might be linked to mucosal inflammation, and a vicious cycle results from a mucosal inflammation driving dysbiosis at the same time. An alteration in gut microbiota can lead to an altered activation of nerve fibres, and subsequent neuronal and muscular dysfunction, thus favoring abdominal symptoms' development. The possible role of dysbiosis and mucosal inflammation in leading to dysmotility is linked, in turn, to bacterial translocation from the lumen of the diverticulum to perivisceral area. There, a possible activation of Toll-like receptors has been described, with a subsequent inflammatory reaction at the level of the perivisceral tissues. Being aware that bacterial colonisation of diverticula is involved in the pathogenesis of acute diverticulitis, the rationale for the potential role of probiotics in the treatment of this disease becomes clearer. For this review, articles were identified using the electronic PubMed database through a comprehensive search conducted by combining key terms such as "gut microbiota", "probiotics and gut disease", "probiotics and acute diverticulitis", "probiotics and diverticular disease", "probiotics mechanism of action". However, the amount of data present on this matter is not sufficient to draw robust conclusions on the efficacy of probiotics for symptoms' management in diverticular disease.
... COVID-19 is a disease caused by a novel coronavirus and it can cause a vast array of symptoms, ranging from mild, flu-like symptoms to severe respiratory failure [52]. Many different therapeutic approaches have been tried, mostly anti-inflammatory therapies, ranging from steroids to antimalaria drugs; even non-conventional therapies, such as ozone-therapy, have been tested [53]. The most severe symptoms seem to be caused, at least in part, by an autoinflammatory reaction, with characteristics of a cytokine storm [52]: Binding of the novel coronavirus to TLRs causes an increase in the levels of IL-1β, which mediate fibrosis and inflammation of the lung [50]. ...
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: The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far.
... On the other hand, the action of ozone at the microcirculation level is well known [41,42] and its action depends on the direct or indirect generation of important mediators such as H2O2, 4HNE, NO, QNO1, HO1 and the regulation of the Pathways Nrf2-NF-Kb and Angpt1 / Tie 1-2, to counteract the overproduction of early-response proinflammatory cytokines (TNF, IL-6 and IL-1β) and ultimately to the fulminating multi-organ failure that we have also seen active intestinal. ...
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COVID-19 is the disease caused by the new coronavirus SARS-CoV-2 and is characterized by clinical manifestations ranging from mild, flu-like symptoms, to severe respiratory failure and multi-organ failure. Patients with more severe symptoms may require intensive care treatments and face a high risk of mortality.COVID 19 is characterized by an abnormal inflammatory response similar to a cytokine storm, which is associated with endothelial dysfunction and microvascular complications. To date, no specific treatments are available for COVID-19 and its potentially life-threatening complications.Numerous experimental and clinical observations have suggested that the gut microbiota plays a key role in sepsis and ARDS pathogenesis. The incidence of diarrhea in COVID-19 patients and the high mortality rate in elderly patients, considered together, indicate a possible involvement of the intestine-lung axis in COVID-19 with association of dysbiosis.Ozonetherapy is the administration of a mixture of ozone and oxygen, or Medical Ozone (MO), which produces a series of benefits capable of counteracting a wide range of pathologies, in use for over a century as an unconventional medicine practice.MO is fundamental to inhibit the activation of the inflammatory reaction and to obtain an antioxidant activity both in the tissue and in the blood. Oxidative ozone preconditioning causes an increase in SOD, GSH-Px values.MO, using large auto-hemo-infusion or rectal insufflation technique or ozonized water, could help oxygenate the tissues better, decrease gut inflammation and regulate immune response, help slow down viral growth, regulate circulation and avoid or slow down vascular hypertrophy and consequent hyperemia , especially in the early stages, with obvious benefit at microbiome level.
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Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has rapidly swept across the world. As new knowledge regarding treatment options for COVID-19 has emerged, the use of ozone therapy in the context of SARS-CoV-2 infection as an integrative therapeutic option supplementary to standard treatment regimen has been assessed in the present literature. We reviewed, critically analyzed, and summarized all present published literature on ozone therapy in association with COVID-19 via the PubMed database. Various reports and studies on the use of ozone (major autohemotherapy, rectal ozone insufflation, ozone inhalation) in patients affected by COVID-19 indicate that ozone therapy may reduce morbidity and accelerate recovery, while exhibiting a high safety profile with no relevant adverse effects. Current literature suggests that integrating ozone therapy into the existing standard of care and best available therapy for the treatment of COVID-19 patients offers major advantages in terms of superior clinical outcome parameters and amelioration of laboratory results. Further prospective studies are warranted to guide the next steps in the clinical application of ozone therapy and examine its impact on the course of COVID-19.
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The objective of this study was to provide lung disinfection by nebulizing ozone gas with distilled water and olive oil for patients who have clinical symptoms due to coronavirus disease 2019 (COVID-19). The study attempted to reduce the viral load of COVID-19 in the lungs of patients, to provide a faster response to medical treatment. Between August 2020 and September 2020, 30 patients who met the study criteria were prospectively evaluated. There were 2 groups with 15 patients in each group: patients in control group were not treated with ozone and only received standard COVID-19 treatment; patients in ozone group received lung disinfection technique with ozone and standard COVID-19 treatment. A statistically significant difference was found in the length of stay in hospital, change in C-reactive protein, polymerase chain reaction results after 5 days, and computed tomography scores between two groups. There was no statistically significant difference in D-dimer, urea, lactate dehydrogenase, lymphocyte, leukocyte, and platelet between two groups. According to the data, we think that the lung disinfection technique applied with ozone inhalation reduces the rate of pneumonia in COVID-19 patients and makes the patients respond faster to the treatment and become negative according to the polymerase chain reaction tests. The study was approved by the Ethical Committee of the Istanbul Medipol University Clinical Trials (approval No. 0011) on July 2, 2020.
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A ozonioterapia é um tratamento que usa o gás medicinal ozonizado, com uma mistura de ozônio e oxigênio puro em concentrações de 5% e 95% respectivamente. Esta terapia tem consideráveis e expressivos benefícios quando administrada em doses adequadas, por ter uma forte ação antioxidante, bactericida, fungicida e antiviral. Dentre as ações antivirais, a ozonioterapia possui interessantes características para combater o coronavírus. Neste sentido, essa pesquisa pretende realizar uma revisão de literatura da aplicação da ozonioterapia no tratamento da infecção por COVID-19. Este estudo trata-se de uma revisão bibliográfica integrativa do tipo exploratória de caráter qualitativa, com os dados coletados em artigos, monografias e legislações brasileiras no período de março de 2011 a março de 2021. Através dos resultados, foi possível perceber que a ozonioterapia pode ser utilizada como monoterapia ou adjuvante em associação com outros fármacos no tratamento contra a COVID-19, visto que após o uso desta terapia constatou-se uma melhora no quadro clínico, nos marcadores bioquímicos de inflamação e radiológicos sem apresentar efeitos colaterais, tornando-se um tratamento efetivo e benéfico aos pacientes. Este trabalho corrobora com a ampliação sobre o entendimento e propagação da ozonioterapia e relata a relevância social e científica do uso da ozonioterapia no tratamento da COVID-19.
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Importance The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations. Objective To study the neurologic manifestations of patients with COVID-19. Design, Setting, and Participants This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection. Main Outcomes and Measures Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. Results Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). Conclusions and Relevance Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.
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Harch Paul 1 Department of Medicine, Section of Emergency and Hyperbaric Medicine, Louisiana State University Health Sciences Center, New Orleans, LA Zhong X, Tao X, Tang Y, Chen R. The outcomes of hyperbaric oxygen therapy to retrieve hypoxemia of severe novel coronavirus pneumonia: first case report. Zhonghua Hanghai Yixue yu Gaoqiya Yixue Zazhi. 2020. doi: 10.3760/cma.j.issn.1009-6906.2020.0001 Zhong XL, Niu XQ, Tao XL, Chen RY, Liang Y, Tang YC. The first case of HBOT in critically ill endotracheal intubation patient with COVID-19. Beijing, China: Novel Coronavirus Pneumonia Research Network Sharing Platform of China Association for Science and Technology. 2020 Jain KK. Textbook of Hyperbaric Medicine. 6th ed. Cham, Switzerland: Springer. 2017 Rogatsky GG, Shifrin EG, Mayevsky A. Acute respiratory distress syndrome in patients after blunt thoracic trauma: the influence of hyperbaric oxygen therapy. Adv Exp Med Biol. 2003;540:77-85 Sellers LM. The fallibility of the forrestian principle. 'semper primus pervenio maxima cum VI' Laryngoscope. 1964;74:613-633.
Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n=5) and purpuric skin rash (n=3). The pattern of COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the inter-alveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic ARDS, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the alternative and lectin-based complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the inter-alveolar septa and the cutaneous microvasculature of two cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.
A hallmark of severe COVID‐19 is coagulopathy, with 71.4% of patients who die of COVID‐19 meeting ISTH criteria for disseminated intravascular coagulation (DIC) while only 0.6% of patients who survive meet these criteria (1). Additionally, it has become clear that this is not a bleeding diathesis but rather a predominantly pro‐thrombotic DIC with high venous thromboembolism rates, elevated D‐dimer levels, high fibrinogen levels in concert with low anti‐thrombin levels, and pulmonary congestion with microvascular thrombosis and occlusion on pathology in addition to mounting experience with high rates of central line thrombosis and vascular occlusive events (e.g. ischemic limbs, strokes, etc.) observed by those who care for critically ill COVID‐19 patients (1‐7). There is evidence in both animals and humans that fibrinolytic therapy in Acute Lung Injury and ARDS improves survival, which also points to fibrin deposition in the pulmonary microvasculature as a contributory cause of ARDS and would be expected to be seen in patients with ARDS and concomitant diagnoses of DIC on their laboratory values such as what is observed in more than 70% of those who die of COVID‐19 (8‐10).
Importance In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) emerged in China and has spread globally, creating a pandemic. Information about the clinical characteristics of infected patients who require intensive care is limited. Objective To characterize patients with coronavirus disease 2019 (COVID-19) requiring treatment in an intensive care unit (ICU) in the Lombardy region of Italy. Design, Setting, and Participants Retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinator center (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network and treated at one of the ICUs of the 72 hospitals in this network between February 20 and March 18, 2020. Date of final follow-up was March 25, 2020. Exposures SARS-CoV-2 infection confirmed by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swabs. Main Outcomes and Measures Demographic and clinical data were collected, including data on clinical management, respiratory failure, and patient mortality. Data were recorded by the coordinator center on an electronic worksheet during telephone calls by the staff of the COVID-19 Lombardy ICU Network. Results Of the 1591 patients included in the study, the median (IQR) age was 63 (56-70) years and 1304 (82%) were male. Of the 1043 patients with available data, 709 (68%) had at least 1 comorbidity and 509 (49%) had hypertension. Among 1300 patients with available respiratory support data, 1287 (99% [95% CI, 98%-99%]) needed respiratory support, including 1150 (88% [95% CI, 87%-90%]) who received mechanical ventilation and 137 (11% [95% CI, 9%-12%]) who received noninvasive ventilation. The median positive end-expiratory pressure (PEEP) was 14 (IQR, 12-16) cm H2O, and Fio2 was greater than 50% in 89% of patients. The median Pao2/Fio2 was 160 (IQR, 114-220). The median PEEP level was not different between younger patients (n = 503 aged ≤63 years) and older patients (n = 514 aged ≥64 years) (14 [IQR, 12-15] vs 14 [IQR, 12-16] cm H2O, respectively; median difference, 0 [95% CI, 0-0]; P = .94). Median Fio2 was lower in younger patients: 60% (IQR, 50%-80%) vs 70% (IQR, 50%-80%) (median difference, −10% [95% CI, −14% to 6%]; P = .006), and median Pao2/Fio2 was higher in younger patients: 163.5 (IQR, 120-230) vs 156 (IQR, 110-205) (median difference, 7 [95% CI, −8 to 22]; P = .02). Patients with hypertension (n = 509) were older than those without hypertension (n = 526) (median [IQR] age, 66 years [60-72] vs 62 years [54-68]; P < .001) and had lower Pao2/Fio2 (median [IQR], 146 [105-214] vs 173 [120-222]; median difference, −27 [95% CI, −42 to −12]; P = .005). Among the 1581 patients with ICU disposition data available as of March 25, 2020, 920 patients (58% [95% CI, 56%-61%]) were still in the ICU, 256 (16% [95% CI, 14%-18%]) were discharged from the ICU, and 405 (26% [95% CI, 23%-28%]) had died in the ICU. Older patients (n = 786; age ≥64 years) had higher mortality than younger patients (n = 795; age ≤63 years) (36% vs 15%; difference, 21% [95% CI, 17%-26%]; P < .001). Conclusions and Relevance In this case series of critically ill patients with laboratory-confirmed COVID-19 admitted to ICUs in Lombardy, Italy, the majority were older men, a large proportion required mechanical ventilation and high levels of PEEP, and ICU mortality was 26%.
Coagulopathy in corona virus infection has been shown to be associated with high mortality with high D‐dimers being a particularly important marker for the coagulopathy.¹ In the latest paper from the same group, the use of anticoagulant therapy with heparin was shown to decrease mortality as well. ² This is especially so in patients i) who have met the sepsis induced coagulopathy (SIC) criteria ≥4 (40.0% vs 64.2%, P=0.029) compared to those with SIC score <4 (29.0% vs 22.6%, P=0.419).or ii) with markedly elevated D‐dimer (greater than six‐fold at the upper limit of normal).
Background The SARS‐CoV‐2 pandemic is an ongoing global health emergency. The aim of our study was to investigate the changes of liver function and its clinical significance in COVID‐19 patients. Method This retrospective, single‐center study was conducted on 115 confirmed cases of COVID‐19 in Zhongnan hospital of Wuhan University from Jan 18 to Feb 22, 2020. Liver function and related indexes were analyzed to evaluate its relationship with disease progression in COVID‐19 patients. Results Part of the COVID‐19 patients presented with varying degrees of abnormality in liver function indexes. However, the levels of ALT, AST, TBIL, GGT and LDH in COVID‐19 patients were not significantly different in compared with hospitalized community‐acquired pneumonia patients, and the levels of albumin is even significantly higher. Levels of ALT, AST, TBIL, LDH and INR showed statistically significant elevation in severe COVID‐19 cases compared with that in mild cases. However, the clinical significance of the elevation is unremarkable. Majority of severe COVID‐19 patients showed significantly decreasing in albumin level and continuously decreasing in the progress of illness. Most of the liver function indexes in COVID‐19 patients were correlated with CRP and NLR, the markers of inflammation. Logistic regression analysis further identified NLR as the independent risk factor for severe COVID‐19, as well as age. Conclusions Although abnormalities of liver function indexes are common in COVID‐19 patients, the impairment of liver function is not a prominent feature of COVID‐19, and also may not have serious clinical consequences.
Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.