Clinical characteristics, management, and prevention of coronavirus disease 2019

Weijie Guan; Jianxing He

doi:10.2478/fzm-2023-0019

Clinical characteristics, management, and prevention of coronavirus disease 2019

doi: 10.2478/fzm-2023-0019

Weijie Guan^{1, 2, 3},
Jianxing He^{1, 2
, ,}

1.
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
2.
Department of Thoracic Surgery, Guangzhou Institute for Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
3.
Department of Respiratory and Critical Care Medicine, Foshan Second People's Hospital, Affiliated Foshan Hospital of Southern Medical University, Foshan 528000, China

Funds:

the National Science Foundation - Outstanding Youth Fund 82222001

the Emergency Key Program of Guangzhou Laboratory EKPG22-02

the Guangzhou Institute for Respiratory Health Open Project (funded by China Evergrande Group) 2020GIRHHMS09

the Guangzhou Institute for Respiratory Health Open Project (funded by China Evergrande Group) 2020GIRHHMS19

the Zhongnanshan Medical Foundation of Guangdong Province funding number not applicable

the Penghua Care Fund to the Medical Pioneers against Covid-19 of Shenzhen Social Commonweal Foundation funding number not applicable, Guan W J

More Information

Corresponding author: Jianxing He, E-mail address: hejx@vip.163.com

摘要

Abstract: Coronavirus disease 2019 (COVID-19) is the third severe acute respiratory disease of the 21st century and the most aggressive global pandemic to date. The whole population has been susceptible to the disease, particularly the emerging variants of the virus. The core pathophysiological mechanism is viral sepsis that can lead to the respiratory tract disorders and even systemic disorders such as cytokine release syndrome, thrombosis, abnormal angiogenesis, and multiple organ dysfunction. Despite only few licensed treatments to date, rapid advances have been made in exploring the effectiveness and safety of pharmacological interventions and vaccines. However, three pillars of preventative and control measures - proactive contact tracing, wearing facial masks, and social distancing - are essential to combat the ongoing pandemic. As the number of patients recovering from COVID-19 rapidly increases, the world has entered the era of caring for patients during the convalescence phase. This phase still represents a largely unmet medical need globally.
- COVID-19 /
- antibody /
- variant /
- anti-viral drug /
- vaccine

HTML全文

Figure 1. The global prevalence and mortality rate of coronavirus disease 2019 from January 2020 to March 2022

下载: 全尺寸图片幻灯片

Figure 2. A schematic diagram illustrating the pathophysiology of severe acute respiratory syndrome coronavirus-2 infections in the lower airways

下载: 全尺寸图片幻灯片

Figure 3. A schematic diagram illustrating the time course of various antibodies produced after symptom onset. The rapid antigen test and polymerase chain reaction (PCR) are used for diagnostic testing with the latter as the gold-standard test.

下载: 全尺寸图片幻灯片

Figure 4. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections at the cellular levels and the potential targets for intervention

下载: 全尺寸图片幻灯片

Table 1. Summary of therapeutic effects of antiviral and anti-inflammatory drugs reported in major prospective randomized clinical trials

Drug	Enrollment period	The main countries	No. randomized	Dosing scheme	Control	Primary endpoint	Primary endpoint met	Main findings	Main adverse events
Lopinavir-ritonavir	Feb 10 - Mar 20, 2020	China	127	Ribavirin 400 mg every 12 h, three doses of 8 million international units of interferon beta-1b on alternate days and Lopinavir 400 mg + ritonavir 100 mg twice daily for 14 days	Lopinavir 400 mg + ritonavir 100 mg twice daily for 14 days	Time to nasopharyngeal swab negative for SARS-CoV-2	Yes	The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab	Nausea, diarrhea
	Jan 18 - Feb 3, 2020	China	199	Lopinavir 400 mg + ritonavir 100 mg twice daily for 14 days	Standard care	Time to clinical improvement	No	No difference in the time to clinical improvement, viral loads and mortality at 28 days	Nausea, vomiting, and diarrhea
	Mar 19 - Jun 29, 2020	United Kingdom	5, 040	Lopinavir 400 mg + ritonavir 100 mg twice daily for 10 days until discharge	Standard care	28-day all-cause mortality	No	No significant difference in time until discharge alive from hospital or the proportion of patients discharged from hospital alive within 28 days	Not specified
	Mar - Jul 4, 2020	30 countries	11, 330 (1, 411 in lopinavir group)	Two tablets twice daily for 14 days	The local standard of care	in-hospital mortality	No	Death occurred in 148 of 1, 399 patients receiving lopinavir and in 146 of 1, 372 receiving a control drug (rate ratio, 1.00; 95% CI, 0.79 to 1.25)	Not specified
Remdesivir	Feb 21 - Apr 19, 2020	United States	1, 062	Remdesivir 200 mg on day 1, followed by 100 mg daily for up to 9 additional days)	placebo for up to 10 days	Time to clinical recovery	Yes	Patients receiving remdesivir had a significantly shorter median recovery time (10 vs. 15 days)	Not specified
	Mar 15-Apr 18, 2020	United States, Europe and Asia	596	Remdesivir intravenously at 200 mg on day 1 followed by 100 mg/d	Standard care	Clinical status on day 11 on a 7-point ordinal scale	Yes	Patients in the 5-day group had significantly higher odds of a better clinical status distribution	Nausea, hypokalemia, and headache
	Mar 6 - Mar 26, 2020	United States and other countries	397	Intravenous remdesivir for 5 days	intravenous remdesivir for 10 days	Clinical status on day 14, assessed on a 7-point ordinal scale	No	A clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group	Nausea, worsening respiratory failure, elevated alanine aminotransferase level, constipation
	Feb 6 - Mar 12, 2020	China	237	Remdesivir 200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions for 10 days	The same volume of placebo infusions for 10 days	Time to a decline of two levels on a six-point ordinal scale of clinical status or discharged from hospital	No	Remdesivir use was not associated with a difference in time to clinical improvement	Constipation, hypoalbuminaemia, hypokalaemia, anaemia, thrombocytopenia, increased total bilirubin
	Mar 2020 - NA	30 countries	11, 330 (2, 750 in remdesivir group)	200 mg on day 0 and 100 mg intravenously on days 1 through 9	The local standard of care	in-hospital mortality	No	Death occurred in 301 of 2, 743 patients receiving remdesivir and in 303 of 2, 708 receiving a control agent (rate ratio, 0.95; 95% CI, 0.81 to 1.11)	Not specified
Hydroxychloroquine	Mar 25 - Jun 5, 2020	United Kingdom	4, 716	The usual standard of care plus hydroxychloroquine or one of the other available treatments	Usual standard of care	28-day mortality	No	No significant difference in death within 28 days (27.0% in the hydroxychloroquine group vs. 25.0% in the usual-care group)	Supraventricular tachycardia, atrial flutter
	Mar 29 - May 17, 2020	Brazil	667	Standard care plus hydroxychloroquine at 400 mg twice daily plus azithromycin at 500 mg once daily for 7 days	Standard care; standard care plus hydroxychloroquine at 400 mg twice daily	Clinical status at 15 days as assessed with the use of seven-level ordinal scale	No	The odds of having a higher score at 15 days was not affected by hydroxychloroquine alone (odds ratio: 1.21) or hydroxychloroquine plus azithromycin (odds ratio: 0.99)	Prolongation of the QTc interval, elevated liver enzymes
	Apr 2 - Jul 17, 2020	United States	479	Hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses)	Placebo	Clinical status 14 days after randomization (7-category ordinal scale)	No	Clinical status at 14 days did not significantly differ between the hydroxychloroquine and the placebo groups (median: 6 vs. 6).	QTc interval greater than 500 ms
	Mar - Jun 19, 2020	30 countries	11, 330 (954 in hydroxychloroquine group)	Four tablets at hour 0, four tablets at hour 6, and starting at hour 12, two tablets twice daily for 10 days	The local standard of care	In-hospital mortality	No	Death occurred in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving a control agent (rate ratio, 1.19; 95% CI, 0.89 to 1.59)	Not specified
	Feb 11- Feb 29, 2020	China	150	A loading dose of 1, 200 mg daily for three days followed by a maintenance dose of 800 mg daily (total duration: two or three weeks)	Standard care	Negative conversion by 28 days	No	The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group (85.4%%) was similar to that in the standard care group (81.3%)	Diarrhoea being most common; serious adverse events rare
	Mar 17 - May 6, 2020	United States and Canada	821	Hydroxychloroquine 800 mg once, followed by 600 mg in 6-8 hours, then 600 mg daily for 4 additional days	Placebo	Incidence of lab confirmed Covid-19 or illness compatible with Covid-19 within 14 days	No	The incidence of new illness compatible with Covid-19 did not differ significantly	Nausea, loose stools, abdominal discomfort
	Mar 17 - Apr 28, 2020	Spain	2, 314	Hydroxychloroquine 800 mg once, followed by 400 mg daily for 6 days	Usual care (no specific therapy)	PCR-confirmed, symptomatic Covid-19 within 14 days	No	Similar incidence of PCR-confirmed, symptomatic Covid-19 in the hydroxychloroquine and usual-care groups (5.7% and 6.2%)	Diarrhea, nausea, abdominal pain, drowsiness, headache
Ivermectin	Jul 15 - Dec 21, 2020	Colombia	476	ivermectin 300 μg/kg of body weight per day for 5 days	Placebo for 5 days	Time to resolution of symptoms within 21-day follow-up	No	The median time to resolution of symptoms was 10 days in the ivermectin group compared with 12 days in the placebo group	Headache, dizziness, diarrhea, nausea
Favipiravir	Feb 4 - Mar 8, 2020	Iran	380	Favipiravir (1.6 gr loading, 1.8 gr daily)	Lopinavir/Ritonavir (800/200 mg daily)	The number of admissions to the intensive care unit	No	The number of deaths, intubations, and ICU admissions were not significantly different	Nausea, anorexia, fatigue, headache
Interferon beta-1a	Mar 30 - May 30, 2020	United Kingdom	101	6 MIU interferon beta-1a by inhalation via a mouthpiece daily for 14 days	Placebo	Change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period	Yes	Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2.32) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment	Headache; few serious adverse events
Interferon beta-1a	Mar - Jul 4, 2020	30 countries	11, 330 (2, 063 in interferon beta-1a group)	Subcutaneous: three doses over 6 days (randomization and days 3 and 6) of 44 μg of interferon beta-1a Intravenous: 10 μg daily for 6 days	The local standard of care	in-hospital mortality	No	Death occurred in 243 of 2, 050 patients receiving interferon beta-1a and in 216 of 2, 050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39)	Not specified
Corticosteroids	Mar 19 - Jun 8, 2020	United Kingdom	2, 104	Oral or intravenous dexamethasone (6 mg once daily) for up to 10 days	Usual care	28-day mortality	Yes	Significantly lower percentage of patients died in the dexamethasone group than in the usual care group (22.9% vs. 25.7%)	Not specified
	Apr 17 - Jun 23, 2020	Brazil	299	Dexamethasone intravenously daily for 5 days, 10 mg dexamethasone daily for 5 days or until ICU discharge, plus standard care	Standard care alone	Ventilator-free days during the first 28 days	Yes	Patients in the dexamethasone group had a mean of 6.6 ventilator-free days vs 4.0 ventilator-free days in the standard care group	Insulin use for glycemia
	Mar 9 - Jun 17, 2020	Australia and other countries	614	A fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) A shock-dependent course (50 mg every 6 hours)	No hydrocortisone	Organ support-free days within 21 days (Bayesian cumulative logistic model)	Yes	The adjusted Bayesian probability of superiority was 93% for the fixed-dose hydrocortisone group	Not specified
	Mar 7-Jun 1, 202	France	149	Continuous intravenous infusion of hydrocortisone at 200 mg/d at day 1 and continued at 200 mg/d until day 7 and then decreased to 100 mg/d for 4 days and 50 mg/d for 3 days	Placebo (saline) for 14 days	Treatment failure on day 21	No	No significant difference in the percentage of patients (42.1%) in the hydrocortisone group and in the placebo group (50.7%), who reached the primary endpoint	Not specified
Azithromycin	Apr 7 - Nov 27, 2020	United Kingdom	16, 442	Usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge	Usual standard of care alone for 10 days or until discharge	28-day all-cause mortality	No	No significant difference in the 28-day all-cause mortality between the azithromycin group and the control group (22% vs. 22%)	Not specified
	May 22 - Nov 30, 2020	United Kingdom	2, 265	Usual care plus azithromycin 500 mg daily for three days	Usual care plus other interventions, or usual care alone	Time to first recovery in 28 days Hospital admission or death related to COVID-19 in 28 days	No	No significant effect by azithromycin in time to first reported recovery; No significant difference in the percentage of participants being hospitalized or died	Not specified
	Mar 28 - May 19, 2020	Brazil	447	Azithromycin (500 mg via oral, asogastric, or intravenous administration once daily for 10 days) plus standard of care	Standard of care without macrolides	SARS-CoV-2 infection confirmed by testing before randomisation	No	SARS-CoV-2 infection was not significantly different between the azithromycin and control groups (odds ratio: 1.36)	QTc interval prolongation, gastrointestinal intolerance
Baricitinib	May 8- Jul 1, 2020	United States	1, 033	Remdesivir: 200-mg on day 1, 100-mg daily on days 2-10 or until hospital discharge or death Baricitinib: 4-mg daily dose for 14 days or until hospital discharge	Placebo	Time to recovery within 15 days	Yes	Patients receiving baricitinib experienced a shorter time to recovery and had higher odds of improvement in clinical status at day 15	Hyperglycemia, anemia, decreased lymphocyte count, acute kidney injury
Fluvoxamine	Apr 10 - Aug 5, 2020	United States	181	100 mg of fluvoxamine 3 times daily for 15 days	Placebo 3 times daily for 15 days	Clinical deterioration within 15 days of randomization	Yes	Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group	Pneumonia, nausea, vomiting
Inhaled budesonide	Jul 16 - Dec 9, 2020	United Kingdom	146	Budesonide dry powder 800 μg twice daily until symptom resolution	Usual care	COVID-19-related urgent care visit	Yes	The primary outcome occurred in 15% participants in the usual care group and 3% in the budesonide group	Sore throat; dizziness
Ruxolitinib	Feb 9 - Feb 28, 2020	China	43	Ruxolitinib 5 mg twice a day plus standard-of-care treatment	Placebo (100 mg vitamin C) twice daily with standard care	Time to clinical improvement	No	No differences in terms of clinical improvement between ruxolitinib (median: 12 days) and placebo group (median: 15 days)	Anemia, thrombocytopenia, hypercholestrolemia
Vitamin D	Jun 2 - Aug 27, 2020	Brazil	240	A single oral dose of 200 000 IU of vitamin D3	A single dose of placebo	Length of stay	No	Median length of stay was not significantly different between the vitamin D3 (7.0 days) and placebo groups (7.0 days)	Not specified

下载: 导出CSV

Table 2. Summary of therapeutic effects of biologics reported in major prospective randomized clinical trials

Drug	Enrollment period	The main countries	No. randomized	Dosing scheme	Control	Primary endpoint	Primary endpoint met	Main findings	Main adverse events
Tocilizumab	Mar 9 - Nov 19, 2020	United Kingdom	755	Tocilizumab (8 mg per kilogram of body weight)	Standard care alone	Respiratory and cardiovascular organ support-free days to day 21	Yes	The median number of organ support-free days was 10 in tocilizumab group and 0 in control group (median adjusted cumulative odds ratios: 1.64)	Not specified
	Apr 23, 2020, - Jan 24, 2021	United Kingdom	4, 116	Tocilizumab 400 mg-800 mg given intravenously (the 2^nd dose can be given 12-24 h later) plus standard of care	Standard of care alone	28-day mortality	Yes	31% of patients allocated tocilizumab and 35% of patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76-0·94)	Not specified
	Apr 20 - Jun 15, 2020	United States	243	Tocilizumab (8 mg per kilogram of body weight administered intravenously, not to exceed 800 mg)	Placebo	Intubation or death, assessed in a time-to-event analysis	No	The hazard ratio for intubation or death in the tocilizumab group compared with the placebo group was 0.83 (95% confidence interval: 0.38 - 1.81)	Neutropenia, elevated liver enzyme
	Apr 3 - May 28, 2020	Europe and North America	452	A single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight)	Placebo intravenous injection	Clinical status at day 28 on an ordinal scale ranging from 1 to 7	No	The median value for clinical status at day 28 was 1.0 in the tocilizumab group and 2.0 in the placebo group	Infection, bleeding, hypersensitivity
	May 30 - Aug 31, 2020	India	180	Tocilizumab 6 mg/kg plus standard care	Standard care alone	Progression of COVID-19 up to day 14	No	Progression of COVID-19 occurred in 9% of patients in the tocilizumab group and 13% in the standard care group (difference −3·71; p=0·42)	Infections
	Mar 31 - Apr 18, 2020	France	131	Tocilizumb 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated	Usual care alone	Scores higher than 5 on WHO 10-point Clinical Progression Scale on day 4 and survival without ventilation at day 14	No	In the tocilizumab group, 12 patients vs 19 in the usual care group had scores higher than 5. At day 14, 12% fewer patients needed ventilation or died in the tocilizumab group.	Hepatic cytolysis, anemia, neutropenia
	Mar 31 - Jun 11, 2020	Italy	126	Intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to 800 mg), followed by a second dose after 12 hours	Supportive care until clinical worsening (could receive tocilizumab)	Entry into intensive care unit with invasive ventilation, death from all causes, or clinical aggravation	No	28.3% in tocilizumab arm and 27.0% in the standard care group showed clinical worsening within 14 days. Two patients in the tocilzumab group and 1 in the control group died before 30 days; 6 and 5 patients were intubated	Laboratory abnormalities, infection, infestation
	May 8- Jul 20, 2020	Brazil	129	Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care	standard care alone	Clinical status measured at 15 days	No	28% of patients in the tocilizumab group and 20% in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio, 1.54, P=0.32)	Abnormal liver function, anemia, thrombocytopenia
Sarilumab	Jun 20 - Nov 19, 2020	United Kingdom	755	Sarilumab (400 mg)	Standard care alone	Respiratory and cardiovascular organ support-free days up to day 21	Yes	The median of organ support-free days was 11 in the sarilumab group and 0 in the control group	Not specified
Sarilumab	Mar 28 - Jul 3, 2020	Argentina and other countries	431	intravenous sarilumab 400 mg, sarilumab 200 mg	Placebo	Time to clinical improvement of two or more points (seven point scale)	No	No significant differences in median time to improvement between the placebo (12.0 days) and sarilumab 200 mg (10.0 days) or 400 mg groups (10.0 days)	Increased alanine aminotransferase, invasive bacterial or fungal infection
Anakinra	Apr 8- Apr 26, 2020	France	116	Usual care plus anakinra (200 mg twice daily on days 1-3, 100 mg twice on day 4, 100 mg once on day 5)	Usual care alone	Proportion of patients who had died or needed ventilation by day 4; Survival without ventilation at day 14	No	36% of patients in the anakinra group had WHO-CPS score > 5 at day 4 versus 38% in the usual care group; 47% patients in the anakinra group and 51% in the usual care group needed ventilation or died	Acute respiratory distress syndrome, bacterial sepsis, hepatic cytolysis
Granulocyte colony stimulating factor	Feb 18 - Apr 10, 2020	China	199	3 doses of recombinant human granulocyte colony-stimulating factor (5 μg/kg, subcutaneously at days 0-2)	Standard care	The time to improvement of at least 1 point on 7-category severity score	No	Time to clinical improvement was similar (median 12 days in the rhG-CSF group vs 13 days in the usual care group; hazard ratio, 1.28; 95% CI, 0.95-1.71)	Neutrophilia, osteodynia, muscle soreness
Marilimumab	May 28 - Sep 15, 2020	United States	40	Mavrilimumab 6 mg/kg as a single intravenous infusion	Placebo intravenous infusion	The proportion of patients alive and off supplemental oxygen therapy at day 14	No	Similar percentages of patients (odds Ratio: 1·48, 95% confidence interval: 0·43-5·16) remained alive and were off supplemental oxygen therapy	Bacterial pneumonia
Vilobelimab	Mar 31 - Apr 24, 2020	The Netherlands	30	Vilobelimab (up to seven doses of 800 mg intravenously) plus best supportive care	Best supportive care	Percentage change in PaO₂/FiO₂ in supine position between baseline and day 5	No	No differences between treatment groups (17% change in the vilobelimab group vs 41% in the control group; difference 24% [95% CI: 58 to 9]).	pulmonary embolisms; infections

下载: 导出CSV

Table 3. Summary of effects of vaccines reported in major prospective clinical studies in humans

Vaccine	Enrollment period	The main countries	Participants	No. randomized	Dosing scheme	Control	Primary endpoint	Vaccine efficacy	Efficacy against variants	Main immunogenicity outcomes	Main safety outcomes
mRNA-1273	Apr 16 - May 12, 2020	United States	Older adults	40	Two doses of either 25 μg or 100 μg of vaccine administered 28 days apart	NA	Antibody responses on days 1, 15, 29, 36, 43, and 57	NA	NA	Anti-S-2P GMT: 25-μg: 323, 945 in 56-70 yr; 1, 128, 391 in ≥71 yr group; 100-μg: 1, 183, 066 and 3, 638, 522	Predominantly mild or moderate in severity (fatigue, chills, headache, myalgia, pain)
mRNA-1273	Jul 27 - Oct 23, 2020	United States	Individuals 18 years of age or older	30, 420	A two-dose regimen containing 0.5 mL injections containing 100 μg of mRNA-1273	Placebo (saline)	Prevention of Covid-19 with onset > 14 days after 2^nd injection in non-infected participants	94.1%	NA	NA	(Mainly) pain after injection
BNT162b1	May 4 - Jun 22, 2020	United States	Healthy adults (18-55 yrs; 65-85 yrs)	195	Two doses of vaccine (10 μg, 20 μg, 30 μg, and 100 μg), with a 21-day interval; One dose 100 μg of BNT162b1 in one group only	Placebo	Safety ( e.g. , local and systemic reactions and adverse events)	NA	NA	Similar dose-dependent neutralizing GMTs in younger and older adults	Lower incidence and severity of systemic reactions than BNT162b2
BNT162b2	Jul 27, - Nov 14, 2020	United States and other countries	Adults 16 yrs or older	43, 548	BNT162b2 vaccine twice (30 μg per dose), at 21-day interval	Placebo	Efficacy against laboratory-confirmed Covid-19 and safety	95%	NA	NA	Short-term, mild-to-moderate pain at injection site, fatigue, headache
	Dec 20, 2020, to Feb 1, 2021	Israel	Non-infected individuals aged 16 yrs or greater	596, 618	Having received BNT162b2 vaccination	No vaccination	COVID-19 infection, symptomatic Covid-19, hospitalization, severe illness, death	7 days after 2^nd dose: 92%	NA	NA	NA
	Dec 8 - Dec 29, 2020	United Kingdom	Patients with cancer	151	Two 30 μg doses of BNT162b2 administered intramuscularly 21 days apart	Single dose of vaccine	Seroconversion to spike protein and vaccine boosting after 21 days on seroconversion	NA	NA	One dose yields poor efficacy. Immunogenicity increased in patients with solid cancer in 2 weeks of boost	No toxicities in 54% patients following the first dose
Ad26.COV2.S	Jul 22 - Aug 7, 2020	Belgium and the United States	Healthy adults aged 18-55 yrs and 65 yrs or greater	805	5×10¹⁰ viral particles (low dose); 1×10¹¹ viral particles (high dose) per milliliter	Placebo	Safety and reactogenicity	NA	NA	Neutralizing antibody detected in ≥90% of participants on day 29 after dose 1 and was 100% by day 57	NA
	Sep 21, 2020 - Jan 22, 2021	Argentina, Brazil and other countries	Adults 18-59 yrs and 60 yrs or older	19, 630	5×10¹⁰ viral particles as a single intramuscular injection (0.5 mL)	Placebo	Vaccine efficacy against moderate to severe-critical Covid-19 with an onset at least 14 and 28 days	76.7% at ≥14 days; 85.4% at ≥28 days	52.0% and 64.0% (20H/501Y. V2 variant)	Higher reactogenicity than with placebo (mild to moderate and transient)	injection-site pain, headache, fatigue, myalgia, nausea
	Jun 18 - Aug 3, 2020	Russia	Adults aged 18-60 yrs	76	One dose of rAd26-S or one dose of rAd5-S	NA	SARS-CoV-2-specific antibodies on days 0, 14, 21, 28, and 42; number of participants with adverse events	NA	NA	At day 42, RBD IgG titers were 14703 (frozen) and 11 143 (lyophilised) Neutralising antibodies: 49·25 and 45·95, respectively	Common: pain at injection site, hyperthermia, headache, asthenia, muscle and joint pain
	Jul 29 - Aug 7, 2020	United States	Participants 18-55 yrs old	25	1 or 2 intramuscular injections with 5 × 10¹⁰ viral particles or 1 × 10¹¹ viral particles of Ad26. COV2.S vaccine	Placebo	Cellular immune responses and T cell responses	NA	NA	Binding and neutralizing antibodies emerged by day 8 in 90% and 25% of vaccine recipients	NA
Recombinant spike protein nanoparticle vaccine	May 26, - Jun 6, 2020	Australia	Young and middle-aged adults	131	rSARS-CoV-2 vaccine (in 5-μg and 25-μg doses, with or without Matrix-M1 adjuvant)	Placebo	Reactogenicity; serum chemistry, hematology; IgG anti-spike protein response	NA	NA	Two-dose 5-μg regimen induced marked anti-spike IgG and neutralization responses	No serious adverse events; Overall reactogenicity was absent or mild
Recombinant spike protein nanoparticle vaccine	Aug 17 - Nov 25, 2020	South Africa	HIV-positive and -negative adults aged 18-64 yrs	4, 387	NVX-CoV2373 (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant)	Placebo (0.5 mL)	Safety and vaccine efficacy against lab-confirmed symptomatic Covid-19 at 7 days or more after 2^nd dose	60.1%	51.0%	Vaccine efficacy among HIV-negative participants was 60.1%	Headache, muscle pain, and fatigue most common; no serious adverse events
Recombinant spike protein vaccine	Sep 3 - Sep 29, 2020	Untied States	Adults 18-49 yrs and ≥50 yrs	441	One dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low dose (effective dose 1·3 μg) or high-dose (2·6 μg) antigen with adjuvant AF03 or AS03	Unadjuvanted high-dose antigen	Safety up to day 43, and immunogenicity (neutralising antibodies on days 1, 22, and 36)	NA	NA	Neutralizing antibody titers: 13·1 in low-dose + AF03 group, 20·5 in low-dose + AS03 group, 43·2 in high-dose + AF03 group, 75·1 in high-dose + AS03 group	No vaccine-related unsolicited immediate adverse events, serious adverse events
ChAdOx1 nCoV-19 vaccine	Jun 24 - Nov 9, 2020	South Africa	Adults 18-65 yrs	2, 026	Two doses of vaccine containing 5×10¹⁰ viral particles 21 to 35 days apart	Placebo (0.9% saline)	Safety and efficacy against lab-confirmed symptomatic Covid-19 > 14 days after 2^nd dose	21.9%	21.9%	Strong neutralizing antibodies at 28 days after dose 1 and increased after dose 2	No serious adverse events
	Apr 23 - May 21, 020	United Kingdom	Healthy adults aged 18-55 years	1, 077	ChAdOx1 nCoV-19 vaccine (5×10¹⁰ viral particles)	Menigococcal ACWY vaccine	Cases of symptomatic virologically confirmed COVID-19; Occurrence of serious adverse events	NA	NA	Anti-spike IgG responses rose by day 28, and were boosted following a second dose	Pain, feverish, chills, muscle ache, headache, malaise; No serious adverse events
	May 30 - Aug 8, 2020	United Kingdom	Adults aged 18-55 yrs, 56-69 yrs, and 70 yrs and older	560	intramuscular ChAdOx1 nCoV-19 (2.2×10¹⁰ virus particles)	Meningococcal ACWY vaccine	The number of cases of symptomatic, virologically confirmed COVID-19, serious adverse events	NA	NA	Median anti-spike IgG responses 28 days after the boost dose were similar across the three age cohorts	Injection-site pain, feeling feverish, muscle ache, headache (less common in older adults)
	Apr 23 - Nov 4, 2020	United Kingdom, Brazil, South Africa	Adults aged 18 yrs and older	23, 848	Two doses containing 5×10¹⁰ viral particles; A half dose as their first dose; A standard dose as their second dose	Meningococcal ACWY vaccine	Symptomatic COVID-19 in seronegative participants with PCR-positive swab > 14 days after a second dose	70.4%	NA	Two standard doses: 62.1%; Low dose followed by standard dose: 90.0%	Good safety profile with serious adverse events balanced across the study arms
	Apr 23 - Dec 6, 2020	United Kingdom, Brazil	individuals aged 18 years and older	24, 422	Two standard doses of ChAdOx1 nCoV-19 (5×10¹⁰ viral particles)	Control vaccine or placebo	Virologically confirmed symptomatic COVID-19 disease	66.7%	NA	Antibody levels were maintained with minimal waning by day 90 (geometric mean ratio 0·66 [95%CI 0·59-0·74])	The most common serious adverse events were infections and infestations
	May 31 - Dec 30, 2020	United Kingdom	Healthy people aged 18 years and older	8, 534	Standard-dose ChAdOx1 nCoV-19 vaccine (5×10¹⁰ viral particles)	Meningococcal conjugate control vaccine	Symptomatic COVID-19 in seronegative participants with positive swab > 14 days after dose 2	81.5% for non-B.1.1.7 variant	70.4% for B.1.1.7 variant	NA	NA
BBIBP-CorV	Phase 1: Apr 29 - Jun 28, 2020 Phase 2: May 18 - Jul 30, 2020	China	Healthy people Phase 1: 18-80 yrs Phase 2: 18-59 yrs	640	A single-dose schedule of 8 μg on day 0; A two-dose schedule of 4 μg on days 0 and 14, 0 and 21, or 0 and 28	Placebo	Safety and tolerability	NA	NA	Neutralizing antibody titers on day 28 were greater in the 4 μg days 0 and 14, days 0 and 21, and days 0 and 28 schedules	Mild or moderate; No serious adverse event within 28 days
Inactivated vaccine	Apr 16 - Apr 25, 020	China	Adults aged 18-59 years	Phase 1: 144 Phase 2: 743	Low dose CoronaVac [3 μg per 0·5 mL of aluminium hydroxide diluent per dose]; High-dose Coronavc [6 μg per 0·5 mL of aluminium hydroxide diluent per dse]	Placebo	Adverse reactions within 28 days; Seroconversion rates of neutralizing antibodies at day 14 and 28	NA	NA	Phase 1: Seroconversion rates: 46% in 3μg group, 50% in 6μg group, 0% in placebo group Phase 2: 92%, 98% and 3%	Phase 1: 29% in the 3μg group, 38% in 6μg group, 8% in the placebo group Phase 2: 33%, 35% and 22%
	July 13 - Jul 30, 2020	United Kingdom and Brazil	Healthy adults aged 18-55 years	827	3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel	Algel only	Solicited local and systemic reactogenicity events at 2 h and 7 days and throughout the study	NA	NA	Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups	Mild or moderate; more frequent after the first dose
	May 22 - Jun 1, 2020	China	healthy adults aged 60 yrs and older	72	CoronaVac at 1·5 μg, 3 μg, or 6 μg per dose	Placebo	Adverse reactions within 28; seroconversion rate at 28 days after the second injection	NA	NA	Seroconversion was seen in 90.7% of participants in the 1·5 μg group, 98% in the 3 μg group and 99·0% in the 6 μg group	Mild or moderate in severity; injection site pain was most frequent
	April 12 - Jul 27, 2020	China	Healthy adults aged 18-59 yers	Phase 1: 96 Phase 2: 224	2.5, 5, and 10 μg/dose inactivated vaccine	Aluminum hydroxide adjuvant	Combined adverse reactions at 7 days Neutralizing antibody response after 14 days	NA	NA	GMTs of neutralizing antibodies in low-, medium-, and high-dose groups at day 14: 316, 206 and 297 in phase 1	Injection site pain, followed by fever (mild and self-limiting)
Non-replicating adenovirus type-5-vectored COVID-19 vaccine	Apr 11 - 16, 2020	China	Healthy adults aged 18 yrs or older	603	1×10¹¹ viral particles per mL or 5×10¹⁰ viral particles per mL	Placebo	GMTs of specific ELISA antibody responses to RBD and neutralising antibody responses at day 28	NA	NA	The RBD-specific ELISA antibodies peaked at 656·5 and 571·0, with seroconversion rates at 96% and 97% at day 28	Mostly mild to moderate adverse events; pain being the most common adverse event
Non-replicating adenovirus type-5-vectored COVID-19 vaccine	Jun 19 - Sep 23, 2020	Australia	Younger (18-54 yrs) and older adults (55-75 yrs)	151	S-trimer vaccine either 3 μg, 9 μg, or 30 μg	Placebo (0.9% saline)	Safety, tolerability, and immunogenicity of three increasing doses	NA	NA	Fixed doses vaccine induced high titers and seroconversion rates of binding and neutralizing antibodies	Well tolerated overall
MF59-adjuvanted subunit vaccine	Jun 23 - Aug 17, 2020	Australia	Healthy adults (aged ≥18 to ≤55 years)	314	Two doses via intramuscular injection 28 days apart of either sclamp vaccine at 5 μg, 15 μg, or 45 μg, or one dose of sclamp vaccine at 45 μg followed by placebo	Placebo	Antigen-specific IgG titer at 28 days; Solicited adverse events in the 7 days Unsolicited events up to 12 months	NA	NA	Vaccination with SARS-CoV-2 clamp elicited a similar antigen-specific response irrespective of dose	Severe solicited reactions occurred at similar rates in participants receiving vaccines at any dose
GMT: geometric mean titer; RBD: receptor-binding domain; NAAT: nucleic acid amplification test

下载: 导出CSV

Table 4. Major challenges and future research directions in the battle against coronavirus disease 2019 (COVIDF-19)

Key unanswered questions related to COVID-19	Proposed future research directions
The origin of SARS-CoV-2 and the mode of zoonotic transmissions	To unravel the reservoir of SARS-CoV-2 and understanding the mechanisms of zoonotic infections
Durability of infectiousness of viral particles in the environment	To investigate the immune escape mechanisms of the emerging variants
Immunologic mechanisms contributing to the sudden deterioration of clinical status and the clinical recovery	To validate a novel diagnostic method for identifying asymptomatic individuals
The upper limit of duration of the protective effect of antibodies after natural infection and the receipt of vaccination	To assess the effectiveness of mass vaccination programs in reducing global incidence of COVID-19
Factors associated with re-infection	To develop new rapid diagnostic testing for point-of-care use
Molecular mechanisms underlying prolonged shedding of the live viruses or viral fragments	To identify monoclonal antibody cocktails to improve clinical outcomes
Association between variants and the efficacy of different types of vaccines	To develop medications that target cellular surface markers in addition to ACE2
The mechanisms leading to interstitial lung diseases and the reversibility with immunosuppressants during convalescent phase	To determine the optimal treatment options for non-intubated patients with severe COVID-19
The probability and duration of complete recovery after discharge from hospital	To explore new intervention strategies to accelerate the functional and psychological recovery post-discharge from COVID-19

下载: 导出CSV

参考文献(267)

[1]	Koh D, Sng J. Lessons from the past: perspectives on severe acute respiratory syndrome. Asia Pac J Public Health, 2010; 22(3): 132S-136S.
[2]	Donnelly C A, Malik M R, Elkholy A, et al. Worldwide Reduction in MERS Cases and Deaths since 2016. Emerg Infect Dis, 2019; 25(9): 1758-1760. doi: 10.3201/eid2509.190143
[3]	World Health Organization. WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/. WHO. Accessed on 07 December, 2022
[4]	Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from patients with pneumonia in China, 2019. N Engl J Med, 2020; 382(8): 727-733. doi: 10.1056/NEJMoa2001017
[5]	Zhang Y Z, Holmes E C. A genomic perspective on the origin and emergence of SARS-CoV-2. Cell, 2020; 181(2): 223-227. doi: 10.1016/j.cell.2020.03.035
[6]	Passamonti F, Cattaneo C, Arcaini L, et al. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol, 2020; 7(10): e737-e745. doi: 10.1016/S2352-3026(20)30251-9
[7]	Chan J F, Yuan S, Kok K H, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet, 2020; 395(10223): 514-23. doi: 10.1016/S0140-6736(20)30154-9
[8]	Guan W J, Ni Z Y, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med, 2020; 382(18): 1708-1720. doi: 10.1056/NEJMoa2002032
[9]	Chan J F, Poon V K, Chan C C, et al. Low Environmental Temperature Exacerbates Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Golden Syrian Hamsters. Clin Infect Dis, 2021; 75: e1101-e1111.
[10]	Liu M, Li Z, Liu M, et al. Association between temperature and COVID-19 transmission in 153 countries. Environ Sci Poll Res Int, 2022; 29(11): 16017-16027. doi: 10.1007/s11356-021-16666-5
[11]	Tian F, Liu X, Chao Q, et al. Ambient air pollution and low temperature associated with case fatality of COVID-19: A nationwide retrospective cohort study in China. Innovation, 2021; 2(3): 100139.
[12]	Carta M G, Minerba L, Demontis R, et al. The COVID-19 incidence in Italian regions correlates with low temperature, mobility and PM10 pollution but lethality only with low temperature. J Pub Health Res, 2021; 10(4): 2303.
[13]	Zhu G, Zhu Y, Wang Z, et al. The association between ambient temperature and mortality of the coronavirus disease 2019 (COVID-19) in Wuhan, China: a time-series analysis. BMC Public Health, 2021; 21(1): 117. doi: 10.1186/s12889-020-10131-7
[14]	Chinazzi M, Davis J T, Ajelli M, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science, 2020; 368(6489): 395-400. doi: 10.1126/science.aba9757
[15]	Clapp P W, Sickbert-Bennett E E, Samet J M, et al. Evaluation of Cloth Masks and Modified Procedure Masks as Personal Protective Equipment for the Public During the COVID-19 Pandemic. JAMA Intern Med, 2021; 181(4): 463-469. doi: 10.1001/jamainternmed.2020.8168
[16]	Koo J R, Cook A R, Park M, et al. Interventions to mitigate early spread of SARS-CoV-2 in Singapore: a modelling study. Lancet Infect Dis, 2020; 20(6): 678-688. doi: 10.1016/S1473-3099(20)30162-6
[17]	Shi Q, Hu Y, Peng B, et al. Effective control of SARS-CoV-2 transmission in Wanzhou, China. Nat Med, 2021; 27(1): 86-93. doi: 10.1038/s41591-020-01178-5
[18]	Chen S, Zhang Z, Yang J, et al. Fangcang shelter hospitals: a novel concept for responding to public health emergencies. Lancet, 2020; 395(10232): 1305-1314. doi: 10.1016/S0140-6736(20)30744-3
[19]	Li R, Pei S, Chen B, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2). Science, 2020; 368(6490): 489-493. doi: 10.1126/science.abb3221
[20]	Poustchi H, Darvishian M, Mohammadi Z, et al. SARS-CoV-2 antibody seroprevalence in the general population and high-risk occupational groups across 18 cities in Iran: a population-based cross-sectional study. Lancet Infect Dis, 2021; 21(4): 473-481. doi: 10.1016/S1473-3099(20)30858-6
[21]	Stringhini S, Wisniak A, Piumatti G, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SERO-CoV-POP): a population-based study. Lancet, 2020; 396(10247): 313-319. doi: 10.1016/S0140-6736(20)31304-0
[22]	Pallett S J C, Rayment M, Patel A, et al. Point-of-care serological assays for delayed SARS-CoV-2 case identification among healthcare workers in the UK: a prospective multicentre cohort study. Lancet Respir Med, 2020; 8(9): 885-894. doi: 10.1016/S2213-2600(20)30315-5
[23]	Xu X, Sun J, Nie S, et al. Seroprevalence of immunoglobulin M and G antibodies against SARS-CoV-2 in China. Nat Med, 2020; 26(8): 1193-1195. doi: 10.1038/s41591-020-0949-6
[24]	Li C, Luo F, Liu C, et al. Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe COVID-19: a randomised clinical trial. Ann Med, 2021; 53(1): 391-401. doi: 10.1080/07853890.2021.1890329
[25]	Bajema K L, Wiegand R E, Cuffe K, et al. Estimated SARS-CoV-2 Seroprevalence in the US as of September 2020. JAMA Intern Med, 2021; 181(4): 450-460. doi: 10.1001/jamainternmed.2020.7976
[26]	Hallal P C, Hartwig F P, Horta B L, et al. SARS-CoV-2 antibody prevalence in Brazil: results from two successive nationwide serological household surveys. Lancet Glob Health, 2020; 8(11): e1390-e1398. doi: 10.1016/S2214-109X(20)30387-9
[27]	Zhou P, Yang X L, Wang X G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020; 579(7798): 270-273. doi: 10.1038/s41586-020-2012-7
[28]	Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature, 2020; 579(7798): 265-269. doi: 10.1038/s41586-020-2008-3
[29]	McCallum M, De Marco A, Lempp FA, et al. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell, 2021; 184(9): 2332-2347. doi: 10.1016/j.cell.2021.03.028
[30]	Cerutti G, Guo Y, Zhou T, et al. Potent SARS-CoV-2 neutralizing antibodies directed against spike N-terminal domain target a single supersite. Cell host Microbe, 2021; 29: 819-833. doi: 10.1016/j.chom.2021.03.005
[31]	Chi X, Yan R, Zhang J, et al. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science, 2020; 369(6504): 650-655. doi: 10.1126/science.abc6952
[32]	Liu L, Wang P, Nair M S, et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature, 2020; 584(7821): 450-456. doi: 10.1038/s41586-020-2571-7
[33]	Johnson B A, Xie X, Bailey A L, et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature, 2021; 591(7849): 293-299. doi: 10.1038/s41586-021-03237-4
[34]	Zhou Z, Huang C, Zhou Z, et al. Structural insight reveals SARS-CoV-2 ORF7a as an immunomodulating factor for human CD14(+) monocytes. iScience, 2021; 24(3): 102187. doi: 10.1016/j.isci.2021.102187
[35]	Golden J W, Cline C R, Zeng X, et al. Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease. JCI Insight, 2020; 5(19): e142032. doi: 10.1172/jci.insight.142032
[36]	Bao L, Deng W, Huang B, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature, 2020; 583(7818): 830-833. doi: 10.1038/s41586-020-2312-y
[37]	Jiang R D, Liu M Q, Chen Y, et al. Pathogenesis of SARS-CoV-2 in transgenic mice expressing Human Angiotensin-Converting Enzyme 2. Cell, 2020; 182(1): 50-58. doi: 10.1016/j.cell.2020.05.027
[38]	Zheng J, Wong LR, Li K, et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature, 2021; 589(7843): 603-607. doi: 10.1038/s41586-020-2943-z
[39]	Dinnon K H 3rd, Leist S R, Schäfer A, et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature, 2020; 586(7830): 560-566. doi: 10.1038/s41586-020-2708-8
[40]	Rathnasinghe R, Strohmeier S, Amanat F, et al. Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection. Emerg Microbes Infect, 2020; 9(1): 2433-2445. doi: 10.1080/22221751.2020.1838955
[41]	Sun J, Zhuang Z, Zheng J, et al. Generation of a broadly useful model for COVID-19 pathogenesis, vaccination, and treatment. Cell, 2020; 182(3): 734-743. doi: 10.1016/j.cell.2020.06.010
[42]	Munster V J, Feldmann F, Williamson B N, et al. Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature, 2020; 585(7824): 268-272. doi: 10.1038/s41586-020-2324-7
[43]	Deng W, Bao L, Gao H, et al. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in rhesus macaques. Nat Comm, 2020; 11(1): 4400. doi: 10.1038/s41467-020-18149-6
[44]	Chandrashekar A, Liu J, Martinot A J, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science, 2020; 369(6505): 812-817. doi: 10.1126/science.abc4776
[45]	Feng L, Wang Q, Shan C, et al. An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques. Nat Comm, 2020; 11(1): 4207. doi: 10.1038/s41467-020-18077-5
[46]	Yu J, Tostanoski L H, Peter L, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science, 2020; 369(6505): 806-11. doi: 10.1126/science.abc6284
[47]	Yuan S, Yin X, Meng X, et al. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature, 2021; 593: 418-423. doi: 10.1038/s41586-021-03431-4
[48]	Fox S E, Akmatbekov A, Harbert J, et al. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med, 2020; 8(7): 681-686. doi: 10.1016/S2213-2600(20)30243-5
[49]	Schurink B, Roos E, Radonic T, et al. Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study. Lancet Microbe, 2020; 1(7): e290-e299. doi: 10.1016/S2666-5247(20)30144-0
[50]	Ackermann M, Verleden S E, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med, 2020; 383(2): 120-128. doi: 10.1056/NEJMoa2015432
[51]	McGonagle D, O'Donnell J S, Sharif K, et al. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol, 2020; 2(7): e437-e445. doi: 10.1016/S2665-9913(20)30121-1
[52]	Hanley B, Naresh K N, Roufosse C, et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study. Lancet Microbe, 2020; 1(6): e245-e253. doi: 10.1016/S2666-5247(20)30115-4
[53]	Puelles V G, Lütgehetmann M, Lindenmeyer M T, et al. Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med, 2020; 383(6): 590-592. doi: 10.1056/NEJMc2011400
[54]	Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet, 2020; 395(10235): 1517-1520. doi: 10.1016/S0140-6736(20)30920-X
[55]	Feng E, Balint E, Poznanski S M, et al. Aging and interferons: impacts on inflammation and viral disease outcomes. Cells, 2021; 10(3): 708. doi: 10.3390/cells10030708
[56]	Ballow M, Haga C L. Why do some people develop serious COVID-19 Disease after infection, while others only exhibit mild symptoms? J Allergy Clin Immunol Pract, 2021; 9(4): 1442-1448. doi: 10.1016/j.jaip.2021.01.012
[57]	Fajgenbaum D C, June C H. Cytokine storm. N Engl J Med, 2020; 383(23): 2255-2273. doi: 10.1056/NEJMra2026131
[58]	Jiang L, Tang K, Levin M, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect dis, 2020; 20(11): e276-288. doi: 10.1016/S1473-3099(20)30651-4
[59]	Wölfel R, Corman V M, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature, 2020; 581(7809): 465-469. doi: 10.1038/s41586-020-2196-x
[60]	He X, Lau E H Y, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med, 2020; 26(5): 672-675. doi: 10.1038/s41591-020-0869-5
[61]	To K K, Tsang O T, Leung W S, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis, 2020; 20(5): 565-574. doi: 10.1016/S1473-3099(20)30196-1
[62]	Guo W L, Jiang Q, Ye F, et al. Effect of throat washings on detection of 2019 Novel Coronavirus. Clin Infect Dis, 2020; 71(8): 1980-1981. doi: 10.1093/cid/ciaa416
[63]	Shan D, Johnson J M, Fernandes S C, et al. N-protein presents early in blood, dried blood and saliva during asymptomatic and symptomatic SARS-CoV-2 infection. Nat Comm, 2021; 12(1): 1931. doi: 10.1038/s41467-021-22072-9
[64]	Cevik M, Tate M, Lloyd O, et al. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe, 2021; 2(1): e13-22. doi: 10.1016/S2666-5247(20)30172-5
[65]	Wang Y, Zhang L, Sang L, et al. Kinetics of viral load and antibody response in relation to COVID-19 severity. J Clin Invest, 2020; 130(10): 5235-5244. doi: 10.1172/JCI138759
[66]	Hong K, Cao W, Liu Z, et al. Prolonged presence of viral nucleic acid in clinically recovered COVID-19 patients was not associated with effective infectiousness. Emerg Microbe Infect, 2020; 9(1): 2315-2321. doi: 10.1080/22221751.2020.1827983
[67]	Boum Y, Fai K N, Nicolay B, et al. Performance and operational feasibility of antigen and antibody rapid diagnostic tests for COVID-19 in symptomatic and asymptomatic patients in Cameroon: a clinical, prospective, diagnostic accuracy study. Lancet Infect Dis, 2021; 21: 1089-1096. doi: 10.1016/S1473-3099(21)00132-8
[68]	Long Q X, Liu B Z, Deng H J, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Natmed, 2020; 26(6): 845-848.
[69]	Yu H Q, Sun B Q, Fang Z F, et al. Distinct features of SARS-CoV-2-specific IgA response in COVID-19 patients. Eur Respir J, 2020; 56(2): 2001526. doi: 10.1183/13993003.01526-2020
[70]	Sterlin D, Mathian A, Miyara M, et al. IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med, 2021; 13(577): eabd2223. doi: 10.1126/scitranslmed.abd2223
[71]	Chen M, Qin R, Jiang M, et al. Clinical applications of detecting IgG, IgM or IgA antibody for the diagnosis of COVID-19: A meta-analysis and systematic review. Int J Infect Dis, 2021; 104: 415-422. doi: 10.1016/j.ijid.2021.01.016
[72]	Niu X, Li S, Li P, et al. Longitudinal analysis of T and B cell receptor repertoire transcripts reveal dynamic immune response in COVID-19 patients. Front Immunol, 2020; 11: 582010. doi: 10.3389/fimmu.2020.582010
[73]	Wilk A J, Rustagi A, Zhao N Q, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med, 2020; 26(7): 1070. doi: 10.1038/s41591-020-0944-y
[74]	Bost P, Giladi A, Liu Y, et al. Host-Viral infection maps reveal signatures of severe COVID-19 Patients. Cell, 2020; 181(7): 1475-1488. doi: 10.1016/j.cell.2020.05.006
[75]	Liao M, Liu Y, Yuan J, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med, 2020; 26(6): 842-844. doi: 10.1038/s41591-020-0901-9
[76]	Dejnirattisai W, Zhou D, Supasa P, et al. Antibody evasion by the P. 1 strain of SARS-CoV-2. Cell, 2021; 184: 2939-2954. doi: 10.1016/j.cell.2021.03.055
[77]	Emary K R W, Golubchik T, Aley P K, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet, 2021; 397(10282): 1351-1362. doi: 10.1016/S0140-6736(21)00628-0
[78]	Challen R, Brooks-Pollock E, Read J M, et al. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ, 2021; 372: n579.
[79]	Frampton D, Rampling T, Cross A, et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. Lancet Infect Dis, 2021; 21: 1246-1256. doi: 10.1016/S1473-3099(21)00170-5
[80]	Keehner J, Horton L E, Pfeffer M A, et al. SARS-CoV-2 infection after vaccination in health care workers in California. N Engl J Med, 2021; 384(18): 1774-1775. doi: 10.1056/NEJMc2101927
[81]	Li Q, Nie J, Wu J, et al. SARS-CoV-2 501Y. V2 variants lack higher infectivity but do have immune escape. Cell, 2021; 184(9): 2362-2371. doi: 10.1016/j.cell.2021.02.042
[82]	Zhou D, Dejnirattisai W, Supasa P, et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell, 2021; 184(9): 2348-2461. doi: 10.1016/j.cell.2021.02.037
[83]	Hoffmann M, Arora P, Groß R, et al. SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies. Cell, 2021; 184(9): 2384-2393. doi: 10.1016/j.cell.2021.03.036
[84]	Wolter N, Jassat W, Walaza S, et al. Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study. Lancet, 2022; 399(10323): 437-446. doi: 10.1016/S0140-6736(22)00017-4
[85]	Abu-Raddad L J, Chemaitelly H, Butt A A. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. BMJ Med, 2022; 12(3): 386.
[86]	Shinde V, Bhikha S, Hoosain Z, et al. Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med, 2021; 384: 1899-1909. doi: 10.1056/NEJMoa2103055
[87]	Shen X, Tang H, Pajon R, et al. Neutralization of SARS-CoV-2 variants B.1.429 and B.1.351. N Engl J Med, 2021; 384: 2352-2354. doi: 10.1056/NEJMc2103740
[88]	Supasa P, Zhou D, Dejnirattisai W, et al. Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera. Cell, 2021; 184(8): 2201-2211. doi: 10.1016/j.cell.2021.02.033
[89]	Madhi S A, Baillie V, Cutland C L, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Engl J Med, 2021; 384: 1885-1898. doi: 10.1056/NEJMoa2102214
[90]	Moyo-Gwete T, Madzivhandila M, Makhado Z, et al. Cross-Reactive neutralizing antibody responses elicited by SARS-CoV-2 501Y. V2 (B.1.351). N Engl J Med, 2021; 384: 2161-2163. doi: 10.1056/NEJMc2104192
[91]	Wang G L, Wang Z Y, Duan L J, et al. Susceptibility of circulating SARS-CoV-2 variants to Neutralization. N Engl J Med, 2021; 384: 2354-2356. doi: 10.1056/NEJMc2103022
[92]	Lustig Y, Nemet I, Kliker L, et al. Neutralizing response against variants after SARS-CoV-2 infection and one dose of BNT162b2. N Engl J Med, 2021; 384: 2453-2454. doi: 10.1056/NEJMc2104036
[93]	Andrews N, Stowe J, Kirsebom F, et al. Covid-19 vaccine effectiveness against the Omicron (B.1.1.529) variant. N Engl J Med, 2022; 386: 1532-1546. doi: 10.1056/NEJMoa2119451
[94]	Pajon R, Doria-Rose N A, Shen X, et al. SARS-CoV-2 Omicron variant neutralization after mRNA-1273 booster vaccination. N Engl J Med, 2022; 386(11): 1088-1091. doi: 10.1056/NEJMc2119912
[95]	Regev-Yochay G, Gonen T, Gilboa M, , et al. Efficacy of a fourth dose of Covid-19 mRNA Vaccine against Omicron. N Engl J Med, 2022; 386: 1377-1380. doi: 10.1056/NEJMc2202542
[96]	Chia W N, Zhu F, Ong S W X, et al. Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study. Lancet Microbe, 2021; 2: e240-249. doi: 10.1016/S2666-5247(21)00025-2
[97]	Hansen C H, Michlmayr D, Gubbels S M, et al. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet, 2021; 397(10280): 1204-1212. doi: 10.1016/S0140-6736(21)00575-4
[98]	Hall V J, Foulkes S, Charlett A, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet, 2021; 397(10283): 1459-1469. doi: 10.1016/S0140-6736(21)00675-9
[99]	Letizia A G, Ge Y, Vangeti S, et al. SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study. Lancet Respir Med, 2021; 9: 712-720. doi: 10.1016/S2213-2600(21)00158-2
[100]	Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 2020; 395(10223): 507-513. doi: 10.1016/S0140-6736(20)30211-7
[101]	Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA, 2020; 323(11): 1061-1069. doi: 10.1001/jama.2020.1585
[102]	Feldstein L R, Rose E B, Horwitz S M, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med, 2020; 383(4): 334-346. doi: 10.1056/NEJMoa2021680
[103]	Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis, 2020; 20(4): 425-434. doi: 10.1016/S1473-3099(20)30086-4
[104]	Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet, 2020; 395(10229): 1054-1062. doi: 10.1016/S0140-6736(20)30566-3
[105]	Yanes-Lane M, Winters N, Fregonese F, et al. Proportion of asymptomatic infection among COVID-19 positive persons and their transmission potential: a systematic review and meta-analysis. PloS One, 2020; 15(11): e0241536. doi: 10.1371/journal.pone.0241536
[106]	Long Q X, Tang X J, Shi Q L, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med, 2020; 26(8): 1200-1204. doi: 10.1038/s41591-020-0965-6
[107]	Yang M, Li L, Huang T, et al. SARS-CoV-2 detected on environmental fomites for both asymptomatic and symptomatic patients with COVID-19. Am J Respir Crit Care Med, 2021; 203(3): 374-378. doi: 10.1164/rccm.202006-2136LE
[108]	Melis M, Littera R. Undetected infectives in the Covid-19 pandemic. Int J Infect Dis, 2021; 104: 262-268. doi: 10.1016/j.ijid.2021.01.010
[109]	Davies N G, Klepac P, Liu Y, et al. Age-dependent effects in the transmission and control of COVID-19 epidemics. Nat Med, 2020; 26(8): 1205-1211. doi: 10.1038/s41591-020-0962-9
[110]	Ahrenfeldt L J, Otavova M, Christensen K, et al. Sex and age differences in COVID-19 mortality in Europe Res Sq, 2020; rs. 3. rs-61444.
[111]	Torres Acosta M A, Singer B D. Pathogenesis of COVID-19-induced ARDS: implications for an ageing population. Eur Respir J, 2020; 56(3): 2002049. doi: 10.1183/13993003.02049-2020
[112]	Koff W C, Williams M A. Covid-19 and immunity in aging populations - a new research agenda. N Engl J Med, 2020; 383(9): 804-805. doi: 10.1056/NEJMp2006761
[113]	Wang X Q, Song G, Yang Z, et al. Association between ageing population, median age, life expectancy and mortality in coronavirus disease (COVID-19). Aging, 2020; 12(24): 24570-24578. doi: 10.18632/aging.104193
[114]	Imam Z, Odish F, Gill I, et al. Older age and comorbidity are independent mortality predictors in a large cohort of 1305 COVID-19 patients in Michigan, United States. J Intern Med, 2020; 288(4): 469-476. doi: 10.1111/joim.13119
[115]	Guan W J, Laing W H, Zhao Y, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J, 2020; 55(5): 2000547. doi: 10.1183/13993003.00547-2020
[116]	Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 fection: a nationwide analysis in China. Lancet Oncol, 2020; 21(3): 335-337. doi: 10.1016/S1470-2045(20)30096-6
[117]	Guan W J, Liang W H, Shi Y, et al. Chronic respiratory diseases and the outcomes of COVID-19: a nationwide retrospective cohort study of 39, 420 Cases. J Allergy Clin Immunol Pract, 2021; 9: 2645-2655. doi: 10.1016/j.jaip.2021.02.041
[118]	Bloom C I, Drake T M, Docherty A B, et al. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK. Lancet Respir Med, 2021; 9: 699-711. doi: 10.1016/S2213-2600(21)00013-8
[119]	Calmes D, Graff S, Maes N, et al. Asthma and COPD are not risk factors for ICU stay and death in case of SARS-CoV2 Infection. J Allergy Clin Immunol Pract, 2021; 9(1): 160-169. doi: 10.1016/j.jaip.2020.09.044
[120]	Skevaki C, Karsonova A, Karaulov A, et al. Asthma-associated risk for COVID-19 development. J Allergy Clin Immunol, 2020; 146(6): 1295-1301. doi: 10.1016/j.jaci.2020.09.017
[121]	Song J, Zeng M, Wang H, et al. Distinct effects of asthma and COPD comorbidity on disease expression and outcome in patients with COVID-19. Allergy, 2021; 76(2): 483-496. doi: 10.1111/all.14517
[122]	World Health Organization. Clinical management of COVID-19: interim guidance, 27 May 2020. https://apps.who.int/iris/handle/10665/332196. Accessed on December 2022.
[123]	Wei P F. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). Chin Med J (Engl), 2020; 133(9): 1087-1095. doi: 10.1097/CM9.0000000000000819
[124]	International Severe Acute Respiratory and emerging Infection Consortium. https://isaric.tghn.org/. Accessed on December 2022.
[125]	Zhang X, Tan Y, Ling Y, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature, 2020; 583(7816): 437-40. doi: 10.1038/s41586-020-2355-0
[126]	Chen R, Sang L, Jiang M, et al. Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China. J Allergy Clin Immunol, 2020; 146(1): 89-100. doi: 10.1016/j.jaci.2020.05.003
[127]	Shen B, Yi X, Sun Y. et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell, 2020; 182(1): 59-72. doi: 10.1016/j.cell.2020.05.032
[128]	Ren L, Wang Y, Zhong J, et al. Dynamics of the upper respiratory tract microbiota and its association with mortality in COVID-19. Am J Respir Crit Care Med, 2021; 204(12): 1379-1390. doi: 10.1164/rccm.202103-0814OC
[129]	Liang W, Liang H, Ou L, et al. Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. JAMA Intern Med, 2020; 180(8): 1081-9. doi: 10.1001/jamainternmed.2020.2033
[130]	Alemany A, Bar C B, Ouchi D, et al. Analytical and clinical performance of the panbio COVID-19 antigen-detecting rapid diagnostic test. J Infect, 2021; 82(5): 186-230.
[131]	Kitagawa Y, Orihara Y, Kawamura R, et al. Evaluation of rapid diagnosis of novel coronavirus disease (COVID-19) using loop-mediated isothermal amplification. J Clin Virol, 2020; 129: 104446. doi: 10.1016/j.jcv.2020.104446
[132]	Xing W, Liu Y, Wang H, et al. A high-throughput, multi-index isothermal amplification platform for rapid detection of 19 types of common respiratory viruses including SARS-CoV-2. Engineering, 2020; 6(10): 1130-1140. doi: 10.1016/j.eng.2020.07.015
[133]	Xing W, Wang J, Zhao C, et al. A highly automated mobile laboratory for on-site molecular diagnostics in the COVID-19 pandemic. Clin Chem, 2021; 67(4): 672-683. doi: 10.1093/clinchem/hvab027
[134]	Joung J, Ladha A, Saito M, et al. Detection of SARS-CoV-2 with sherlock one-pot testing. N Engl J Med, 2020; 383(15): 1492-1494. doi: 10.1056/NEJMc2026172
[135]	Brendish N J, Poole S, Naidu V V, et al. Clinical impact of molecular point-of-care testing for suspected COVID-19 in hospital (COV-19POC): a prospective, interventional, non-randomised, controlled study. Lancet Respir Med, 2020; 8(12): 1192-1200. doi: 10.1016/S2213-2600(20)30454-9
[136]	Gibani M M, Toumazou C, Sohbati M, et al. Assessing a novel, lab-free, point-of-care test for SARS-CoV-2 (CovidNudge): a diagnostic accuracy study. Lancet Microbe, 2020; 1(7): e300-307. doi: 10.1016/S2666-5247(20)30121-X
[137]	Zhang K, Liu X, Shen J, et al. Clinically applicable AI system for accurate diagnosis, quantitative measurements, and prognosis of COVID-19 pneumonia using computed tomography. Cell, 2020; 182(5): 1360. doi: 10.1016/j.cell.2020.08.029
[138]	Mei X, Lee H C, Diao K Y, et al. Artificial intelligence-enabled rapid diagnosis of patients with COVID-19. Nat Med, 2020; 26(8): 1224-1228. doi: 10.1038/s41591-020-0931-3
[139]	Jiao Z, Choi J W, Halsey K, et al. Prognostication of patients with COVID-19 using artificial intelligence based on chest x-rays and clinical data: a retrospective study. Lancet Digit Health, 2021; 3(5): e286-294. doi: 10.1016/S2589-7500(21)00039-X
[140]	Wang G, Liu X, Shen J, et al. A deep-learning pipeline for the diagnosis and discrimination of viral, non-viral and COVID-19 pneumonia from chest X-ray images. Nat Biomed Eng, 2021; 5: 943. doi: 10.1038/s41551-021-00787-w
[141]	Menni C, Valdes A M, Freidin M B, et al. Real-time tracking of self-reported symptoms to predict potential COVID-19. Nat Med, 2020; 26(7): 1037-1040. doi: 10.1038/s41591-020-0916-2
[142]	Mendels D A, Dortet L, Emeraud C, et al. Using artificial intelligence to improve COVID-19 rapid diagnostic test result interpretation. Proc Natl Aca Sci, 2021; 118(12): : e2019893118. doi: 10.1073/pnas.2019893118
[143]	Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med, 2020; 382(19): 1787-1799. doi: 10.1056/NEJMoa2001282
[144]	Recovery Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (Recovery): a randomised, controlled, open-label, platform trial. Lancet, 2020; 396(10259): 1345-1352. doi: 10.1016/S0140-6736(20)32013-4
[145]	Panerai S, Raggi A, Tasca D, et al. Telephone-based reality orientation therapy for patients with dementia: a pilot study during the COVID-19 outbreak. Am J Occup Ther, 2021; 75(2): 1-9.
[146]	Hung I F, Lung K C, Tso E Y, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet, 2020; 395(10238): 1695-1704. doi: 10.1016/S0140-6736(20)31042-4
[147]	Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med, 2022; 386: 1397-1408. doi: 10.1056/NEJMoa2118542
[148]	Goldman J D, Lye D C B, Hui D S, et al. Remdesivir for 5 or 10 Days in patients with severe Covid-19. N Engl J Med, 2020; 383(19): 1827-1837. doi: 10.1056/NEJMoa2015301
[149]	Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 2020; 395(10236): 1569-1578. doi: 10.1016/S0140-6736(20)31022-9
[150]	Beigel J H, Tomashek K M, Dodd L E, et al. Remdesivir for the treatment of Covid-19-final report. N Engl J Med, 2020; 383(19): 1813-1826. doi: 10.1056/NEJMoa2007764
[151]	Spinner C D, Gottlieb R L, Criner G J, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA, 2020; 324(11): 1048-1057. doi: 10.1001/jama.2020.16349
[152]	Yan D, Liu X Y, Zhu Y N, et al. Factors associated with prolonged viral shedding and impact of lopinavir/ritonavir treatment in hospitalised non-critically ill patients with SARS-CoV-2 infection. Eur Respir J, 2020; 56(1): 2000799. doi: 10.1183/13993003.00799-2020
[153]	Gottlieb R L, Vaca C E, Paredes R, et al. Early Remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med, 2022; 386(4): 305-315. doi: 10.1056/NEJMoa2116846
[154]	Jayk Bernal A, Gomes da Silva M M, Musungaie D B, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med, 2022; 386(6): 509-520. doi: 10.1056/NEJMoa2116044
[155]	Reis G, Silva E, Silva D C M, et al. Effect of early treatment with ivermectin among patients with Covid-19. N Engl J Med, 2022; 386: 1721-1731. doi: 10.1056/NEJMoa2115869
[156]	Cavalcanti A B, Zampieri FG, Rosa R G, et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med, 2020; 383(21): e119. doi: 10.1056/NEJMx200021
[157]	Self W H, Semler M W, Leither L M, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA, 2020; 324(21): 2165-2176. doi: 10.1001/jama.2020.22240
[158]	Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ, 2020; 369: m1849.
[159]	Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med, 2020; 383(21): 2030-2040. doi: 10.1056/NEJMoa2022926
[160]	Boulware D R, Pullen M F, Bangdiwala A S, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med, 2020; 383(6): 517-525. doi: 10.1056/NEJMoa2016638
[161]	Mitjà O, Corbacho-Monné M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19. N Engl J Med, 2021; 384(5): 417-427. doi: 10.1056/NEJMoa2021801
[162]	Zhao H, Zhang C, Zhu Q, et al. Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: a multicenter, open-label, randomized trial. Int Immunopharmacol, 2021; 97: 107702. doi: 10.1016/j.intimp.2021.107702
[163]	Solaymani-Dodaran M, Ghanei M, Bagheri M, et al. Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. Int Immunopharmacol, 2021; 95: 107522. doi: 10.1016/j.intimp.2021.107522
[164]	López-Medina E, López P, Hurtado I C, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA, 2021; 325(14): 1426-1435. doi: 10.1001/jama.2021.3071
[165]	Monk P D, Marsden R J, Tear V J, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med, 2021; 9(2): 196-206. doi: 10.1016/S2213-2600(20)30511-7
[166]	Tomazini B M, Maia I S, Cavalcanti A B, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA, 2020; 324(13): 1307-1316. doi: 10.1001/jama.2020.17021
[167]	Horby P, Lim W S, Emberson J R, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med, 2021; 384(8): 693-704. doi: 10.1056/NEJMoa2021436
[168]	Angus D C, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA, 2020; 324(13): 1317-1329. doi: 10.1001/jama.2020.17022
[169]	Dequin P F, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among Critically Ill patients with COVID-19: a randomized clinical trial. JAMA, 2020; 324(13): 1298-1306. doi: 10.1001/jama.2020.16761
[170]	Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med, 2020; 180(7): 934-943. doi: 10.1001/jamainternmed.2020.0994
[171]	Kalil A C, Patterson T F, Mehta A K, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med, 2021; 384(9): 795-807. doi: 10.1056/NEJMoa2031994
[172]	Lenze E J, Mattar C, Zorumski C F, et al. Fluvoxamine vs Placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA, 2020; 324(22): 2292-2300. doi: 10.1001/jama.2020.22760
[173]	Ramakrishnan S, Nicolau D V, Jr Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med, 2021; 9(7): 763-772. doi: 10.1016/S2213-2600(21)00160-0
[174]	Principle Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (Principle): a randomised, controlled, open-label, adaptive platform trial. Lancet, 2021; 397(10279): 1063-1074. doi: 10.1016/S0140-6736(21)00461-X
[175]	Bhattacharya B, Kumar R, Meena V P, et al. SARS-CoV-2 RT-PCR profile in 298 Indian COVID-19 patients: a retrospective observational study. Path Dis, 2021; 79(1): 64.
[176]	Furtado R H M, Berwanger O, Fonseca H A, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION Ⅱ): a randomised clinical trial. Lancet, 2020; 396(10256): 959-967. doi: 10.1016/S0140-6736(20)31862-6
[177]	Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol, 2020; 146(1): 137-146. doi: 10.1016/j.jaci.2020.05.019
[178]	Murai I H, Fernandes A L, Sales L P, et al. Effect of a single high dose of Vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: a randomized clinical trial. JAMA, 2021; 325(11): 1053-1060. doi: 10.1001/jama.2020.26848
[179]	Recovery Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (Recovery): a randomised, controlled, open-label, platform trial. Lancet Respir Med, 2021; 9(12): 1419-1426. doi: 10.1016/S2213-2600(21)00435-5
[180]	Gordon A C, Mouncey P R, Al-Beidh F, et al. Interleukin-6 receptor antagonists in Critically Ill patients with Covid-19. N Engl J Med, 2021; 384(16): 1491-1502. doi: 10.1056/NEJMoa2100433
[181]	Recovery Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (Recovery): a randomised, controlled, open-label, platform trial. Lancet, 2021; 397(10285): 1637-1645. doi: 10.1016/S0140-6736(21)00676-0
[182]	Rosas I O, Bräu N, Waters M, et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med, 2021; 384(16): 1503-1516. doi: 10.1056/NEJMoa2028700
[183]	Hermine O, Mariette X, Tharaux P L, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med, 2021; 181(1): 32-40. doi: 10.1001/jamainternmed.2020.6820
[184]	Veiga V C, Prats J, Farias D L C, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ, 2021; 372: n84.
[185]	Soin A S, Kumar K, Choudhary N S, et al. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Respir Med, 2021; 9(5): 511-521. doi: 10.1016/S2213-2600(21)00081-3
[186]	Stone J H, Frigault M J, Serling-Boyd N J, et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med, 2020; 383(24): 2333-2344. doi: 10.1056/NEJMoa2028836
[187]	Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med, 2021; 181(1): 24-31. doi: 10.1001/jamainternmed.2020.6615
[188]	Lescure F X, Honda H, Fowler R A, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med, 2021; 9(5): 522-532. doi: 10.1016/S2213-2600(21)00099-0
[189]	Cremer P C, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatol, 2021; 3: e410-e418. doi: 10.1016/S2665-9913(21)00070-9
[190]	Cheng L L, Guan W J, Duan C Y, et al. Effect of recombinant human granulocyte colony-stimulating factor for patients with Coronavirus Disease 2019 (COVID-19) and lymphopenia: a randomized clinical trial. JAMA Intern Med, 2021; 181(1): 71-78. doi: 10.1001/jamainternmed.2020.5503
[191]	Okoh A K, Bishburg E, Grinberg S, et al. Tocilizumab use in COVID-19-associated pneumonia. J Med Virol, 2021; 93(2): 1023-1028. doi: 10.1002/jmv.26471ternmed.2020.5503
[192]	Vlaar A P J, de Bruin S, Busch M, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol, 2020; 2(12): e764-773. doi: 10.1016/S2665-9913(20)30341-6
[193]	Cheng Y, Wong R, Soo Y O, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis, 2005; 24(1): 44-46. doi: 10.1007/s10096-004-1271-9
[194]	Weinreich D M, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med, 2021; 384(3): 238-251. doi: 10.1056/NEJMoa2035002
[195]	Wang J, Zheng X, Chen J. Clinical progression and outcomes of 260 patients with severe COVID-19: an observational study. Sci Rep, 2021; 11(1): 3166. doi: 10.1038/s41598-021-82943-5
[196]	Gottlieb R L, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA, 2021; 325(7): 632-644. doi: 10.1001/jama.2021.0202
[197]	Andreano E, Nicastri E, Paciello I, et al. Extremely potent human monoclonal antibodies from COVID-19 convalescent patients. Cell, 2021; 184(7): 1821-1835. doi: 10.1016/j.cell.2021.02.035
[198]	Libster R, Pérez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med, 2021; 384(7): 610-618. doi: 10.1056/NEJMoa2033700
[199]	Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase Ⅱ multicentre randomised controlled trial (PLACID Trial). BMJ, 2020; 371: m3939.
[200]	Simonovich V A, Burgos Pratx L D, Scibona P, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med, 2021; 384(7): 619-629. doi: 10.1056/NEJMoa2031304
[201]	Lundgren J D, Grund B, Barkauskas C E, et al. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med, 2021; 384(10): 905-914. doi: 10.1056/NEJMoa2033130
[202]	Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA, 2020; 324(5): 460-470. doi: 10.1001/jama.2020.10044
[203]	Janiaud P, Axfors C, Schmitt A M, et al. Association of convalescent plasma treatment with clinical outcomes in patients with COVID-19: a systematic review and meta-analysis. JAMA, 2021; 325(12): 1185-1195. doi: 10.1001/jama.2021.2747
[204]	Sullivan D J, Gebo K A, Shoham S, et al. Early outpatient treatment for Covid-19 with convalescent plasma. N Engl J Med, 2022; 386: 1700-1711. doi: 10.1056/NEJMoa2119657
[205]	Mancia G, Rea F, Ludergnani M, et al. Renin-Angiotensin-Aldosterone system blockers and the risk of Covid-19. N Engl J Med, 2020; 382(25): 2431-2440. doi: 10.1056/NEJMoa2006923
[206]	Reynolds H R, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone system inhibitors and risk of Covid-19. N Engl J Med, 2020; 382(25): 2441-2448. doi: 10.1056/NEJMoa2008975
[207]	Morales D R, Conover M M, You S C, et al. Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis. Lancet Digit health, 2021; 3(2): e98-114. doi: 10.1016/S2589-7500(20)30289-2
[208]	=Mehta N, Kalra A, Nowacki A S, et al. Association of use of angiotensin-converting enzyme inhibitors and Angiotensin Ⅱ receptor blockers with testing positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol, 2020; 5(9): 1020-1026. doi: 10.1001/jamacardio.2020.1855
[209]	de Abajo F J, Rodríguez-Martín S, Lerma V, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet, 2020; 395(10238): 1705-1714. doi: 10.1016/S0140-6736(20)31030-8
[210]	Lopes R D, Macedo A V S, de Barros E Silva P G M, , et al. Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and Angiotensin Ⅱ receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: a randomized clinical trial. JAMA, 2021; 325(3): 254-264. doi: 10.1001/jama.2020.25864
[211]	Cohen J B, Hanff T C, William P, et al. Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet Respir Med, 2021; 9(3): 275-284. doi: 10.1016/S2213-2600(20)30558-0
[212]	Haas E J, Angulo F J, McLaughlin J M, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet, 2021; 397: 1819-1829. doi: 10.1016/S0140-6736(21)00947-8
[213]	Anderson E J, Rouphael N G, Widge A T, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med, 2020; 383(25): 2427-2438. doi: 10.1056/NEJMoa2028436
[214]	Walsh E E, Frenck R W Jr, Falsey A R, et al. Safety and immunogenicity of two RNA-Based Covid-19 vaccine candidates. N Engl J Med, 2020; 383(25): 2439-2450. doi: 10.1056/NEJMoa2027906
[215]	Keech C, Albert G, Cho I, et al. Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med, 2020; 383(24): 2320-2332. doi: 10.1056/NEJMoa2026920
[216]	Sadoff J, Gray G, Vandebosch A, et al. Safety and efficacy of single-dose Ad26. COV2. S vaccine against Covid-19. N Engl J Med, 2021; 384: 2187-2201. doi: 10.1056/NEJMoa2101544
[217]	Sadoff J, Le Gars M, Shukarev G, et al. Interim results of a phase 1-2a trial of Ad26. COV2. S Covid-19 vaccine. N Engl J Med, 2021; 384: 1824-1835. doi: 10.1056/NEJMoa2034201
[218]	Polack F P, Thomas S J, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med, 2020; 383(27): 2603-2615. doi: 10.1056/NEJMoa2034577
[219]	Baden L R, El Sahly H M, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med, 2021; 384(5): 403-416. doi: 10.1056/NEJMoa2035389
[220]	Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med, 2021; 384(15): 1412-1423. doi: 10.1056/NEJMoa2101765
[221]	Goepfert P A, Fu B, Chabanon A L, et al. Safety and immunogenicity of SARS-CoV-2 recombnant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1-2, dose-ranging study. Lancet Infect Dis, 2021; 21: 1257-1270. doi: 10.1016/S1473-3099(21)00147-X
[222]	Stephenson K E, Le Gars M, Sadoff J, et al. Immunogenicity of the Ad26. COV2. S Vaccine for COVID-19. JAMA, 2021; 325(15): 1535-44. doi: 10.1001/jama.2021.3645
[223]	Monin L, Laing A G, Muñoz-Ruiz M, et al. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study. Lancet Oncol, 2021; 22: 765-778. doi: 10.1016/S1470-2045(21)00213-8
[224]	Folegatti P M, Ewer K J, Aley P K, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet, 2020; 396(10249): 467-78. doi: 10.1016/S0140-6736(20)31604-4
[225]	Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis, 2021; 21(1): 39-51. doi: 10.1016/S1473-3099(20)30831-8
[226]	Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis, 2021; 21(2): 181-192. doi: 10.1016/S1473-3099(20)30843-4
[227]	Zhu F C, Guan X H, Li Y H, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet, 2020; 396(10249): 479-488. doi: 10.1016/S0140-6736(20)31605-6
[228]	Logunov D Y, Dolzhikova I V, Shcheblyakov D V, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet, 2021; 397(10275): 671-681. doi: 10.1016/S0140-6736(21)00234-8
[229]	Ramasamy M N, Minassian A M, Ewer K J, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet, 2021; 396(10267): 1979-1993.
[230]	Voysey M, Clemens S A C, Madhi S A, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet, 2021; 397(10269): 99-111. doi: 10.1016/S0140-6736(20)32661-1
[231]	Voysey M, Costa Clemens S A, Madhi S A, et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet, 2021; 397(10277): 881-891. doi: 10.1016/S0140-6736(21)00432-3
[232]	Ella R, Vadrevu K M, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis, 2021; 21(5): 637-646. doi: 10.1016/S1473-3099(20)30942-7
[233]	Richmond P, Hatchuel L, Dong M, et al. Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: a phase 1, randomised, double-blind, placebo-controlled trial. Lancet, 2021; 397(10275): 682-694. doi: 10.1016/S0140-6736(21)00241-5
[234]	Chappell K J, Mordant F L, Li Z, et al. Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Infect Dis, 2021; 21: 1383-1394. doi: 10.1016/S1473-3099(21)00200-0
[235]	Xia S, Duan K, Zhang Y, et al. Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials. JAMA, 2020; 324(10): 951-960. doi: 10.1001/jama.2020.15543
[236]	Wu Z, Hu Y, Xu M, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis, 2021; 21: 803-812. doi: 10.1016/S1473-3099(20)30987-7
[237]	Greinacher A, Thiele T, Warkentin T E, et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med, 2021.
[238]	Schultz N H, Sørvoll I H, Michelsen A E, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med, 2021.
[239]	Scully M, Singh D, Lown R, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med, 2021; 384: 2202-2211. doi: 10.1056/NEJMoa2105385
[240]	Muir K L, Kallam A, Koepsell S A, et al. Thrombotic thrombocytopenia after Ad26. COV2. S vaccination. N Engl J Med, 2021; 384: 1964-1965. doi: 10.1056/NEJMc2105869
[241]	Pottegård A, Lund L C, Karlstad Ø, et al. Events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study. BMJ, 2021; 373: n1114.
[242]	Goldberg Y, Mandel M, Bar-On Y M, et al. Waning immunity after the BNT162b2 vaccine in israel. n engl j med, 2021; 385(24): e85. doi: 10.1056/NEJMoa2114228
[243]	Levin E G, Lustig Y, Cohen C, et al. Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months. N Engl J Med, 2021; 385(24): e84. doi: 10.1056/NEJMoa2114583
[244]	Atmar R L, Lyke K E, Deming M E, et al. Homologous and heterologous Covid-19 booster vaccinations. N Engl J Med, 2022; 386(11): 1046-1057. doi: 10.1056/NEJMoa2116414
[245]	Stuart A S V, Shaw R H, Liu X, et al. Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial. Lancet, 2022; 399(10319): 36-49. doi: 10.1016/S0140-6736(21)02718-5
[246]	Munro A P S, Janani L, Cornelius V, et al. Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet, 2021; 398(10318): 2258-2276. doi: 10.1016/S0140-6736(21)02717-3
[247]	Rearte A, Castelli J M, Rearte R, et al. Effectiveness of rAd26-rAd5, ChAdOx1 nCoV-19, and BBIBP-CorV vaccines for risk of infection with SARS-CoV-2 and death due to COVID-19 in people older than 60 years in Argentina: a test-negative, case-control, and retrospective longitudinal study. Lancet, 2022; 399(10331): 1254-1264. doi: 10.1016/S0140-6736(22)00011-3
[248]	Costa Clemens S A, Weckx L, Clemens R, et al. Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study. Lancet, 2022; 399(10324): 521-529. doi: 10.1016/S0140-6736(22)00094-0
[249]	Widge A T, Rouphael N G, Jackson L A, et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N Engl J Med, 2021; 384(1): 80-82. doi: 10.1056/NEJMc2032195
[250]	Doria-Rose N, Suthar M S, Makowski M, et al. Antibody persistence through 6 months after the second dose of mRNA-1273 vaccine for Covid-19. N Engl J Med, 2021; 384: 2259-2261. doi: 10.1056/NEJMc2103916
[251]	Wang Z, Wang Y, Yang Z, et al. The use of non-invasive ventilation in COVID-19: a systematic review. Int J Infect Dis, 2021; 106: 254-261. doi: 10.1016/j.ijid.2021.03.078
[252]	Schünemann H J, Khabsa J, Solo K, et al. Ventilation techniques and risk for transmission of Coronavirus disease, including COVID-19: a living systematic review of multiple streams of evidence. Ann Intern Med, 2020; 173(3): 204-216. doi: 10.7326/M20-2306
[253]	Grieco D L, Menga L S, Cesarano M, et al. Effect of helmet noninvasive ventilation vs high-flow nasal oxygen on days free of respiratory support in patients with COVID-19 and moderate to severe hypoxemic respiratory failure: the HENIVOT randomized clinical trial. JAMA, 2021; 325(17): 1731-1743. doi: 10.1001/jama.2021.4682
[254]	Sartini C, Tresoldi M, Scarpellini P, et al. Respiratory parameters in patients with COVID-19 after using noninvasive ventilation in the prone position outside the intensive care unit. JAMA, 2020; 323(22): 2338-2340. doi: 10.1001/jama.2020.7861
[255]	Coppo A, Bellani G, Winterton D, et al. Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study. Lancet Respir Med, 2020; 8(8): 765-774. doi: 10.1016/S2213-2600(20)30268-X
[256]	Botta M, Tsonas A M, Pillay J, et al. Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study. Lancet Respir Med, 2021; 9(2): 139-148. doi: 10.1016/S2213-2600(20)30459-8
[257]	Barbaro R P, MacLaren G, Boonstra P S, et al. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet, 2020; 396(10257): 1071-1078. doi: 10.1016/S0140-6736(20)32008-0
[258]	Schmidt M, Hajage D, Lebreton G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med, 2020; 8(11): 1121-1131. doi: 10.1016/S2213-2600(20)30328-3
[259]	Lebreton G, Schmidt M, Ponnaiah M, et al. Extracorporeal membrane oxygenation network organisation and clinical outcomes during the COVID-19 pandemic in Greater Paris, France: a multicentre cohort study. Lancet Respir Med, 2021; 9: 851-862. doi: 10.1016/S2213-2600(21)00096-5
[260]	Bharat A, Machuca T N, Querrey M, et al. Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries. Lancet Respir Med, 2021; 9(5): 487-497. doi: 10.1016/S2213-2600(21)00077-1
[261]	Morin L, Savale L, Pham T, et al. Four-Month clinical status of a cohort of patients after hospitalization for COVID-19. JAMA, 2021; 325(15): 1525-1534. doi: 10.1001/jama.2021.3331
[262]	Wu X, Liu X, Zhou Y, et al. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study. Lancet Respir Med, 2021; 9(7): 747-754. doi: 10.1016/S2213-2600(21)00174-0
[263]	Myall K J, Mukherjee B, Castanheira A M, et al. Persistent post-COVID-19 interstitial lung disease. An observational study of corticosteroid treatment. Ann Am Thorac Soc, 2021; 18(5): 799-806. doi: 10.1513/AnnalsATS.202008-1002OC
[264]	Taquet M, Geddes J R, Husain M, et al. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psych, 2021; 8(5): 416-427. doi: 10.1016/S2215-0366(21)00084-5
[265]	Ayoubkhani D, Khunti K, Nafilyan V, et al. Post-covid syndrome in individuals admitted to hospital with Covid-19: retrospective cohort study. BMJ, 2021; 372: n693.
[266]	Aldhahir A M, Aldabayan Y S, Alqahtani J S, et al. A double-blind randomised controlled trial of protein supplementation to enhance exercise capacity in COPD during pulmonary rehabilitation: a pilot study. ERJ Open Res, 2021; 7(1): 747-754.
[267]	Center for Global Development. Financing for Global Health Security and Pandemic Preparedness: Taking Stock and What's Next. https://www.cgdev.org/blog/financing-global-health-securityand-pandemic-preparedness-taking-stock-whats-next. Accessed on December 2022.