Received: 20 October 2020 | Revised: 16 November 2020 | Accepted: 21 December 2020

DOI: 10.1002/jmv.26754

REVIEW

COVID‐19 pathogenesis, prognostic factors, and treatment

strategy: Urgent recommendations

Bin Zhou MD, PhD | Shinsuke Kojima MD, PhD | Atsuhiko Kawamoto MD, PhD |
Masanori Fukushima MD, PhD

Department of Medscience, Translational

Research Center for Medical Innovation, Abstract
Foundation for Biomedical Research and
The pandemic of novel coronavirus disease (COVID‐19) is not yet close to being over,
Innovation, Kobe, Japan
more than 8 months after the first cases, but researchers are making great progress in
Correspondence fighting the disease. We have conducted a brief review of the geographic differences in
Bin Zhou, MD, PhD and Shinsuke Kojima, MD,
PhD, Translational Research Informatics the prevalence of COVID‐19, the updated pathological findings, prognostic factors, and
Center, Foundation for Biomedical Research treatments for disease prevention and improvement of prognosis. Although hydroxy-
and Innovation, 1‐5‐4 Minatojima‐
minamimachi, Chuo‐ku, Kobe 650‐0047, chloroquine and tocilizumab have been recommended by some researchers, many
Japan. clinical trials have failed to confirm any beneficial effect of these and other drugs on
Email: zhoubin@tri-kobe.org (BZ) and
shinkx@tri-kobe.org (SK) COVID‐19, in terms of improved clinical status or reduced patient mortality. Currently,
glucocorticoid is the only drug that reduces the mortality of COVID‐19 in a randomized
controlled trial; however, it is still necessary to establish the optimal timing of ad-
ministration. It is also urgent to set up an international or national cohort to address the
risk factors associated with infection, the natural history of COVID‐19, including the
disease type, surrogate markers for critically ill, long‐term sequelae, and reinfection
after exposure, identify responders to glucocorticoid, and establish optimal treatment
strategies for disease control.

KEYWORDS
cohort study, COVID‐19, pathogenesis, prognostic factors, treatment strategy

The novel coronavirus disease (COVID‐19) caused by severe acute re- 1 | G LO B A L E P I D E MI O L O G Y O F

spiratory syndrome coronavirus 2 (SARS‐CoV‐2) was first described CO V ID‐ 1 9
during the outbreak in Wuhan, China in December 2019. More than
6 months after the new coronavirus first emerged, the COVID‐19 pan- 1.1 | Prevalence and distribution
demic is not even close to being over, and on June 8, 2020, numbers of
new cases were still increasing rapidly in several countries.1 Globally, the The novel coronavirus disease (COVID‐19) caused by SARS‐CoV‐2
pandemic is actually speeding up. In some countries such as Switzerland, emerged in Wuhan, China in December 2019. It has now spread to
Japan, Israel, and Australia, the outbreak appeared to be under control in 188 countries around the world, and more than 6.2 million patients
late June; however, even in these countries new cases have a tendency had been infected by June 2, 2020.1 Out of all infected patients, 80%
to lead to local outbreaks, indicating that the epidemic may strike back at were mild or asymptomatic, 20% required hospital admission, and
any time.1 No effective antiviral therapy has yet been established; approximately 5% required intensive care unit (ICU) admission.2
therefore, prevention and management are critical to control the The case‐fatality rate (number of death/number of infected
COVID‐19 pandemic. Here, we conduct a brief review of the epide- cases reported) was higher in Europe than in Asia and America, at
miological features, pathogenesis, and prognosis to help governments over 10% and approximately 5%–6%, respectively. From June 8 to
and clinicians make the right decisions in the fight against the disease. June 30, there was a large increase in case numbers in the United

2694 | © 2020 Wiley Periodicals LLC wileyonlinelibrary.com/journal/jmv J Med Virol. 2021;93:2694–2704.

ZHOU ET AL.
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States, Mexico, Brazil, Peru, Chile, India, and Pakistan (Figure 1). The incubation period for COVID‐19, which is the duration from
Mortality was higher in North America and Europe than in other exposure to the virus (becoming infected) to the onset of symptoms, is on
areas (Figure 2). All data are from website.1 average 5–6 days; however, it can be up to 14 days. The viral load and
The reasons for the geographic differences in prevalence rate shedding pattern is different in each patient. Generally, the virus can be
and mortality are not yet clear. Our hypothesis is that the use of face detected 1 day before and peaks soon after the onset of symptoms, and
masks, cultural differences in character and behavior patterns, and viral shedding times range from 8 to 37 days, with a median of 20 days,
genetic background may be involved in different prevalence. Except based on the testing of oropharyngeal samples.22 The infectious period
biological prognostic factors, average ages of COVID‐19 patients and appears to start 2–3 days before and peak on the onset of symptoms. It
health care difference between countries are associate with mor- has been estimated that 44% of cases were infected during the index
tality. Further research is needed to verify this. case's asymptomatic stage.23 Infectivity of patients with an E‐gene
SARS‐CoV‐2 real‐time polymerase chain reaction cycle threshold (CT)
more than 24 and duration of symptoms more than 8 days may be low.24
1.2 | Transmission routes and prevention In normal conditions without lockdown, the origin of infection is
unclear for the majority of early COVID‐19 cases due to limited testing
The possible modes of transmission of SARS‐CoV‐2 include contact,3–7 capacity and contact tracing at onset of outbreak in China and Japan.
droplet,3–7 airborne,8–10 fomite,11–13 fecal–oral,14–16 Urine,17,18 Saliva19 The data in China showed that 72% from January 1 to January 11, 2020
and animal‐to‐human20 transmission. Virus transmission does not seem and 73% from January 12 to January 22 had no exposure to either the
to be influenced by temperature as COVID‐19 has spread rapidly all Seafood Market or patients with respiratory diseases.25 The data in
over the world. Possible preventive measures against the outbreak of Tokyo, Japan showed the infection route was unclear in 75.4%–49.3% of
such infectious diseases are controlling the source of infection and cases from April 10 to April 30, 30.0%–46.3% from May 1 to May 23,
cutting off the route of transmission to vulnerable groups and people at and 46.9%–54.0% from May 24 to June 7.26 The lack of a clear infection
high risk. SARS‐CoV‐2 is primarily transmitted between people via re- route suggests that infection may be spread by index cases in a pre-
spiratory droplets, which can be produced through talking, coughing, or symptomatic or asymptomatic stage, defined as silent spreaders.
sneezing at the contact routes. The positive rate of virus detected is Wearing a face mask and maintaining physical distance may,
0.92 (0.80–1.07) in specimens of Bronchoalveolar lavage fluid, 0.88 therefore, be the key prevention methods for avoiding COVID‐19 in-
(0.79–0.97) in rectal swab, 0.68 (0.57–0.79) in sputum, 0.67 (0.13–1.2) fection. Surgical face masks significantly reduced detection of influenza
in throat swab, 0.63 (0.29–0.96) nasal swab, 0.46 (0.19–0.73) fibro- virus RNA in respiratory droplets and coronavirus RNA in aerosols.27
bronchoscope brush biopsy, 0.46 (0.31–0.60) nasopharyngeal swabs, Philip et al. confirmed that normal speaking caused airborne virus
0.39 (0.32–0.46) in pharyngeal swabs, 0.33 (−0.20–0.87) in serum, 0.33 transmission in confined environments and a damp cloth cover over the
14,21
(0.16–0.50) in feces. mouth can curb the emission of speech‐generated droplets.28 Because

F I G U R E 1 COVID‐19 case numbers in selected countries by June 8th and June 30th, 2020. The prevalence of COVID‐19 in eastern Asia,
some south Asia, and Australia is much lower than that in Europe, and America. COVID‐19, coronavirus disease 2019
2696 | ZHOU ET AL.

F I G U R E 2 Case‐fatality and mortality by June 8th, 2020. The Case‐fatality of COVID‐19 in eastern Asia, some south Asia and Australia is
much lower than that in Europe, and America. COVID‐19, coronavirus disease 2019

of the risk posed by silent spreaders, it is recommended that not only they symptomatic or asymptomatic? What are the sequelae after re-
infected people but also everyone who is unaware of their health status covery? In the same exposure environment, some people get infected
wear face masks to prevent potential asymptomatic or presymptomatic and some do not. What are the predisposing factors? Data from Italy
transmission. In addition, the development of a rapid and easy method showed that around the time one town was locked down, the prevalence
of detecting silent spreaders is urgently needed, as this could help to of infection was 2.6%, and 42.5% of the confirmed SARS‐CoV‐2 infec-
prevent cluster infection in hospitals, nursing homes, and other orga- tions across the two surveys were asymptomatic.30 A simulation in Japan
nizations, allowing a safe return to work. estimated the infection rate as approximately 30% in the whole popu-
lation. Data from the cruise ship Diamond Princess revealed that the
natural history of 90 people with asymptomatic SARS‐CoV‐2 infection
1.3 | Natural history of COVID‐19 remained unchanged until the resolution of infection. The median num-
ber of days between the first positive PCR test and the first of the two
Symptoms may appear 2–14 days after exposure to the virus. The serial negative PCR tests was 9 days.31 However, it is necessary to
symptoms include fever or chills, cough, shortness of breath or dif- confirm these data in a large national or international cohort, and also to
ficulty breathing, fatigue, muscle or body aches, headache, new loss clarify the long‐term sequelae of COVID‐19. Prognostic factors at the
of taste or smell, sore throat, congestion or runny nose, nausea or time of onset to predict severity or death have been studied extensively,
vomiting, and diarrhea. Dyspnea, a respiratory rate of 30 or more but the factors associated with a sudden turn for the worse are not yet
breaths per minute, appears at the moderate‐to‐severe stage. clear. The factors associated with the outcomes of people who have
We now know that the average incubation time from exposure asymptomatic SARS‐CoV‐2 infection are limited. Precision prevention
to symptom onset is 5–6 days. SARS‐CoV‐2 RNA can be detected in and treatment will be based on disease classification, which has not yet
people 1–3 days before the onset of their symptoms. However, the been established.
time to detectable RNA following exposure is unknown. As shown in
Figure 3, there are many issues to be addressed. A registration study
from exposure to outcome is urgently needed to clarify the natural 2 | FACT ORS A SS OCIAT ED WITH P O OR
history of COVID‐19 to assist in disease control. All people who PR OGN O SIS
accepted the SARS‐cov‐2 RNA PCR test can be included in the co-
hort, in which the majority are supposed to be exposed to the virus. Although approximately 5% of all infected patients require fadmis-
First, from exposure to infection: how high is the infection rate of sion, no effective treatment has yet been established for COVID‐19.
SARS‐CoV‐2? In subjects with a positive PCR test, how frequently are Identification of the prognostic factors associated with progression
ZHOU ET AL.
| 2697

F I G U R E 3 Natural history of subjects with COVID‐19 from time of exposure. PCR test: polymerase chain reaction test for SARS‐CoV‐2
virus. Mild Illness: individuals who have any of the various signs and symptoms of COVID‐19 but who do not have shortness of breath or
abnormal chest imaging. Moderate Illness: individuals who show evidence of lower respiratory disease during clinical assessment or imaging
and who have saturation of oxygen (SpO2) ≥94% on room air at sea level. Severe Illness: Individuals who have SpO2 less than 94% on room air
at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) less than 300 mmHg, respiratory
frequency more than 30 breaths per minute, or lung infiltrates more than 50%. Critical Illness: individuals who have respiratory failure, septic
shock, and/or multiple organ dysfunction.29 SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2

and survival would facilitate the establishment of prevention meth- 3.1 | Immune‐mediated inflammation15,17,33–36,42
ods. The factors associated with poor prognosis of COVID‐19 are as
follows.32–38 (i) Immune‐mediated inflammation plays an important role in the
pathogenesis of COVID‐19. Patients with severe COVID‐19 showed
1. Age ≥65, male, having dyspnea lymphopenia, particularly a reduction in peripheral blood T cells
2. Comorbidities: cardiovascular or respiratory diseases and while CRP, ferritin, IL‐6, IL‐10, C‐X‐C motif chemokine 10 (IP10),
diabetes monocyte chemotactic and activating factor‐1 (MCP‐1), macrophage
3. Hematologic: low lymphocyte count, high neutrophil–lymphocyte inflammatory protein 1 alpha (MIP‐1α), and TNF‐alpha were mark-
ratio edly elevated.42
4. Biochemical: LDH more than 245 U/L, procalcitonin more (ii) CD4+ and CD8+ T cell counts decreased; however, these cells
than 0.05 ng/ml, raised AST, bilirubin, creatinine were highly activated.34
5. Inflammation: raised C‐reactive protein (CRP), interleukin (IL)−6, (iii) CD14+CD16+ inflammatory monocyte subsets, which sel-
serum ferritin dom exist in healthy controls, were found at higher frequency in
6. D‐dimer: raised D‐dimer associated with poor prognosis COVID‐19 patients. CD14+CD16+ monocytes also showed high le-
7. Endotheliopathy and angiogenesis: increase in angiopoietin‐2, von vels of expression of IL‐6, which can accelerate the progression of
Willebrand factor (vWF)37–39 and soluble thrombomodulin,40 the systemic inflammatory response.42,43

In the pre‐Covid‐19 era, an increase in levels of factors 1. COVID‐19 ARDS is diagnosed when a patient with confirmed
regulating angiogenesis and inflammation, including COVID‐19 infection meets the Berlin 2012 ARDS diagnostic criter-
angiopoietin‐2, IL‐6, and IL‐8 have long been acknowledged as ia44 of: (1) acute hypoxemic respiratory failure; (2) presentation within
40,41
predictors of acute respiratory distress syndrome (ARDS). 1 week of worsening respiratory symptoms; (3) bilateral airspace
The interactions between innate immunity and regulation of disease on chest X‐ray, computed tomography, or ultrasound that is
vascular permeability and alveolar epithelial injury may be key not fully explained by effusions, lobar or lung collapse, or nodules; and
drivers of ARDS in COVID‐19 (Table 1). However, it is still im- (4) cardiac failure is not the primary cause of acute hypoxemic re-
portant to identify the surrogate markers for critically ill patients spiratory failure. COVID‐19 ARDS occurs as a result of an acute
with COVID‐19. systemic inflammatory response, which can be caused by insults to
the lung, either direct or indirect. ARDS develops in 13%–42% of
patients presenting with COVID‐19 pneumonia, and in 61%–81% of
3 | PATHOGENESIS those requiring ICU care, a rate higher than for other organ injuries
including acute myocardial injury (7.2%–17.0%) and acute renal injury
COVID‐19 starts as a simple viral infection that goes out of (2.9%–15.0%) in severe patients.32,45,46 Ackermann and colleagues
control and progresses towards a deadly result with the devel- presented diffuse alveolar damage, with widespread signs of throm-
opment of a cytokine storm and serious organ damage. To un- bosis and increased levels of angiogenesis (intussusceptive angiogenic
derstand why and how this process occurs, and develop potential feature, density of conventional sprouting angiogenesis, and
treatments to control this process, we need to know further angiogenesis‐related gene expression) in an early stage of diffuse al-
details of the pathogenesis of COVID‐19 and the cascade of the veolar damage by ARDS in patients with COVID‐19.47 Research in
cytokine storm. the pre‐Covid‐19 era showed regulators of angiogenesis (e.g.,
2698 | ZHOU ET AL.

TABLE 1 Factors associated with poor prognosis of COVID‐19

Factors Change

(1) Age ≥65, male, having dyspnea Age ≥65, male, having dyspnea14,32,42

(2) Comorbidity Medical history of cardiovascular or respiratory disease or diabetes increased

the risk of poor prognosis14,32,42

(3) Hematologic: lymphocyte count, neutrophil–lymphocyte ratio Decrease in lymphocyte count and increase in neutrophil–lymphocyte ratio7,32,34

(4) Biochemical: LDH more than 245 U/L, procalcitonin more than 0.05 ng/ml, increase in AST,
bilirubin, creatinine7,32

(5) Inflammation factors Increase in CRP, interleukin (IL)‐6, serum ferritin33,34,36,42

(6) D‐dimer Increase in D‐dimer23,32,35,37,

(7) Endotheliopathy and angiogenesis Increase in angiopoietin‐2, von Willebrand factor (vWF),37–39 soluble
thrombomodulin40

Abbreviation: COVID‐19, coronavirus disease 2019.

angiopoietin‐2 and vWF antigen) have long been acknowledged as severe or recovery phase (from 14 days after infection). Treatment
ARDS biomarkers.39,48,49 Although more evidence is needed, current of COVID‐19 should be selected based on the staging of the dis-
data suggests that vascular angiogenesis factors upregulated by en- ease57 (Figure 4).
dothelial injury may be associated with the pathogenesis of ARDS and
mortality in patients with COVID‐19. 1. Antiviral medication should be started from the onset. Several
2. Severe and critical patients with COVID‐19 exhibit a hypercoagul- antiviral drugs including lopinavir/ritonavir and arbidol, which had
able state. Autopsy revealed deep venous thrombosis in 7 of been recommended by the guidelines in China, showed no ben-
12 patients (58%) in whom venous thromboembolism was not sus- eficial effect on COVID‐19 in terms of the time to clinical im-
pected before death; pulmonary embolism was the direct cause of provement measured by a seven‐category ordinal scale or
50
death in four patients. Studies have revealed that 71.4% of non- discharge from the hospital.58 Evidence was conflicting and in-
survivors of COVID‐19 matched the criteria of overt disseminated sufficient regarding the effect of hydroxychloroquine on clinical
intravascular coagulation (≥5 points according to International outcomes such as all‐cause mortality, progression to severe dis-
51
Society on Thrombosis and Haemostasis criteria). In the Nether- ease, clinical symptoms, and upper respiratory virologic clearance
lands, the incidence of thrombotic complications in ICU‐admitted with antigen testing and harms. Most observational studies59–63
52
patients with COVID‐19 infections was remarkably high, at 31%. showed that hydroxychloroquine administration was not asso-
Thrombosis and pulmonary embolism featured elevated levels of ciated with lowered mortality. Limited observational studies in-
D‐dimer and fibrinogen, and prolonged prothrombin time. dicated treatment with hydroxychloroquine alone and in
combination with azithromycin was associated with a reduction in
(i) Certain cytokines including IL‐6 may activate the coagulation mortality.64–66 Currently, the results of clinical trials suggest that
42,53–56
system and suppress the fibrinolytic system. hydroxychloroquine did not result in significant negative con-
(ii) Angiotensin‐converting enzyme 2 (ACE2) is expressed in version of SARS‐CoV‐2 67 or there was no significant difference in
endothelial cells of the lung, heart, kidney, and bladder. Endothelium the primary endpoint of mortality.68–70 On July 4, 2020, the
plays a significant role in thrombotic regulation including promotion World Health Organization (WHO) discontinued hydroxy-
of vasodilation, fibrinolysis, and antiaggregation. The spike protein of chloroquine and lopinavir/ritonavir treatment arms for
SARS‐CoV‐2 binds to the ACE2 receptor that triggers the T‐cell‐ COVID‐19 due to the lack of a reduction in the mortality of
52–55
mediated response and hypercoagulation hospitalized COVID‐19 patients.71 Hydroxychloroquine failed
(iii) Hypercoagulable profiles seen in the severe stages of to show efficacy for COVID‐19 prophylaxis.72 However, the
COVID‐19 are likely to indicate significant endothelial injury. potential prevention and treatment benefits of hydroxy-
Microvascular permeability as a result of the endothelial injury can chloroquine remain to be determined, because many clinical
53–56
facilitate viral invasion. trials to test the effect of hydroxychloroquine on COVID‐19
are still ongoing.73 Remdesivir, which improved the duration of
hospital admission but showed no significant difference in
3.2 | Therapy mortality,74 was approved by Food and Drug Administration in
the United States. and the PMDA in Japan in May 2020. Five
The clinical course of SARS‐CoV‐2 infection can have three phases: clinical trials of camostat mesylate and two of nafamostat
viremia, acute (pneumonia) phase (7–10 days after infection) and a mesylate, both inhibitors of TMPRSS2 serine protease, are
ZHOU ET AL.
| 2699

FIGURE 4 The pathological process and treatment strategy

ongoing. Further development of effective antiviral drugs is cytokine syndrome, and recover possible lung fibrosis. An animal
still necessary (Table 2). study showed that MSC treatment significantly reduced acute
2. During the acute pneumonia phase (7–10 days after infection), lung injury and pulmonary inflammation and improved survival in
antiinflammatory or anticoagulant drugs have been re- H9N2 AIV‐induced mice.89 MSCs also prevented or reduced
commended. Observational and case series studies showed that A/H5N1‐associated acute lung injury in vivo.90,91 Clinical trials of
tocilizumab (TCZ) was associated with rapid improvement in time MSCs in ARDS are limited. However, a beneficial effect on lung
to discharge from hospital or reduced mortality75–81 or asso- protective strategies was shown in ARDS using adoptively
ciated with significant improvement in acute respiratory failure transferred MSCs.92 A small clinical trial with seven patients
assessed by means of the Brescia COVID Respiratory Severity showed that transplantation of ACE2− MSCs improved the in-
Scale.79 TCZ administration did not reduce ICU admission or flammation, immune and pulmonary function of patients with
mortality rate, and did not result in clinical improvement in cohort COVID‐19.93 A systematic review indicated that after in-
82–84
studies. The Italian Medicines Agency (AIFA) announced on travenous or intratracheal administration of MSCs in 117 parti-
June 18, 2020 that Actemra (TCZ) did not reduce severe re- cipants with ARDS, there was a trend towards improvement in
spiratory symptoms, intensive care visits, or death compared with mortality, radiographic findings, pulmonary function, and in-
standard treatments in 126 patients with COVID‐19 in a clinical flammatory biomarker levels, although no significant differences
trial.85 A global randomized, double‐blind, placebo‐controlled were seen. All MSCs used in clinical trials have so far been allo-
phase III clinical trial of Actemra is ongoing to clarify the benefit geneic, from bone marrow, umbilical cord, menstrual blood, adi-
in COVID‐19 patients. Subject registration for an Actemra and pose tissue, or unreported sources.94 The angiogenesis and
Remdesivir combination trial also began in June, 2020. endothelial factors associated with the prognosis of ARDS in-
Anticoagulant therapy, mainly with low molecular weight heparin, dicate that CD34+ cells may also be a potential cell therapy tool
appeared to be associated with better prognosis in severe in COVID‐19 patients. Further well designed research is needed
COVID‐19 patients meeting sepsis‐induced coagulopathy (SIC) to clarify the effect on ARDS of the source of the MSCs.
criteria or with markedly elevated D‐dimer.86 Longer duration of 4. Glucocorticoid: the use of glucocorticoid in patients with
anticoagulant treatment was associated with a reduced risk of COVID‐19 is controversial.95 A meta‐analysis indicated corticos-
mortality.87 Anastasios et al suggested that all hospitalized teroid use in patients with SARS‐CoV‐2, SARS‐CoV, and MERS‐
COVID‐19 patients should receive thromboprophylaxis if they CoV infections delayed virus clearing and did not convincingly
meet SIC criteria or has markedly elevated D‐dimer.88 improve survival or reduce hospitalization duration, ICU admis-
3. If ARDS develops at the acute pneumonia phase, standard sion rate and/or use of mechanical ventilation96 and may even
treatment for severe ARDS should be applied (lower tidal volume, lead to increased mortality.97 However, a retrospective study
prone positioning, and relatively high positive end‐expiratory showed that early, low‐dose and short‐term application of me-
pressure). At this stage mesenchymal stem cell (MSC) therapy thylprednisolone was associated with better clinical outcomes in
may also be suggested to improve immunity, suppress the severe patients with COVID‐19 pneumonia.32 A clinical trial
2700 | ZHOU ET AL.

TABLE 2 Clinical trials of treatment on COVID‐19

Drugs Status Results Clinical trial ID

Anti‐SARS‐CoV‐2

1. Lopinavir/ritonavir Completed No benefit ChiCTR2000029308

2. Hydroxychloroquine Completed No benefit, higher adverse events ChiCTR2000029868

Completed No postexposure prophylaxis effect NCT04308668

Terminated No benefit NCT04381936

3. Remdesivir Completed Shortened the time to recovery NCT04280705

Terminated No significant clinical benefits NCT04257656

4. Camostat mesylate 8 Studies NCT04353284,NCT04455815,NCT04338906, NCT04470

ongoing 544,NCT04435015, NCT04355052 NCT04321096, NCT04374019

Antiinflammation

1. Tocilizumab Completed Not available yet NCT04331795

Completed Reduced mortality ChiCTR2000029765

2. Glucocorticoid Completed Reduced mortality NCT04381936

Completed Reduced mortality NCT04323592

3. Mesenchymal stem cells Completed Decreased Inflammatory factors ChiCTR2000029990

Abbreviations: COVID‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.

between March 28, 2013 and December 31, 2018 showed that (p = .0003) and by one‐fifth in other patients receiving oxygen
early administration of dexamethasone could reduce the duration only (p = .0021). There was no benefit among patients who did not
of mechanical ventilation and overall mortality in patients with require respiratory support (p = .14).102 The RECOVERY study is
98
established moderate‐to‐severe ARDS. Based on experience, the first of so many clinical trials since the COVID‐19 outbreak
researchers in China suggested a low dose (<0.5–1 mg/kg per day) began to show that one drug can reduce its mortality. Based on
of glucocorticoid could be used in some COVID‐19 patients with the results from the RECOVERY trial, the treatment guidelines in
conditions of a short duration, less than 7 days.99,100 The treat- the United States103 recommend using dexamethasone at 6 mg
101
ment guidelines for COVID‐19 in China included the use of per day for up to 10 days to treat COVID‐19 in patients who are
glucocorticoid if the oxygenation index (PaO2/FiO2) continued to mechanically ventilated and in patients who require supplemental
deteriorate, as shown in Table 3. The RECOVERY clinical trial at oxygen but who are not mechanically ventilated. The Panel re-
Oxford University showed that receiving 6 mg dexamethasone commends against using dexamethasone for the treatment of
once per day (either by mouth or by intravenous injection) for COVID‐19 in patients who do not require supplemental oxygen.
10 days reduced deaths by one‐third in ventilated patients Some conditions for using glucocorticoid have been

TABLE 3 Conditions for administration of glucocorticoid in patients with COVID‐19

Guideline Condition Drugs and dosage

101
China 1. Oxygenation index continues to deteriorate 1. Methylprednisolone, less than 1–2 mg/kg/day, for 3–5 days

2. Rapid progress of pneumonia in imaging 2. Other glucocorticoid, equivalent to methylprednisolone

3. An excessive inflammatory response to SARS‐CoV‐2

102
NIH 1. Patients who are mechanically ventilated 1. Dexamethasone 6 mg/day for up to 10 days

2. Patients who require supplemental oxygen but who are not 2. Alternative glucocorticoids are prednisone,
mechanically ventilated methylprednisolone, or hydrocortisone

3. Recommend against use in patients who do not require

supplemental oxygen

WHO105 WHO recommends against the routine use of systemic NA

corticosteroids for treatment of viral pneumonia

Abbreviations: COVID‐19, coronavirus disease 2019; NA, not available; NIH, National Institute for Health; WHO, World Health Organization.
ZHOU ET AL.
| 2701

recommended in the Chinese and NIH treatment guidelines. It With the threat of a second wave of the pandemic in autumn/
would be helpful for clinicians if the optimal timing for gluco- winter 2020, a diagnosis algorithm that combines rapid screening by
corticoid use, such as quantitative CT findings in the lungs in PCR antigen testing with antibody testing needs to be established, to
terms of lung consolidation and infiltration, and changes in the facilitate estimation of disease stage and treatment selection. The
oxygenation index, can be determined. We expect that several pathogenesis and risk factors for severe progression and mortality
ongoing studies (as of June 18, 2020) of steroid therapy for ARDS indicate that treatment strategy should be selected based on stage of
due to COVID‐19 (methylprednisolone [NCT04263402, the disease. Antiviral treatment can be combined with appropriate
NCT04323592, NCT04343729, NCT04273321, NCT04244591], antiinflammatory treatment and anticoagulation. Although re-
dexamethasone [NCT04327401, NCT04325061] and budesonide commended by some researchers, many clinical trials have failed to
[NCT04331470]) will confirm the positive results and that de- confirm any beneficial effect of hydroxychloroquine and TCZ on
tailed guidelines for glucocorticoid therapy in COVID‐19 will be COVID‐19 in terms of improved clinical status or reduced patient
established. Further studies are necessary to clarify the optimal mortality. Further development of effective antiviral drugs is still ne-
timing and conditions, dosage, and identify the responders to cessary. Currently glucocorticoid is the only drug that reduces the
104,105
glucocorticoid. (Tables 2 and 3). mortality of COVID‐19 in randomized controlled trials; however, it is
5. Antibody treatment: researches showed convalescent plasma are still necessary to establish the timing of administration, identify pa-
also potential treatment for COVID‐19106 or inconsistent.107 tients who will respond to glucocorticoid use and establish an optimal
Data from rigorously controlled clinical trials of convalescent treatment regime for the disease control. MSCs, which can improve
plasma are still few. Several clinical trials of monoclonal neu- immunity, suppress the cytokine syndrome, and recover possible lung
tralizing antibody therapy on COVID‐19 are going on. Further fibrosis, are a potential treatment option and need further investiga-
researches needs RCT trials of convalescent plasma and mono- tion. The virus is slowly mutating and the epidemic status is also
clonal neutralizing antibody to clarify the efficacy and timing of changing that some of our observation based on previous literature
administration to prevent the infection, development of severity has its limitations, which indicated the importance of a national cohort
or decrease the mortality of COVID‐19. to address the changes of clinical and epidemic features of COVID‐19.
6. Monitoring changes in B cells, T cells, particularly CD4+ and
CD8+ T cells, inflammatory factors, and D‐dimer will facilitate ACKNOWLEDGM E NTS
evaluation of the effects of each treatment for COVID‐19. The authors would like to appreciate Dr. Jiexun Wang, Clinical
Research Unit Khoo Teck Puat Hospital, Singapore, who helps for the
figure preparation.
4 | C O N CL U S I O N A N D
RECOMMENDATIONS CO N FLI CT O F I N TER E S TS
The authors declare that there are no conflict of interests.
In this short review, the global geographic differences in prevalence of
COVID‐19, risk factors for severe disease course, pathogenesis, and A U T H OR C O N T R I B U T I ON S
potential treatment strategies have been briefly debated. The pre- Bin Zhou and Masanori Fukushima conceived the idea. Bin Zhou
valence of COVID‐19 in Asia are lower than in Europe and America, wrote the manuscript with support from Atsuhiko Kawamoto,
indicated that the infection to SARS‐cov‐2 has genetic susceptibility. Shinsuke Kojima, and Masanori Fukushima.
Except Behaviors including wearing of face masks, keeping physical
distance, and hand hygiene may be important factors making a big DATA A VAILABILITY STA TEMENT
contribution to this difference, whether genetic susceptibility is in- Data derived from public domain resources of Johns Hopkins
volved needs further research. A registration study will facilitate to Coronavirus Resource Center. These data supporting the findings were
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