Advertisement
Canadian Journal of Cardiology

Management and Treatment of COVID-19: The Chinese Experience

  • Author Footnotes
    ‡ These authors contributed equally to this work.
    Fujun Peng
    Footnotes
    ‡ These authors contributed equally to this work.
    Affiliations
    Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this work.
    Lei Tu
    Footnotes
    ‡ These authors contributed equally to this work.
    Affiliations
    Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this work.
    Yongshi Yang
    Footnotes
    ‡ These authors contributed equally to this work.
    Affiliations
    Department of Allergy and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Immunologic Diseases, Beijing, China
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this work.
    Peng Hu
    Footnotes
    ‡ These authors contributed equally to this work.
    Affiliations
    Department of Respiratory Medicine, Second Medical Center and National Clinical Research Center for Geriatric Diseases, Medical College of the People’s Liberation Army, Chinese People’s Liberation Army General Hospital, Beijing, China
    Search for articles by this author
  • Runsheng Wang
    Affiliations
    Department of Respiratory Medicine, Second Medical Center and National Clinical Research Center for Geriatric Diseases, Medical College of the People’s Liberation Army, Chinese People’s Liberation Army General Hospital, Beijing, China
    Search for articles by this author
  • Qinyong Hu
    Affiliations
    Renmin Hospital of Wuhan University, Wuhan, China
    Search for articles by this author
  • Feng Cao
    Affiliations
    Department of Respiratory Medicine, Second Medical Center and National Clinical Research Center for Geriatric Diseases, Medical College of the People’s Liberation Army, Chinese People’s Liberation Army General Hospital, Beijing, China
    Search for articles by this author
  • Taijiao Jiang
    Correspondence
    Dr Taijiao Jiang, No. 9, Dongdan 3rd, Dongcheng District, Beijing 100005; Tel.: +86-13366191184.
    Affiliations
    Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
    Search for articles by this author
  • Jinlyu Sun
    Correspondence
    Dr Jinlyu Sun, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, China 100730; Tel.: +86-18611382050.
    Affiliations
    Department of Allergy and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Immunologic Diseases, Beijing, China
    Search for articles by this author
  • Guogang Xu
    Correspondence
    Dr Guogang Xu, 28 Fuxing Road, Beijing, China 100853; Tel.: +86-010-66876407.
    Affiliations
    Department of Respiratory Medicine, Second Medical Center and National Clinical Research Center for Geriatric Diseases, Medical College of the People’s Liberation Army, Chinese People’s Liberation Army General Hospital, Beijing, China
    Search for articles by this author
  • Christopher Chang
    Correspondence
    Corresponding authors: Dr Christopher Chang, 1131 N 35th Ave, Suite 220, Hollywood, Florida 33021, USA.
    Affiliations
    Division of Pediatric Immunology and Allergy, Joe DiMaggio Children’s Hospital, Hollywood, Florida, USA

    Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, California, USA
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this work.
Published:April 16, 2020DOI:https://doi.org/10.1016/j.cjca.2020.04.010

      Abstract

      With more than 1,800,000 cases and 110,000 deaths globally, COVID-19 is one of worst infectious disease outbreaks in history. This paper provides a critical review of the available evidence regarding the lessons learned from the Chinese experience with COVID-19 prevention and management. The steps that have led to a near disappearance of new cases in China included rapid sequencing of the virus to establish testing kits, which allowed tracking of infected persons in and out of Wuhan. In addition, aggressive quarantine measures included the complete isolation of Wuhan and then later Hubei Province and the rest of the country, as well as closure of all schools and nonessential businesses. Other measures included the rapid construction of two new hospitals and the establishment of “Fangcang” shelter hospitals. In the absence of a vaccine, the management of COVID-19 included antivirals, high-flow oxygen, mechanical ventilation, corticosteroids, hydroxychloroquine, tocilizumab, interferons, intravenous immunoglobulin, and convalescent plasma infusions. These measures appeared to provide only moderate success. Although some measures have been supported by weak descriptive data, their effectiveness is still unclear pending well controlled clinical trials. In the end, it was the enforcement of drastic quarantine measures that stopped SARS-CoV-2 from spreading. The earlier the implementation, the less likely resources will be depleted. The most critical factors in stopping a pandemic are early recognition of infected individuals, carriers, and contacts and early implementation of quarantine measures with an organised, proactive, and unified strategy at a national level. Delays result in significantly higher death tolls.

      Résumé

      Avec plus de 1 800 000 cas et 110 000 décès dans le monde, la COVID-19 est l'une des pires éclosions de maladies infectieuses de l'histoire. Ce document présente un examen critique des constats disponibles concernant les leçons tirées de l'expérience chinoise en matière de prévention et de gestion de la COVID-19. Les mesures qui ont conduit à la quasi-disparition des nouveaux cas en Chine comprenaient le séquençage rapide du virus pour établir des trousses de tests, ce qui a permis de suivre les personnes infectées à l'intérieur et à l'extérieur de Wuhan. En outre, des mesures agressives de quarantaine ont consisté à isoler complètement Wuhan, puis la province de Hubei et le reste du pays, ainsi qu'à fermer toutes les écoles et les entreprises non essentielles. D'autres mesures ont été prises, notamment la construction rapide de deux nouveaux hôpitaux et la création d'hôpitaux provisoires de type « Fangcang ». En l'absence de vaccin, la gestion de la COVID-19 a compris des antiviraux, de l'oxygène à haut débit, de la ventilation mécanique, des corticostéroïdes, de l'hydroxychloroquine, du tocilizumab, des interférons, des immunoglobulines en intraveineuses et des perfusions de plasma de patients convalescents. Ces mesures ne semblent avoir apporté qu'un succès modéré. Bien que certaines mesures aient été soutenues par des données descriptives modestes, leur efficacité n'est pas encore évidente, en attendant de meilleurs essais cliniques contrôlés. En fin de compte, c'est l'application de mesures de quarantaine drastiques qui a permis d'arrêter la propagation du SARS-CoV-2. Plus la mise en œuvre est précoce, moins il est probable que les limites des ressources soient atteintes. Les facteurs les plus critiques pour stopper une pandémie sont l’identification précoce des personnes infectées, des porteurs et des contacts et la mise en œuvre rapide de mesures de quarantaine grâce à une stratégie organisée, proactive et unifiée au niveau national. Tout retard entraîne une augmentation significative du nombre de décès.
      Since mid-December 2019, there has been a worldwide outbreak of coronavirus disease (COVID)–19, caused by SARS-CoV-2 (formerly 2019-nCoV or HCoV-19) and first detected in Wuhan, China. The incubation period is 1-14 days (mean 5-6 days) in most cases, but can be as long as 24 days.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      The most commonly seen characteristics of COVID-19 are fever, cough, and abnormal chest computed tomography.

      Sun P, Qie S, Liu Z, Ren J, Li K, Xi J. Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: A single arm meta-analysis. [e-pub before print]. J Med Virol https://doi.org/10.1002/jmv.25735.

      ,
      China Centers for Disease Control
      China-WHO new coronavirus pneumonia (COVID-19) joint inspection report.
      At present, the Chinese chrysanthemum bat is thought to be the origin of SARS-CoV-2, based on sequence homology of 96% between SARS-CoV-2 and Bat-CoV-RaTG13.
      • Zhou P.
      • Yang X.-L.
      • Wang X.-G.
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      ,
      • Wu A.
      • Peng Y.
      • Huang B.
      • et al.
      Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
      The pangolin has been proposed as an intermediate host, but this has not been confirmed.

      Li X, Zai J, Zhao Q, et al. Evolutionary history, potential intermediate animal host, and cross-species analyses of SARS-CoV-2 [e-pub before print]. J Med Virol https://doi.org/10.1002/jmv.25731.

      ,
      • Liu P.
      • Jiang J.-Z.
      • Hua Y.
      • et al.
      Are pangolins the intermediate host of the 2019 novel coronavirus (2019-nCoV)?.
      Human-to-human transmission of SARS-CoV-2 occurs mainly via respiratory droplets,
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      direct contact,
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      asymptomatic transmission,
      • Rothe C.
      • Schunk M.
      • Sothmann P.
      • et al.
      Transmission of 2019-nCoV infection from an asymptomatic contact in Germany.
      ,
      • Wang F.-S.
      • Zhang C.
      What to do next to control the 2019-nCoV epidemic?.
      and intrafamilial transmission.
      China Centers for Disease Control
      China-WHO new coronavirus pneumonia (COVID-19) joint inspection report.
      SARS-CoV-2 can affect any demographic, including senior citizens, children, and pregnant women.
      China Centers for Disease Control
      China-WHO new coronavirus pneumonia (COVID-19) joint inspection report.
      ,
      National Health Commission of the People's Republic of China
      [New coronavirus pneumonia prevention and control program (seventh trial edition)].
      According to the World Health Organisation (WHO), the Johns Hopkins Center for Systems Science and Engineering, and the State Council Information Office in Beijing, China, as of April 12, 2020, there have been more than 1,800,000 cases of COVID-19 worldwide, with 83,597 cases of COVID-19 confirmed in China, including 2,101 active cases (121 active severe cases), 1378 imported cases, 3351 deaths (mortality rate 3.99%), and 78,145 recovered cases (cure rate 93.5%). Today, normal life is slowly returning in most regions in an orderly and cautious manner, including in Wuhan, the epicenter of the epidemic in China.
      To stop transmission of the virus and save lives, China adopted strategies and tactics that included a nationwide directive from the central government, governmental oversight, free testing (nucleic acid assay, gene sequencing, and IgM-IgG serology), free treatment, establishment of “Fangcang” hospitals, travel restrictions, new regulations, diagnostic algorithms, and the transfer of resources to the epicenter of the infection in Hubei Province. Very early, on January 23, 2020, when there were about 800 cases and 17 deaths, the entire city of Wuhan and subsequently Hubei Province were locked down and sealed off.
      On March 2, the European Centers for Disease Control and Prevention (CDC) raised the SARS-CoV-2 risk level from moderate to high. On March 11, 2020, WHO declared COVID-19 a pandemic and recommended aggressive action by all countries in the world, warning that most countries were not prepared to handle the spread of SARS-CoV-2. As of April 12, 2020, SARS-CoV-2 has infected 1,770,469 people outside of China, causing 110,867 deaths (mortality rate 6.27%). It has been found in 6 continents, including 212 of 233 (91.0%) countries and international conveyances. The United States (560,402 cases), Spain (166,831 cases), Italy (156,363 cases), Germany (127,854 cases), and Iran (71,686 cases) are among the hardest hit, but cases in other countries are increasing rapidly.

      World Health Organisation. Coronavirus disease (COVID-19) outbreak. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019. Accessed April 12, 2020.

      Managing the Spread of the Epidemic

      The most important strategy to combat a pandemic is to prevent it from even happening. This means that the spread of a virus needs to be countered as early as possible. The COVID-19 epidemic curves and major intervention measures that were implemented in China are shown in Figure 1. Here is a description of the timeline.
      Figure thumbnail gr1
      Figure 1COVID-19 epidemiology curves and major intervention measures implemented in China. China CDC, Chinese Center for Disease Control and Prevention; NHC, National Health Commission of China; WHC, Wuhan Health Commission; WHO, World Health Organization. Data from the NHC, excluding Hong Kong and Macau Special Administrative Regions and Taiwan.
      On December 31, 2019, the Wuhan Municipal Health Commission revealed a cluster of cases of pneumonia of unknown etiology. The Chinese CDC sent experts to Wuhan to support the investigation and control effort.
      Novel Coronavirus Pneumonia Emergency Response Epidemiology Team
      The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China.
      On January 3, 2020, the first genomic sequence of the novel β-genus coronaviruses, now known as SARS-CoV-2, was determined by scientists of the National Institute of Viral Disease Control and Prevention.
      • Wenjie T.
      • Xiang Z.
      • Xuejun M.
      • et al.
      A novel coronavirus genome identified in a cluster of pneumonia cases—Wuhan, China 2019-2020.
      China informed the WHO.
      On January 10, 2020, the whole genome sequence of the SARS-CoV-2 was shared with the WHO. Several rapid and sensitive detection tests were developed by the China CDC.
      On January 16, 2020, the National Health Commission (NHC) issued the first of 7 versions of the protocol for the diagnosis and treatment of COVID-19.
      On January 20, 2020, the NHC upgraded the management of the COVID-19 to the highest level pertaining to class A infectious diseases.
      On January 21, 2020, the NHC officially started to release daily disease information on the government website.
      On January 23, 2020, the Chinese government began to limit movement of people in and out of Wuhan and announced that all public transportation, including city buses, subways, ferries, long-distance coaches, outbound channels at airports, and railway stations in Wuhan had been suspended or closed.
      On January 24, 2020, the local government planned 2 new quarantine hospitals with 1000 and 1600 beds to be constructed within 10 days. By March 8, 2020, 42,600 health professionals from outside Hubei and 1,800 epidemiologic teams participated in battling COVID-19 in Hubei.
      The Joint Prevention and Control Mechanism of the State Council
      Caring frontline healthworks in epidemic prevention and control.
      On January 27, 2020, the Chinese government announced the extension of the Lunar New Year holidays, and postponement of reopening of schools and factories.
      On January 29, 2020, all 31 provinces on the Chinese mainland had activated a level 1 public health emergency response, the highest in the country, to prevent further spread.
      On February 3, 2020, public facilities such as conference venues and sports stadiums were converted into makeshift hospitals to isolate patients with mild to moderate COVID-19 from their families and communities, while providing medical care, disease monitoring, food, shelter, and social activity.
      • Chen S.
      • Zhang Z.
      • Yang J.
      • et al.
      Fangcang shelter hospitals: a novel concept for responding to public health emergencies.
      As of March 10, 2020, more than 12,000 patients had recovered and all makeshift hospitals were temporarily closed.
      Xinhuanet
      Ma Xiaowei: The Fangcang hospital did “zero infection, zero death and zero return.” February 28, 2020.
      On February 7, 2020, the Chinese government announced that all medical expenses of confirmed patients would be covered by health insurance or financial compensation.
      On February 8, 2020, the Chinese central and local governments began to take measures to ensure the orderly resumption of production by companies to provide material support for the control of the epidemic. These included offering free health check-ups and arranging chartered buses, trains, and airplanes to send migrant workers back to resume work in other regions.

      Quarantine Strategies

      Quarantine and surveillance are still the most effective means of controlling the spread of infectious diseases. Some of the strategies and tactics are described below.
      • 1)
        Limiting migration—Wuhan city announced a citywide lockdown on January 23, 2020. Subsequently, the Chinese government banned all domestic travel, extended the Lunar New Year holidays, and postponed reopening of schools and factories to reduce the nationwide migration of the population.
      • 2)
        Designated hospitals—In Wuhan, to consolidate patients, medical experts, resources, and treatment, there were 45 COVID-19–designated hospitals: 6 for critical patients and 39 for severe patients and patients > 65 years of age. All regional hospitals established standardized fever clinics to timely screen for fever and strengthen isolation management. Designated hospitals were increased as needed by conversion of public and nonpublic hospitals.
      • 3)
        Community isolation—Travelers from Wuhan and other epidemic areas were required to register at their destination along with their travel history with the use of smartphones and to self-quarantine for 2 weeks to prevent community transmission. Only 1 family member could leave the house to purchase daily living supplies every 2 days.
      • 4)
        Maintaining adequate supply of essential items and revamping supply chains—Express delivery companies conducted “noncontact delivery” in communities. Shelves in stores were kept stocked by criminalizing price gouging and preventing hoarding. Opening green channels and coordinating transportation of supplies helped to ensure the safe delivery of key supplies. In the early stages of the COVID-19 outbreak, there was a shortage of personal protection equipment (PPE), which was mitigated by the use of reserve supplies, acquiring donations, and increases of production (Supplemental Appendix S1; Supplemental Fig. S1).
      • 5)
        Testing—Early testing provided the basis for tracking and isolation in Wuhan to identify persons who could potentially spread the disease. The numbers of tests performed in Wuhan are shown in Figure 2.
        Figure thumbnail gr2
        Figure 2The daily number of nucleic acid tests performed in Wuhan. Data from the Wuhan Municipal Health Commission.
      • 6)
        Tracking—A major part of the success in controlling the spread of COVID-19 was rooted in the tracking strategy. All patients testing positive for COVID-19 were tracked and their contacts isolated. Big data and artificial intelligence (AI) were used to strengthen contact tracing and the management of priority populations.
      • 7)
        Temperature screening—Temperature screening checkpoints were established at supermarkets, residential area entrances, and transportation hubs. Everyone was screened for temperature when entering public areas. Temperature screening is a cheap, easily implemented, and rapid method of screening large numbers of the population for possible COVID-19. Fever is the most common symptom in patients with COVID-19. Persons who had traveled to Hubei or had close contact with COVID-19 patients in the preceding 14 days were required to undergo temperature checks.
        National Health Commission of the People's Republic of China
        [New coronavirus pneumonia prevention and control program (seventh trial edition)].
      • 8)
        Personal protection—All residents were required to wear medical surgical masks or N95 masks when accessing public places. The internet and media were leveraged to publicize the correct knowledge of protection and prevention of spread, such as using masks, daily disinfection, and washing hands correctly.
      • 9)
        Controlling cross-infection—Hospitals offered online consultation and medical services to reduce the frequency that patients visited hospitals. Online work and learning were used to avoid cross-infection.

      Managing Human and Equipment Resources

      Physician scheduling was optimized.
      • Wu X.Y.Y.
      • Ke S.
      Practical effect of continuous seamless scheduling and level management model in isolated wards during COVID-19.
      This scheduling is shown in Supplemental Table S1. Emergency staffing was arranged as needed within half an hour.
      Nurses 1-3 jointly completed all of the nursing work for patients, including daily care, disinfecting the isolation areas, etc. Nurse 4 was the team leader, who was mainly responsible for counting supplementary materials, delegating resources, and completing nursing records.
      Workflow was optimized and the correct use of protective equipment, cleaning, and disinfection measures was ensured.
      Hubei Province Pediatric Medical Quality Control Center
      Practice for management of pediatric ward and prevention of infection during the epidemic period of COVID-19.
      During the outbreak, many elective surgeries were not performed. In addition, surgery may accelerate and exacerbate disease progression of COVID-19.
      • Lei S.
      • Jiang F.
      • Su W.
      • et al.
      Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection.

      Treatment of COVID-19

      Suspected and confirmed patients were quarantined and treated in designated hospitals. High-risk patients were hospitalized to proactively prevent complications and secondary infections, treat underlying diseases, and provide organ function support according to the patients’ conditions.
      National Health Commission of the People's Republic of China
      [New coronavirus pneumonia prevention and control program (seventh trial edition)].

      Clinical classification

      Physicians classified the disease severity of patients with SARS-CoV-2 infection according to the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia” issued by NHC (trial version 7)
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      or “Clinical Management of Severe Acute Respiratory Infection When Novel Coronavirus (2019-nCoV) Infection Is Suspected” from WHO.

      World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

      The severity definitions in the Chinese guidance were more widely used in clinical practice in China owing to its simplicity. According to the Chinese guidelines,
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      ,
      • Yi Jiang Y.
      • Lu X.
      • Jin R.
      • et al.
      Diagnosis, treatment and prevention of 2019 novel coronavirus infection in children: experts' consensus statement (Second Edition). [J].
      the clinical classification of COVID-19 patients includes 4 levels of severity: mild, moderate, severe, and critical (Table 1). So far, there is no special COVID-19 clinical classification criteria for pregnant women, which may be due to the fact that clinical characteristics of COVID-19–infected pregnant women are generally similar to those of nonpregnant women with COVID-19 infection.
      • Chen H.
      • Guo J.
      • Wang C.
      • et al.
      Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.
      Table 1COVID-19 clinical classification and treatment recommendations
      ClassificationWHO interim guidance

      World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

      Chinese clinical guideline
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      ,
      • Yi Jiang Y.
      • Lu X.
      • Jin R.
      • et al.
      Diagnosis, treatment and prevention of 2019 novel coronavirus infection in children: experts' consensus statement (Second Edition). [J].
      Treatment recommendations
      AdultChildAdultChild
      Asymptomatic infectionNANANALaboratory-confirmed patients without any clinical symptoms or radiologic findingsMonitoring
      MildPatients with nonspecific symptoms, such as fever, fatigue, cough, anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, or headache. Rarely, patients may also present with diarrhea, nausea, and vomiting
      The elderly and immunosuppressed may present with atypical symptoms. Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events, such as dyspnea, fever, gastrointestinal symptoms,or fatigue, may overlap with COVID-19.
      Patients with mild clinical symptoms and no sign of pneumonia on imagingGeneral treatment, symptomatic treatment, antiviral treatment
      ModerateAdult with pneumonia but no signs of severe pneumonia and no need for supplemental oxygenChild with nonsevere pneumonia who has cough or difficulty breathing plus fast breathing,
      Fast breathing: age < 2 months ≥ 60 breaths/min; age 2-11 months: ≥ 50 breaths/min; age 1–5 years: ≥ 40 breaths/min.
      and no signs of severe pneumonia
      Patients who have fever and respiratory symptoms with radiologic findings of pneumoniaSame as above, and supplemental oxygen therapy
      SevereAdolescent or adult with fever or suspected respiratory infection, plus respiratory rate > 30 breaths/min, severe respiratory distress, or oxygen saturation ≤ 93% on room airChild with cough or difficulty breathing, plus at least one of the following: 1) central cyanosis or oxygen saturation < 90%; 2) severe respiratory distress (eg, grunting, very severe chest retractions); or 3) signs of pneumonia with a general danger sign
      Other signs of pneumonia may be present: chest retractions, fast breathing (in breaths/min†).
      : inability to breastfeed or drink, lethargy or unconsciousness, or convulsions. Although the diagnosis is made on clinical grounds, chest imaging may identify or exclude pulmonary complications.
      Adult who meets any of the following criteria: 1) respiratory distress (≥ 30 breaths/min); 2) oxygen saturation ≤ 93% at rest; 3) PaO2FiO2 ≤ 300 mm Hg (l mm Hg = 0.133 kPa)
      In high-altitude areas (> 1000 metres above sea level), PaO2/FiO2 should be corrected by the following formula: PaO2/FiO2 × [atmospheric pressure (mm Hg)/760].
      or chest imaging shows obvious lesion progression > 50% within 24-48 hours
      Child who meets any of the following criteria: 1) tachypnea
      Respiratory rate: age < 2 months: ≥ 60 breaths/min; age 2-12 months: ≥ 50 breaths/min; age 1–5 years: ≥ 40 breaths/min; age > 5 years: ≥ 30 breaths/min.
      independent from fever and crying; 2) oxygen saturation ≤ 92% according to finger pulse oximeter taken at rest; 3) laboured breathing,
      Moaning, nasal fluttering, and infrasternal, supraclavicular, and intercostal retractions.
      cyanosis, and intermittent apnea; 4) lethargy and convulsion; 5) difficulty feeding and signs of dehydration; 6) HRCT shows infiltration in both lungs or multiple lobes, lesion progress in a short time, or pleural effusion
      Same as above (for mild), and respiratory support (high-flow nasal oxygen and noninvasive ventilation or invasive mechanical ventilation)
      Critical
       ARDSAdults who meet the ARDS diagnostic criteria of the Berlin definition
      • Force A.D.T.
      • Ranieri V.M.
      • Rubenfeld G.D.
      • et al.
      Acute respiratory distress syndrome: the Berlin definition.
      (oxygenation impairment identified according to the Berlin definition
      • Force A.D.T.
      • Ranieri V.M.
      • Rubenfeld G.D.
      • et al.
      Acute respiratory distress syndrome: the Berlin definition.
      )
      Children who meet the ARDS diagnostic criteria of the Berlin definition
      • Force A.D.T.
      • Ranieri V.M.
      • Rubenfeld G.D.
      • et al.
      Acute respiratory distress syndrome: the Berlin definition.
      Patients who meet any of the following criteria: 1) respiratory failure and requiring mechanical ventilation; 2) shock; 3) with other organ failure that requires ICU careSame as above (for mild), and respiratory support (invasive mechanical ventilation, extracorporeal membrane oxygenation)
       SepsisAdults with life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection
      Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate, or hyperbilirubinemia.
      Children with suspected or proven infection and ≥ 2 age-based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count
       Septic shockAdults with persistent hypotension despite volume resuscitation, requiring vasopressors to maintain MAP (≥ 65 mm Hg) and serum lactate level > 2 mmol/LChildren who have any hypotension (SBP < 5th percentile or > 2 SD below normal for age) or 2 or 3 of the following: altered mental state; tachycardia or bradycardia (HR < 90 beats/min or > 160 beats/min in infants and HR < 70 beats/min or > 150 beats/min in children); prolonged capillary refill (> 2 s) or feeble pulse; tachypnea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermia
      ARDS, acute respiratory distress syndrome; FiO2, fraction of inspired oxygen; HR, heart rate; HRCT, high-resolution computed tomography; ICU, intensive care unit; MAP, mean arterial pressure; NA, not available; PaO2, arterial partial pressure of oxygen; SBP, systolic blood pressure.
      The elderly and immunosuppressed may present with atypical symptoms. Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events, such as dyspnea, fever, gastrointestinal symptoms,or fatigue, may overlap with COVID-19.
      Fast breathing: age < 2 months ≥ 60 breaths/min; age 2-11 months: ≥ 50 breaths/min; age 1–5 years: ≥ 40 breaths/min.
      Other signs of pneumonia may be present: chest retractions, fast breathing (in breaths/min
      Fast breathing: age < 2 months ≥ 60 breaths/min; age 2-11 months: ≥ 50 breaths/min; age 1–5 years: ≥ 40 breaths/min.
      ).
      § In high-altitude areas (> 1000 metres above sea level), PaO2/FiO2 should be corrected by the following formula: PaO2/FiO2 × [atmospheric pressure (mm Hg)/760].
      Respiratory rate: age < 2 months: ≥ 60 breaths/min; age 2-12 months: ≥ 50 breaths/min; age 1–5 years: ≥ 40 breaths/min; age > 5 years: ≥ 30 breaths/min.
      Moaning, nasal fluttering, and infrasternal, supraclavicular, and intercostal retractions.
      ∗∗ Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate, or hyperbilirubinemia.

      Nonpharmacologic Treatment—Supportive and Symptomatic Care

      General treatment

      Symptomatic and supportive treatment is essential and the main treatment for COVID-19.
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      General supportive measures for SARS-CoV-2–infected patients include bed rest, adequate nutrition, water and electrolyte balance, and intensively monitoring vital signs (blood pressure, respiratory rate, heart rate, and oxygen saturation). Laboratory markers of disease progression and clinical outcomes, such as d-dimer, C-reactive protein, procalcitonin, neutrophil count, lymphocyte count, and inflammatory cytokines, were monitored.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.

      Zhang J-J, Dong X, Cao Y-Y, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China [e-pub before print]. Allergy, doi:10.1111/all.14238.

      Symptomatic therapy

      Fever is the most common symptom of SARS-CoV-2 infection.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.

      Zhang J-J, Dong X, Cao Y-Y, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China [e-pub before print]. Allergy, doi:10.1111/all.14238.

      Continuous high fever may cause metabolic disorders and system dysfunction. Therefore, WHO guidance advocates the use of antipyretics and cooling measures.

      World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

      Multiple studies have shown that COVID-19 patients have underlying diseases, including hypertension and diabetes, leading to higher mortality.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • 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.
      For these patients, blood pressure and blood sugar must be monitored, and if abnormal, it should be promptly treated. The onset of severe disease leading to liver, kidney, or cardiac injury should be anticipated and treated appropriately.

      Respiratory support

      Studies have shown that in severe cases, 66.7% of patients (124/186) received oxygen therapy, 44.7% (63/141) received high-flow nasal cannula (HFNC), 39.4% (108/274) received noninvasive mechanical ventilation, and 24.1% (66/274) required invasive mechanical ventilation. Only 6.2% (17/274) patients received extracorporeal membrane oxygenation (ECMO) (Table 2).
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Liu Y.
      • Sun W.
      • Li J.
      • et al.
      Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019 [preprint].
      Table 2Treatment, oxygen support, and death in severe cases with COVID-19
      OutcomeGuan et al.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      Liu et al.
      • Liu Y.
      • Sun W.
      • Li J.
      • et al.
      Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019 [preprint].
      Yang et al.
      • Yang X.
      • Yu Y.
      • Xu J.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      Wang et al.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.
      Huang et al.
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ICU/severe cases, n
      ICU/severe cases included severe and critical cases as defined in Table 1.
      17353523613
      Treatment, n (%)
       Antiviral treatment80 (46.2)52 (98.1)23 (44.2)34 (94.4)12 (92.3)
       Antibiotic treatment139 (80.3)53 (100)49 (94.2)NA13 (100)
       Corticosteroid treatment77 (44.5)37 (69.8)30 (57.7)26 (72.2)6 (46.2)
       Intravenous immunoglobulin58 (33.5)29 (54.7)28 (53.8)NANA
       CRRT9 (5.2)NA9 (17.3)2 (5.6)3 (23.1)
      Oxygen support, n (%)
       Oxygen therapy123 (71.1)NANANA1 (7.7)
       High-flow nasal cannulaNA26 (49.1)33 (63.5)4 (11.1)NA
       Noninvasive mechanical ventilation56 (32.4)NA29 (55.8)15 (41.7)8 (61.5)
       Invasive mechanical ventilation25 (14.5)NA22 (42.3)17 (47.2)2 (15.4)
       ECMO5 (2.9)NA6 (11.5)4 (11.1)2 (15.4)
      Death, n (%)14 (8.1)26 (49.1)32 (61.5)6 (16.7)5 (38.5)
      CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; NA, not available.
      ICU/severe cases included severe and critical cases as defined in Table 1.

      Supplemental oxygen

      In a study of 1099 patients in China, 41.3% of confirmed COVID-19 patients (454/1099) and 35.7% of nonsevere patients (331/926) received oxygen therapy.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      WHO guidelines recommend that supplemental oxygen therapy be given to patients with severe acute respiratory infection (SARI), respiratory distress, hypoxemia, or shock.

      World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

      However, there are no restrictions on which patients can receive supplemental oxygen therapy in the Chinese guidelines,
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      which may have resulted in the overuse of oxygen therapy. In general, patients with blood oxygen saturation (SPO2) ≥ 93% do not require supplemental oxygen, and hyperoxemia may induce further respiratory injury and even higher mortality.
      • Mach W.J.
      • Thimmesch A.R.
      • Pierce J.T.
      • Pierce J.D.
      Consequences of hyperoxia and the toxicity of oxygen in the lung.
      The indications for supplemental oxygen should be carefully applied in patients with COVID-19.

      World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

      High-flow nasal cannula oxygen therapy and noninvasive mechanical ventilation

      HFNC and noninvasive positive-pressure ventilation (NIPPV) was used as step-up therapy in patients who failed to improve on supplemental oxygen.
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      A Chinese expert consensus released in 2019 recommends that physicians can consider providing HFNC to mild or moderately ill patients (arterial oxygen partial pressure [PaO2]/fractional inspired oxygen [FiO2] 100-300 mm Hg). The clinical application of NIPPV on hypoxemic respiratory failure caused by severe pneumonia has long been controversial.
      • He H.
      • Sun B.
      • Liang L.
      • et al.
      A multicenter RCT of noninvasive ventilation in pneumonia-induced early mild acute respiratory distress syndrome.
      ,
      • Carrillo A.
      • Gonzalez-Diaz G.
      • Ferrer M.
      • et al.
      Non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure.
      WHO

      World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

      and Chinese
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      guidelines both recommend using HFNC and NIPPV with extreme care and closely monitoring the condition of patients treated with HFNC or NIPPV for deterioration. Failure of a short trial (1 hour) of NIPPV may require proceeding to invasive mechanical ventilation.

      Invasive mechanical ventilation

      According to Guan et al.,
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      14.5% of severe patients (25/173) received invasive mechanical ventilation and 32.4% (56/173) received noninvasive mechanical ventilation. If standard oxygen therapy fails, Chinese guidelines recommend a trial of HFNC or noninvasive ventilation, but WHO guidelines recommend escalating to invasive mechanical ventilation.

      World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

      It is generally accepted that timely use of invasive mechanical ventilation is an important component of the treatment of severe respiratory failure and acute respiratory distress syndrome (ARDS).
      • Del Sorbo L.
      • Goligher E.C.
      • McAuley D.F.
      • et al.
      Mechanical ventilation in adults with acute respiratory distress syndrome. Summary of the experimental evidence for the clinical practice guideline.
      Based on a Chinese expert consensus,

      Chinese Research Hospital Association of Critical Care Medicine, Youth Committee of Chinese Research Hospital Association Of Critical Care Medicine. [Chinese experts' consensus on diagnosis and treatment of severe and critical coronavirus disease 2019 (Revised Edition)]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020;32:269‐74 [in Chinese].

      it is recommended that invasive mechanical ventilation be the first choice for moderate or severe ARDS patients (PaO2/FiO2 ≤ 150 mm Hg)
      • Force A.D.T.
      • Ranieri V.M.
      • Rubenfeld G.D.
      • et al.
      Acute respiratory distress syndrome: the Berlin definition.
      or for patients after failure of HFNC and NIPPV. Lung-protective ventilation strategy, ie, low tidal volumes (6-8 mL/kg of predicted body weight) and low inspiratory pressures (platform pressure < 30 cm H2O) should be incorporated to prevent ventilator-related lung injury.
      • Del Sorbo L.
      • Goligher E.C.
      • McAuley D.F.
      • et al.
      Mechanical ventilation in adults with acute respiratory distress syndrome. Summary of the experimental evidence for the clinical practice guideline.

      Extracorporeal membrane oxygenation

      ECMO is a form of extracorporeal life support for very ill patients that circulates blood flow through an artificial lung for gas exchange and then back into the bloodstream. It provides a period of pulmonary rest, artificially supports critical ill patents while their heart or lungs recover, and plays a role in the care of heart or lung transplant patients. ECMO has rarely been used in China owing to limited resources.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Moreover, there are no published studies about the efficacy and safety of ECMO with severely ill COVID-19 patients. Previously, the experience of using ECMO in Middle East Respiratory Syndrome (MERS) and influenza has been controversial.
      • Arabi Y.M.
      • Fowler R.
      • Hayden F.G.
      Critical care management of adults with community-acquired severe respiratory viral infection.

      Pharmacologic agents

      We summarize the treatment of 327 pooled cases of severe cases with COVID-19 in Table 2.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.
      ,
      • Yang X.
      • Yu Y.
      • Xu J.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Liu Y.
      • Sun W.
      • Li J.
      • et al.
      Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019 [preprint].
      In severe cases, 87.3% of patients (254/291) received antibiotic treatment, 61.5% (201/327) received antiviral treatment, 53.8% (176/327) received corticosteroid treatment, and 41.3% (115/278) received intravenous immunoglobulin. Only 8.4% of patients (23/274) received continuous renal replacement therapy. The mortality rate of the 327 pooled severe cases was 25.4% (83/327) (Table 2).
      Despite the use of various medications, the consensus of Chinese experts is that neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, etc) and ganciclovir are not generally recommended. Routine prophylactic antibiotics, especially combined wide-spectrum antibiotics, are also not typically recommended.

      Chinese Research Hospital Association of Critical Care Medicine, Youth Committee of Chinese Research Hospital Association Of Critical Care Medicine. [Chinese experts' consensus on diagnosis and treatment of severe and critical coronavirus disease 2019 (Revised Edition)]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020;32:269‐74 [in Chinese].

      However, because of the widespread use of the medications, as indicated in the previous paragraph, ongoing trials are being conducted to clarify which medications may or may not be helpful in treating COVID-19.

      Antiviral treatment

      At present, there is no evidence to support the effectiveness of antiviral drugs for COVID-19, although these are commonly used in the treatment of COVID-19 in China. The guidelines of the NHC recommend interferon-α2b inhalation, lopinavir/ritonavir, ribavirin, chloroquine, and arbidol as antiviral therapy and does not recommend using more than 2 antiviral drugs at the same time (Table 3).
      National Health Commission of the People's Republic of China
      [New coronavirus pneumonia prevention and control program (seventh trial edition)].
      ,
      • Chen Z.
      • Shu Q.
      • Wang
      • et al.
      Diagnosis and treatment recommendation for pediatric coronavirus disease-19 (the second edition).
      Table 3Antiviral drugs for COVID-19 recommended in the guidelines of the NHC
      Medication instructionAlpha-interferonLopinavir/ritonavirRibavirinChloroquineArbidol
      Recommended dosage and course5 million units or equivalent dose per time for adults, adding 2 mL of sterile water, aerosol inhalation, twice per day.

      For children,
      The guidelines of the NHC did not recommend the dosage and course for children. The recommended dosage and course of the drugs for children in the table are from Chen et al.’s studies.36
      100,000-200,000 IU/kg in mild cases, 200,000-400,000 IU/kg in severe cases, twice per day for 5-7 days.
      200 mg/50 mg per capsule, 2 capsules each time, twice per day for adults. The course of treatment should be ≤ 10 days.

      For children,
      The guidelines of the NHC did not recommend the dosage and course for children. The recommended dosage and course of the drugs for children in the table are from Chen et al.’s studies.36
      weight 7-15 kg, (12 mg/3 mg)/kg; weight 15-40 kg, (10 mg/2.5 mg)/kg; weight > 40 kg, same as adults.
      Combining with alpha-interferon or lopinavir/ritonavir, 500 mg for adults per time, intravenous injection 2-3 times per day. The course of treatment should be ≤ 10 days.

      For children,
      The guidelines of the NHC did not recommend the dosage and course for children. The recommended dosage and course of the drugs for children in the table are from Chen et al.’s studies.36
      10 mg/kg per time (maximum 500 mg per time), intravenous injection 2-3 times per day.
      Only for adults aged 18-65 y.

      Weight > 50 kg, 500 mg per time, twice per day for 7 days.

      Weight < 50 kg, 500 mg per time, twice per day for 2 days and then 500 mg per time, once per day for 5 days.
      200 mg for adults, 3 times per day. The course of treatment should be ≤ 10 days.
      Medication for special populations
       ChildrenRecommendedRecommended for children > 2 y oldRecommendedNot recommendedUnclear
       Pregnant/lactating womenPrudent useRecommendedForbiddenPrudent use in lactating womenUnclear
       ElderlyRecommendedSafety unclear; prudent useNot recommendedUnclearUnclear
       Liver dysfunction patientsPrudent usePrudent usePrudent usePrudent useUnclear
       Renal dysfunction patientsPrudent useRecommendedCCR < 50 mL/min: not recommendedPrudent usePrudent use in severe renal dysfunction
      ContraindicationPatients with severe liver/renal dysfunctionPatients with severe liver dysfunctionPregnant/lactating womenPregnant womenUnclear
      Approved indicationsBroad-spectrum antiviral, immunomodulatory, and antitumorHIV-1 infectionRespiratory syncytial virus pneumoniaMalariaA and B influenza viruses
      Adverse reactions
      Refer to product guidelines for specific information.
      Refer to product guidelines for specific information.
      Refer to product guidelines for specific information.
      Refer to product guidelines for specific information.
      Refer to product guidelines for specific information.
      Off-label drug useYesYesYesYes
      Clinical trials
      The number of clinical trials of COVID-19 in China as of April 3, 2020. Data from http://www.chictr.org.cn/.
      691163
      CCR, creatinine clearance rate; NHC, National Health Commission; HIV, human immunodeficiency virus.
      The guidelines of the NHC did not recommend the dosage and course for children. The recommended dosage and course of the drugs for children in the table are from Chen et al.’s studies.
      • Chen Z.
      • Shu Q.
      • Wang
      • et al.
      Diagnosis and treatment recommendation for pediatric coronavirus disease-19 (the second edition).
      Refer to product guidelines for specific information.
      The number of clinical trials of COVID-19 in China as of April 3, 2020. Data from http://www.chictr.org.cn/.
      Xu et al. reported that of 55 of 62 confirmed COVID-19 patients in Zhejiang province received antiviral treatment. Twenty-one patients (34%) received lopinavir/ritonavir and interferon-α2b inhalation, 17 (28%) received arbidol and lopinavir/ritonavir, and 8 (13%) received interferon-α2b by inhalation.
      • Xu X.-W.
      • Wu X.-X.
      • Jiang X.-G.
      • et al.
      Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.
      Chen et al. reported that 75 of 99 confirmed patients in Wuhan received antiviral treatment, including oseltamivir, ganciclovir, and lopinavir/ritonavir.
      • 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.
      The duration of antiviral treatment was 3-14 days.
      • 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.
      However, the results of a clinical trial of lopinavir/ritonavir in China showed no clear benefit beyond standard care in hospitalized adult patients with severe COVID-19.
      • Cao B.
      • Wang Y.
      • Wen D.
      • et al.
      A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19.
      Remdesivir may have the greatest potential for the successful treatment of SARS-CoV-2, but efficacy and safety in COVID-19 need further evaluation.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      ,
      • Lu H.
      Drug treatment options for the 2019-new coronavirus (2019-nCoV).
      Remdesivir has been studied in clinical trials to treat COVID-19 in China.
      Favipiravir was approved for treatment of influenza on February 15, 2020, in China and is being studied in COVID-19 clinical trials. The preliminary results indicate that favipiravir has significantly more potent antiviral action and fewer adverse effects than lopinavir/ritonavir (P < 0.001).
      • Dong L.
      • Hu S.
      • Gao J.
      Discovering drugs to treat coronavirus disease 2019 (COVID-19).
      One of the clinical trials was conducted in Shenzhen, and the results showed that the median time to viral clearance was 4 days in the favipiravir treatment group compared with 11 days in the lopinavir/ritonavir treatment group (P < 0.001). In terms of chest imaging, the improvement rates of the favipiravir treatment group and the lopinavir/ritonavir treatment group were 91.4% and 62.2%, respectively. No significant adverse reactions were noted in the favipiravir treatment group, and there were significantly fewer adverse effects than in the lopinavir/ritonavir group.
      China National Health Commission
      Press conference of the Joint Prevention and Control Mechanism of the State Council. March 17, 2020.
      In early in vitro studies, chloroquine and hydroxychloroquine were found to inhibit SARS-CoV-2 infection efficiently,
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      ,
      • Liu J.
      • Cao R.
      • Xu M.
      • et al.
      Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.
      and several clinical trials have been quickly conducted in China to evaluate the efficacy and safety of chloroquine and hydroxychloroquine. Gao et al. summarized that compared with the control treatment, chloroquine phosphate was effective in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.
      • Gao J.
      • Tian Z.
      • Yang X.
      Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
      The expert consensus on chloroquine phosphate recommends 500 mg twice daily for 10 days for patients diagnosed with COVID-19. Adverse effects of chloroquine and hydroxychloroquine must be carefully monitored.
      Multicenter Collaboration Group of Department of Science And Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia].
      Zhou et al. proposed that hydroxychloroquine could serve as a better therapeutic agent than chloroquine, owing to reduced toxicity, fewer side-effects, lower cost, and relative safety in pregnancy.

      Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression [e-pub before print]. J Antimicrob Chemother, https://doi.org/10.1093/jac/dkaa114.

      Yao et al. used physiologically based pharmacokinetics models and found that hydroxychloroquine was more potent than chloroquine at inhibiting SARS-CoV-2 in vitro. They recommended 400 mg hydroxychloroquine sulfate twice daily for 1 day, followed by 200 mg twice daily for 4 days to treat SARS-CoV-2 infection.

      Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [e-pub before print]. Clin Infect Dis, doi: 10.1093/cid/ciaa237.

      The efficacy and safety data of chloroquine or hydroxychloroquine from high-quality clinical trials are urgently needed.

      Glucocorticoid therapy

      Russell et al. recommended that corticosteroids should not be used in SARS-CoV-2–induced lung injury or shock.
      • Russell C.D.
      • Millar J.E.
      • Baillie J.K.
      Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
      However, Shang et al. suggested using short courses (≤ 7 days) of corticosteroids at low to moderate dose (≤ 0.5-1 mg/kg/d methylprednisolone or equivalent) for critically ill patients with COVID-19.
      • Shang L.
      • Zhao J.
      • Hu Y.
      • Du R.
      • Cao B.
      On the use of corticosteroids for 2019-nCoV pneumonia.
      According to a Chinese experts’ consensus statement, the following criteria should be met before using corticosteroids in patients with COVID-19: 1) adults (≥ 18 years old), 2) laboratory-confirmed cases, 3) symptoms occurring within 10 days, 4) radiographic imaging consistent with COVID-19 pneumonia and progressing rapidly, and 5) SPO2 ≤ 93%, shortness of breath (respiratory rate ≥ 30/min), or oxygenation index ≤ 300 mm Hg at rest and with no oxygen therapy.
      • Zhao J.P.
      • Hu Y.
      • Du R.H.
      • et al.
      [Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia].
      A retrospective study found that low- to moderate-dose glucocorticoid therapy had no effect on the time to viral clearance in patients with COVID-19. Glucocorticoids are not recommended in mild cases, because there was no improvement in the rate of radiographic recovery.
      • Ni Qin D.C.
      • Li Y.
      • Zhao H.H.
      • et al.
      Retrospective study of side effects of low-dose glucocorticoids in rheumatoid arthritis.
      However, a single center in Wuhan shared that early low-dose and short-term corticosteroids (1-2 mg/kg/d for 5-7 days) was associated with a faster improvement of clinical symptoms and absorption of focal lung lesions in severe cases of COVID-19.
      • Wang Y.
      • Jiang W.
      • He Q.
      • et al.
      Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China [preprint].
      Another study analyzed 15 critical cases and suggested that a low dose and short duration of corticosteroids (methylprednisolone < 1 mg/kg, < 7 days) may be beneficial for critically ill patients with COVID-19.
      • Zhou W.
      • Liu Y.
      • Tian D.
      • et al.
      al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia.
      Zhou et al. analyzed 10 patients with COVID-19 who received corticosteroids and found that short-term moderate-dose corticosteroids (160 mg/d) plus immunoglobulin (20 g/d) were effective for reversing the continued deterioration of COVID-19 patients who failed to respond to the low-dose therapy (40-80 mg/d corticosteroids and 10 g/d immunoglobulin).
      • Zhou Z.
      • Xie S.
      • Zhang J.
      • et al.
      Short-term moderate-dose corticosteroid plus immunoglobulin effectively reverses COVID-19 patients who have failed low-dose therapy [preprint].
      An open-label randomized controlled trial has been conducted to investigate the effectiveness of glucocorticoid therapy in patients with severe COVID-19.

      Zhou YH, Qin YY, Lu YQ, et al. Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial [e-pub before print]. Chin Med J https://doi.org/10.1097/CM9.0000000000000791.

      Convalescent plasma

      Previous studies in MERS suggested that convalescent plasma may be effective.

      Brown C, Carson G, Chand M, Dunning J, Zambon M. Treatment of MERS-CoV: information for clinicians clinical decision-making support for treatment of MERS-CoV patients. London: 2014, Public Health England.

      Mair-Jenkins et al. further suggested that convalescent plasma may reduce mortality in patients with SARI of viral etiology.
      • Mair-Jenkins J.
      • Saavedra-Campos M.
      • Baillie J.K.
      • et al.
      The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.
      The NHC (trial version 2) includes convalescent plasma as a potential treatment in severe cases, critical cases, and cases of rapidly worsening clinical status.

      China National Health Commission. The clinical guideline of convalescent plasma treatment (trial version 2). 2020. Available at: http://www.chinadaily.com.cn/a/202002/16/WS5e48cbf6a310128217277d72.html. Accessed February 16, 2020.

      Donors and recipients should be carefully selected, and serum-specific IgG antibodies for SARS-CoV-2 should be tested to guarantee the quality of convalescent plasma. Critical patients who received convalescent plasma showed significant improvement in clinical symptoms and laboratory findings.

      Zhang Y, Wang X. 32 recovered patients donate plasma to others with coronavirus infection. China Daily 2020 Feb 16. Available at: https://www.chinadaily.com.cn/a/202002/16/WS5e48cbf6a310128217277d72.html. Accessed February 16, 2020.

      Multiple clinical trials have been registered in the Chinese Clinical Trial Registry to study the safety and efficacy of convalescent plasma treatment in COVID-19 patients.
      • Xiang Y.
      Clinical trial registration information analysis of COVID-19 in China.

      Intravenous immunoglobulin

      In Guan et al.’s study
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      of 173 severe COVID-19 cases, 58 patients (33.4%) received intravenous immunoglobulin treatment (IVIG). IVIG was considered as a potential therapy for immunologic injury in COVID-19 in clinical practice because of its antiinflammatory action in treating conditions such as hemophagocytic lymphohistiocytosis and cytokine storm. Similarly, two reviews recommended IVIG based on mechanisms of SARS-CoV-2–mediated inflammatory responses.
      • Lin L.
      • Lu L.
      • Cao W.
      • Li T.
      Hypothesis for potential pathogenesis of SARS-CoV-2 infection—a review of immune changes in patients with viral pneumonia.
      ,

      Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2–mediated inflammatory responses: from mechanisms to potential therapeutic tools [e-pub before print]. Virol Sin, https://doi.org/10.1007/s12250-020-00207-4.

      However, further investigation and more clinical studies are needed.

      Biologic modulators

      The results of laboratory findings of COVID-19 patients in China showed an increase in plasma inflammatory cytokine levels, especially interleukin (IL) 6.
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • 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.
      Therefore, the anti-IL6 monoclonal antibody tocilizumab was considered as a potential drug for some COVID-19 cases with extensive lung lesions and elevated IL-6 levels.
      National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
      Three clinical trials have been initiated and registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx), but no results or data have been released at this time.

      Other pharmaceutical measures

      Traditional Chinese medicine treatment

      The potentially beneficial role of traditional Chinese medicine is described in the guidelines of the NHC, and some Chinese patent medicines (CPMs) have been used to treat COVID-19.
      National Health Commission of the People's Republic of China
      [New coronavirus pneumonia prevention and control program (seventh trial edition)].
      However, the experience with most of these treatments is anecdotal. Gu et al. reviewed 93 Chinese medicine prescriptions and 157 forms of constituent medicines for COVID-19 treatment and found that they may be effective in reducing fever, mucous production, cough, and asthma symptoms.
      • Gu M.
      • Shi N.
      • Li X.
      • et al.
      Analysis of property and efficacy of traditional Chinese medicine in staging prevention and treatment of corona virus disease 2019.
      Yan et al. discovered that 10 antiviral components from CPMs can directly bind to both host cell target angiotensin-converting enzyme (ACE) 2 receptor and viral target main protease, suggesting their potential for COVID-19 treatment.

      Yan Y-M, Shen X, Cao Y-K, Zhang J-J, Wang Y, Cheng Y-X. Discovery of anti–2019-nCoV agents from 38 Chinese patent drugs toward respiratory diseases via docking screening. Preprints 2020:2020020254.

      Other treatment measures

      According to the guidelines of the NHC,
      National Health Commission of the People's Republic of China
      [New coronavirus pneumonia prevention and control program (seventh trial edition)].
      vasoactive drugs may be required to supplement fluid resuscitation and to improve microcirculation. Continuous renal replacement therapy has been used in acute kidney injury.
      Expert Team of Chinese Medical Association Nephrology Branch
      Expert consensus on diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infection with acute kidney injury.
      Apheresis methods, including plasma exchange, adsorption, perfusion, and filtration, were used in critical cases with severe inflammatory reactions.
      • Li L.
      Translation: Expert consensus on the application of artificial liver blood purification system in the treatment of severe and critical COVID-19: National Clinical Research Center for Infectious Diseases.
      In addition to the treatment of the patients’ physical condition, psychologic support was provided to address the anxiety and fear that occurs in patients who are suffering from COVID-19 as well as in their loved ones and health workers. During the quarantine, mental health intervention provided online was especially recommended. According to Hu et al., the use of hypnotics can significantly improve clinical outcomes of COVID-19 patients. These improvements may be attributable to decreased oxygen consumption resulting from reduced periods of anxiety and improved immunity from experiencing high-quality sleep.
      • Hu L.
      • Chen S.
      • Fu Y.
      • et al.
      Risk factors associated with clinical outcomes in 323 COVID-19 patients in Wuhan, China [e-pub before print].

      Vaccine development

      The development of a vaccine for SARS-CoV-2 has been accelerated as a priority project. On January 23, the Coalition for Epidemic Preparedness Innovations (CEPI) announced a $12.5 million grant to fund vaccine development by Queensland University in Australia, the National Institutes of Health in the United States, and the pharmaceutical companies Inovio and Moderna. On January 24, a virus strain of SARS-CoV-2 was successfully isolated from patients’ samples in China to provide the basis for vaccine development.

      Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention [e-pub before print]. JAMA, doi:10.1001/jama.2020.2648.

      On February 3, CEPI and GlaxoSmithKline announced collaboration to strengthen the global effort to develop a vaccine. Vaccine safety is a priority. Currently, strategies for SARS-CoV-2 vaccine development include recombinant proteins, DNA vaccines, mRNA vaccines, traditional live vaccines, and recombinant adenovirus vaccines. These are in various phases of development, ranging from nonhuman animal studies to clinical trials.
      China Centers for Disease Control
      China-WHO new coronavirus pneumonia (COVID-19) joint inspection report.
      ,
      First vaccine clinical trials begin in the United States. March 17, 2020.
      ,

      China has successfully developed recombination vaccines of SARS-CoV-2. Available at: https://news.qudong.com/2020/0317/653095.shtml. Accessed March 17, 2020.

      On March 13, mRNA-1273 vaccine clinical trials began in the United States.
      First vaccine clinical trials begin in the United States. March 17, 2020.
      On March 16, recombination vaccines for SARS-CoV-2 entered into phase I clinical trials.

      China has successfully developed recombination vaccines of SARS-CoV-2. Available at: https://news.qudong.com/2020/0317/653095.shtml. Accessed March 17, 2020.

      Although these are significant strides, the prospects for a commercially available vaccine are at least 6 months away, and probably much longer.

      Respiratory nursing support

      Studies have shown that prone positioning was associated with improved oxygenation and a decrease in CO2 retention, leading to reduced mortality, in patients with influenza, MERS, or ARDS.
      • Guerin C.
      • Reignier J.
      • Richard J.C.
      • et al.
      Prone positioning in severe acute respiratory distress syndrome.
      ,
      • Xu Y.
      • Deng X.
      • Han Y.
      • et al.
      A multicenter retrospective review of prone position ventilation (PPV) in treatment of severe human H7N9 avian flu.
      As a result, a Chinese expert consensus recommends that patients be prone for ≥ 12 hours a day when PaO2/FiO2 < 150 mm Hg.

      Nursing Department of Tongji Hospital Affiliated to Tongji Medical College Hust; Nursing Department of Peking Union Medical College Hospital; Intensive Care Professional Committee of the Chinese Nursing Association; Writing Committee Members; Wang H, Zeng T, Wu X, Sun H. Holistic care for patients with severe coronavirus disease 2019: an expert consensus. Int J of Nurs Sci 2020;7:128-34.

      Before placing the patient in prone position, oral secretions should be suctioned regularly to help keep the artificial airway open. In addition, COVID-19 patients suffer from copious proteinaceous exudates in their lungs and airways.
      • Tang S.
      • Hu W.
      • Niu L.
      • et al.
      Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer.
      ,

      Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:P420-2.

      Aspiration of sputum can help to keep the airway intact and potentially improve sample collection and the accuracy of SARS-CoV-2 nucleic acid detection.
      • Yang P.
      • Shao F.
      • Wang G.
      Two cases of increased positive rate of SARS-CoV-2 nucleic acid test by aerosol inhalation to induce sputum excretion.
      The patient’s position should be assessed and changed regularly to avoid decubitus skin injury. Elevating the head of the bed 30-45 degrees,
      Infectious Disease Group, Respiratory Disease Branch, Chinese Medical Association
      Guidelines for the diagnosis and treatment of hospital-acquired pneumonia and ventilator-associated pneumonia in adult in China (2018 edition).
      suctioning out oropharyngeal secretions, and monitoring the pressure of a rebreathing bag can help to prevent ventilator-associated pneumonia.

      Cardiac complications

      Cardiac abnormalities were found to be present in a high proportion of patients who died of COVID-19 and may be more associated with severe disease. Based on current studies, COVID-19 patients with cardiovascular diseases are more likely to develop into critical cases and have higher mortality.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.
      ,
      • 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.
      ,
      Chinese Society of Cardiology of Chinese Medical Association; Editorial Board of Chinese Journal of Cardiovascular Disease
      [Expert consensus on principal of clinical management of patients with severe emergent cardiovascular diseases during the epidemic period of COVID-19].
      Clinicians should be alert to the manifestations of heart injury by closely monitoring patients’ vital signs (blood pressure and heart rate), laboratory tests including creatine kinase, lactate dehydrogenase, high-sensitivity cardiac Troponin I, creatine kinase MB, B-type natriuretic peptide (BNP) and N-terminal proBNP, and electrocardiography. Antiviral drugs, such as ribavirin and lopinavir/ritonavir, have been widely used in cardiac patients, although there no well-designed trials to support that. The hypothesis that COVID-19 directly causes myocardial injury may support the usage of antiviral drugs, but the side-effects of these drugs on the cardiovascular system, such as sudden cardiac death and bradycardia, should be carefully considered.
      • Deng P.
      • Zhong D.
      • Yu K.
      • et al.
      Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans.
      Owing to the fact that cardiac insufficiency can lead to a coagulation disorder and that severe COVID-19 patients were reported to have increased level of d-dimer, low-molecular-weight heparin was recommended to treat COVID-19 patients in the early phase of disease.
      • Lin L.
      • Lu L.
      • Cao W.
      • Li T.
      Hypothesis for potential pathogenesis of SARS-CoV-2 infection—a review of immune changes in patients with viral pneumonia.
      As with SARS-CoV, ACE2 has been identified as the receptor for SARS-CoV-2 to enter cells.
      • Wrapp D.
      • Wang N.
      • Corbett K.S.
      • et al.
      Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.
      The use of ACE inhibitors (ACEIs) may not be of any benefit, because they does not bind to the ACE2 receptor. This also means that discontinuing ACEIs in patients with COVID-19 is not necessary. Regarding angiotensin receptor blockers (ARBs), there is evidence that ARBs could lead to increased expression of ACE2, thus worsening disease, but this remains controversial. There is no current recommendation to discontinue ARBs during treatment of COVID-19 in China. Monteil et al. found that SARS-CoV-2 infection in engineered human blood vessel organoids and human kidney organoids could be inhibited by human recombinant soluble ACE2.
      • Monteil V.
      • Prado P.
      • Hagelkrüys A.
      • et al.
      Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.
      Further investigations are required to shed light on the role of ACE2 in cardiac manifestations of COVID-19.
      Regarding acute myocardial infarction in COVID-19 patients, Peking Union Medical College Hospital and Zhongnan Hospital of Wuhan University provided the following experience.
      • Jing Z.-C.
      • Zhu H.-D.
      • Yan X.-W.
      • et al.
      Recommendations from the Peking Union Medical College Hospital for the management of acute myocardial infarction during the COVID-19 outbreak.
      ,
      • Zhang L.
      • Fan Y.
      • Lu Z.
      Experiences and lesson strategies for cardiology from the COVID-19 outbreak in Wuhan, China, by “on the scene” cardiologists.
      For acute ST-segment-elevation myocardial infarction (STEMI) in patients with confirmed COVID-19, strict isolation should start immediately and thrombolytic contraindications should be evaluated. Patients with thrombolytic contraindications should be transferred to the local infectious disease specialist hospitals immediately for further treatment. Patients without thrombolytic contraindications should first be started on intravenous thrombolysis and then transferred to the local infectious disease specialist hospitals for further treatment.
      • Jing Z.-C.
      • Zhu H.-D.
      • Yan X.-W.
      • et al.
      Recommendations from the Peking Union Medical College Hospital for the management of acute myocardial infarction during the COVID-19 outbreak.
      Considering the increased risk of exposure due to the lack of negative-pressure catheterization chambers and shortages of PPE, and the greater difficulty of finely manipulating the guidewires under level 3 protection, fibrinolysis is preferred when both percutaneous coronary intervention (PCI) and fibrinolysis are available. Once PCI is required, all medical workers should be under level 3 protection and thorough environmental disinfection must be given after each PCI.
      • Zhang L.
      • Fan Y.
      • Lu Z.
      Experiences and lesson strategies for cardiology from the COVID-19 outbreak in Wuhan, China, by “on the scene” cardiologists.

      Effectiveness and Importance of Public Health Interventions

      The WHO-China joint mission report reported that China’s vigorous public health measures to prevent the COVID-19 are the most “ambitious, agile, and aggressive disease containment effort in history.”

      COVID-19: too little, too late? [editorial]. Lancet 2020;395(10266):755.

      The drastic measures taken are listed in Table 4. If not for a national strategy that incorporated all of these measures simultaneously, it was estimated there would have been 744,000 COVID-19 cases outside Wuhan on day 50 of the epidemic, compared with the actual number of fewer than 20,000.
      • Tian H.
      • Liu Y.
      • Li Y.
      • et al.
      The impact of transmission control measures during the first 50 days of the COVID-19 epidemic in China [preprint].
      Table 4Specific lockdown measures in Wuhan later extended to the entire country
      MeasureContent
      Specific limitations
      • Strict travel restriction
      • Mandatory quarantine
      • Restrict public transportation
      • Close schools and entertainment venues
      • Shutdown of all nonessential companies
      • Cancel conferences
      • Cease all public gatherings
      • Stay at home
      Enforcement measures
      • COVID-19 belongs to class B infectious disease but managed as the highest-level class A infectious disease.
      • Building the Joint Prevention and Control Mechanism of the State Council to issue the COVID-19 development
      • Delivering the Prevention and Control Headquarters Notice of COVID-19
      • Enforcement laws including “Law of the People’s Republic of China on the prevention and treatment of infectious diseases,” “Surveillance protocol for pneumonia cases from novel coronavirus (second edition),” “Preventive measures against infectious diseases in business and service business sites,” “Provisions on the emergency handling of entry-exit inspection and quarantine for public health emergencies at border ports,” etc.
      Required measures
      • Temperature screening on the public occasions, such as hospitals, supermarkets
      • Purchasing daily necessities on a regular schedule
      • Delivering food and disinfectants for every family
      • Real-time disinfection of public areas.
      As of April 13, 2020, COVID-19 has spread to 6 continents and 212 countries and regions. We compare the epidemiologic characteristics among China, Italy, South Korea, and the United States in Figure 3. The data from China show that the daily number of infected patients has been less than 50 for the past week. However, there are a steady daily number of imported cases. Similarly, in South Korea, the strategy that worked also included early testing, tracking, and isolation. Unfortunately, lessons learned in China have not been universally adopted, and the numbers of cases in many countries are rapidly increasing.
      Figure thumbnail gr3
      Figure 3Epidemic curves of the confirmed cases of COVID-19 in various countries. Left, timeline of breakouts of SARS-CoV-2. Right, daily numbers of increasing cases. Data for China were obtained from the National Health Commission of China, which excluded Hong Kong and Macau Special Administrative Regions and Taiwan. Data for the remaining countries were obtained from the World Health Organisation.
      The lessons learned in China and South Korea are that in these times of crises, the earlier the intervention from a societal perspective the better. China had implemented an electronic monitoring system for infectious disease outbreaks after SARS in 2003. The question is how early one can reasonably expect to determine that something is out of the ordinary. People die of respiratory failure due to many causes, including influenza, every day. When should there be suspicion that something like a new virus is involved? The lesson here is that one should always have a high index of suspicion, but this must be balanced against causing mass hysteria and panic.
      Once it is recognized that there is a new, potentially lethal, virus, the virus needs to be isolated, the genome sequenced, and testing kits validated and released for rapid distribution. Infected individuals and their contacts need to be tracked and isolated. The earlier this is done, the less impact there will be on the personal and professional lives of people and the economy, and the fewer resources will be needed. When more people are infected, the drastic measures including shutting down cities and restricting travel will need to be more widespread, health care resources will be exhausted, and the economy will take a bigger hit.
      It is perhaps significant to evaluate the number and distribution of cases in China as a basis for aggressive testing, tracking, and quarantining. In the early days of the epidemic, the genomic sequence of the virus was determined and tests kits that would deliver results within hours were developed. It should be emphasized that the lockdown in Wuhan was a complete lockdown, other than bringing in necessary medical personnel, ventilators, and PPE, as well as everyday goods and supplies. The difference between this type of lockdown and the shelter in place recommendations that have been put forward in many Western countries is that the lockdown in Wuhan was strictly enforced. Laws in Wuhan limited grocery shopping to 1 person per household once every 2 days, with identity checks when leaving and returning. This type of enforced lockdown was later extended to the rest of the country, so that even in cities of more than 7 million and only 200 cases, the population experienced the same restrictions (Table 4). The entire country stayed on lockdown for more than 2 months. When lockdown measures were eased over the past few weeks, temperature checks were still being performed and one had to show electronic medical data on one’s electronic device. The lesson here is that if effective quarantine is what needs to occur, these measures must be supported by personnel to enforce them, and they cannot be voluntary or simply recommended.

      Downgrading After the Epidemic or Pandemic Has Been Brought Under Control

      According to relevant laws and regulations in China, when the number of confirmed cases has a steady decline and the risk of the spread of the epidemic is effectively controlled, each province should reduce the emergency response levels accordingly. In fact, local governments adjust emergency response levels according to the local epidemic situation. Provincial governments use counties as a unit to divide different regions into high-risk, medium-risk, and low-risk areas and implement different prevention and control measures in the different risk areas.
      China National Health Commission
      Covid-19 prevention and control scheme.
      Low-risk districts have no confirmed cases or no new confirmed cases for 14 consecutive days. Medium-risk districts have new confirmed cases within the previous 14 days but the cumulative number does not exceed 50 confirmed cases, or there are cumulatively more than 50 confirmed cases but no clustered epidemics within the previous 14 days. High-risk districts have a cumulative number of more than 50 confirmed cases, with clustered epidemics within the previous 14 days.
      Comprehensive Office of the Leading Group for the Prevention and Control of New Coronavirus Pneumonia in Chongqing, Chongqing Municipal People’s Government. [Chongqing COVID-19 epidemic area classification and classification prevention and control implementation scheme].
      Even so, there is always a risk of a second wave if restrictions are relaxed too soon and too drastically.
      Different prevention and control measures were implemented in different risk areas. In low-risk areas the main focus was to prevent import of outside cases with the economy restored back to normal. In medium-risk areas, both preventing internal and external spread was implemented, and screening of body temperature and disinfection of public facilities was continued. The entertainment industry remained closed, but other business activities resumed. In high-risk areas, strict quarantine and control measures were continued, with continued closure of nonessential businesses.

      Conclusion

      The experience in China is unique in that it was the first country to implement drastic measures to combat COVID-19. The strategy in China was early testing, diligent tracking, and strict isolation of patients and contacts, first in Wuhan and then nationwide. Even with this, there were more than 80,000 cases in China and more than 3000 deaths. All countries, even China, can learn from this. Although the drastic measures that China implemented appear for now to have stopped the viral spread, earlier implementation could have reduced the number of cases and deaths even more.
      Viral epidemics need to be countered with a unified national strategy that can be implemented quickly on a very large scale. The ability to mobilize and to stay nimble in adapting to these challenges is paramount. Public buy-in is crucial for all citizens to abide by the rules and recommendations. Rules must be mandatory and cannot be simply recommended and voluntary. Designated officers must be deployed to enforce these rules. The negative short-term public and economic consequences that may result from shutting down services, restricting travel, and aggressive quarantining must be accepted or the virus will keep spreading. Collaboration and sharing among countries are imperative to establish more effective policies to control the spread of future epidemics and minimize mortality and morbidity.

      Funding Sources

      This study was supported in part by the Beijing Municipal Natural Science Foundation General Program, China (7192197), CAMS Innovation Fund for Medical Sciences, China (2016-I2M-1-003), the National Natural Science Foundation of China (31671371 and 81700490), the Central Public-Interest Scientific Institution Basal Research Fund, China (2016ZX310195, 2017PT31026, and 2018PT31016), and the Epidemic Research Project of Guangzhou Regenerative Medicine and Health Guangdong Laboratory, China (2020GZR110406001).

      Disclosures

      The authors have no conflicts of interest to disclose.

      Supplementary Material

      References

        • Guan W.-J.
        • Ni Z.-Y.
        • Hu Y.
        • et al.
        Clinical characteristics of coronavirus disease 2019 in China.
        N Engl J Med. 2020; 382: 1708-1720
      1. Sun P, Qie S, Liu Z, Ren J, Li K, Xi J. Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: A single arm meta-analysis. [e-pub before print]. J Med Virol https://doi.org/10.1002/jmv.25735.

        • China Centers for Disease Control
        China-WHO new coronavirus pneumonia (COVID-19) joint inspection report.
        (Available at:) (Accessed February 29, 2020)
        • 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: 270-273
        • Wu A.
        • Peng Y.
        • Huang B.
        • et al.
        Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
        Cell Host Microbe. 2020; 27: 325-328
      2. Li X, Zai J, Zhao Q, et al. Evolutionary history, potential intermediate animal host, and cross-species analyses of SARS-CoV-2 [e-pub before print]. J Med Virol https://doi.org/10.1002/jmv.25731.

        • Liu P.
        • Jiang J.-Z.
        • Hua Y.
        • et al.
        Are pangolins the intermediate host of the 2019 novel coronavirus (2019-nCoV)?.
        PLoS Pathog. 2020; 16: e1008421
        • Rothe C.
        • Schunk M.
        • Sothmann P.
        • et al.
        Transmission of 2019-nCoV infection from an asymptomatic contact in Germany.
        N Engl J Med. 2020; 382: 970-971
        • Wang F.-S.
        • Zhang C.
        What to do next to control the 2019-nCoV epidemic?.
        Lancet. 2020; 395: 391-393
        • National Health Commission of the People's Republic of China
        [New coronavirus pneumonia prevention and control program (seventh trial edition)].
        China National Health Commission, Beijing2020 ([in Chinese]. Available at:) (Accessed March 4, 2020)
      3. World Health Organisation. Coronavirus disease (COVID-19) outbreak. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019. Accessed April 12, 2020.

        • Novel Coronavirus Pneumonia Emergency Response Epidemiology Team
        The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China.
        Zhonghua liu xing bing xue za zhi. 2020; 41: 145-151
        • Wenjie T.
        • Xiang Z.
        • Xuejun M.
        • et al.
        A novel coronavirus genome identified in a cluster of pneumonia cases—Wuhan, China 2019-2020.
        China CDC Wkly. 2020; 2: 61-62
        • The Joint Prevention and Control Mechanism of the State Council
        Caring frontline healthworks in epidemic prevention and control.
        (Available at:) (Accessed March 08, 2020)
        • Chen S.
        • Zhang Z.
        • Yang J.
        • et al.
        Fangcang shelter hospitals: a novel concept for responding to public health emergencies.
        Lancet. 2020; 395: 1305-1314
        • Xinhuanet
        Ma Xiaowei: The Fangcang hospital did “zero infection, zero death and zero return.” February 28, 2020.
        (Available at:) (Accessed February 28, 2020)
        • Wu X.Y.Y.
        • Ke S.
        Practical effect of continuous seamless scheduling and level management model in isolated wards during COVID-19.
        Chin Gen Pract Nurs. 2013; 11: 3041-3042
        • Hubei Province Pediatric Medical Quality Control Center
        Practice for management of pediatric ward and prevention of infection during the epidemic period of COVID-19.
        Chin J Appl Clin Pediatr. 2020; 35 ([in Chinese]): 105-111
        • Lei S.
        • Jiang F.
        • Su W.
        • et al.
        Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection.
        EClinicalMedicine. 2020; : 100331
      4. National Health Commission of the People's Republic of China. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).
        World Health Organisation, 2020 (Available at: http://www.nhc.gov.cn/xcs/zhengcwj/202002/3b09b894ac9b4204a79db5b8912d4440.shtml2020. Accessed February 5, 2020.)
      5. World Health Organisation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020. Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.

        • Chen H.
        • Guo J.
        • Wang C.
        • et al.
        Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.
        Lancet. 2020; 395: 809-815
        • Huang C.
        • Wang Y.
        • Li X.
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
        Lancet. 2020; 395: 497-506
        • 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: 1061-1069
      6. Zhang J-J, Dong X, Cao Y-Y, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China [e-pub before print]. Allergy, doi:10.1111/all.14238.

        • 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: 1054-1062
        • Yang X.
        • Yu Y.
        • Xu J.
        • et al.
        Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
        Lancet Respir Med. 2020; 8: 475-481
        • Liu Y.
        • Sun W.
        • Li J.
        • et al.
        Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019 [preprint].
        medRxiv. 2020; (02.17.20024166)
        • Mach W.J.
        • Thimmesch A.R.
        • Pierce J.T.
        • Pierce J.D.
        Consequences of hyperoxia and the toxicity of oxygen in the lung.
        Nurs Res Pract. 2011; 2011: 260482
        • He H.
        • Sun B.
        • Liang L.
        • et al.
        A multicenter RCT of noninvasive ventilation in pneumonia-induced early mild acute respiratory distress syndrome.
        Crit Care. 2019; 23: 300
        • Carrillo A.
        • Gonzalez-Diaz G.
        • Ferrer M.
        • et al.
        Non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure.
        Intensive Care Med. 2012; 38: 458-466
        • Del Sorbo L.
        • Goligher E.C.
        • McAuley D.F.
        • et al.
        Mechanical ventilation in adults with acute respiratory distress syndrome. Summary of the experimental evidence for the clinical practice guideline.
        Ann Am Thorac Soc. 2017; 14: S261-S270
      7. Chinese Research Hospital Association of Critical Care Medicine, Youth Committee of Chinese Research Hospital Association Of Critical Care Medicine. [Chinese experts' consensus on diagnosis and treatment of severe and critical coronavirus disease 2019 (Revised Edition)]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020;32:269‐74 [in Chinese].

        • Force A.D.T.
        • Ranieri V.M.
        • Rubenfeld G.D.
        • et al.
        Acute respiratory distress syndrome: the Berlin definition.
        JAMA. 2012; 307: 2526-2533
        • Arabi Y.M.
        • Fowler R.
        • Hayden F.G.
        Critical care management of adults with community-acquired severe respiratory viral infection.
        Intensive Care Med. 2020; 46: 315-328
        • Chen Z.
        • Shu Q.
        • Wang
        • et al.
        Diagnosis and treatment recommendation for pediatric coronavirus disease-19 (the second edition).
        J Zhejiang Univ (Med Sci). 2020; 49: 139-146
        • Xu X.-W.
        • Wu X.-X.
        • Jiang X.-G.
        • et al.
        Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.
        BMJ. 2020; 368: m606
        • 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: 507-513
        • 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: 1787-1799
        • Wang M.
        • Cao R.
        • Zhang L.
        • et al.
        Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
        Cell Res. 2020; 30: 269-271
        • Lu H.
        Drug treatment options for the 2019-new coronavirus (2019-nCoV).
        Biosci Trends. 2020; 14: 69-71
        • Dong L.
        • Hu S.
        • Gao J.
        Discovering drugs to treat coronavirus disease 2019 (COVID-19).
        Drug Discov Ther. 2020; 14: 58-60
        • China National Health Commission
        Press conference of the Joint Prevention and Control Mechanism of the State Council. March 17, 2020.
        (Available at:) (Accessed March 17, 2020)
        • Liu J.
        • Cao R.
        • Xu M.
        • et al.
        Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.
        Cell Discov. 2020; 6: 16
        • Gao J.
        • Tian Z.
        • Yang X.
        Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
        Biosci Trends. 2020; 14: 72-73
      8. Multicenter Collaboration Group of Department of Science And Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia].
        Zhonghua Jie He He Hu Xi Za Zhi. 2020; 43 ([in Chinese]): 185-188
      9. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression [e-pub before print]. J Antimicrob Chemother, https://doi.org/10.1093/jac/dkaa114.

      10. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [e-pub before print]. Clin Infect Dis, doi: 10.1093/cid/ciaa237.

        • Russell C.D.
        • Millar J.E.
        • Baillie J.K.
        Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
        Lancet. 2020; 395: 473-475
        • Shang L.
        • Zhao J.
        • Hu Y.
        • Du R.
        • Cao B.
        On the use of corticosteroids for 2019-nCoV pneumonia.
        Lancet. 2020; 395: 683-684
        • Zhao J.P.
        • Hu Y.
        • Du R.H.
        • et al.
        [Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia].
        Zhonghua Jie He He Hu Xi Za Zhi. 2020; 43 ([in Chinese]): 183-184
        • Ni Qin D.C.
        • Li Y.
        • Zhao H.H.
        • et al.
        Retrospective study of side effects of low-dose glucocorticoids in rheumatoid arthritis.
        Chin J Clin Infect Dis. 2020; : 43
        • Wang Y.
        • Jiang W.
        • He Q.
        • et al.
        Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China [preprint].
        medRxiv. 2020; (03.06.20032342)
        • Zhou W.
        • Liu Y.
        • Tian D.
        • et al.
        al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia.
        Signal Transduct Target Ther. 2020; 5: 18
        • Zhou Z.
        • Xie S.
        • Zhang J.
        • et al.
        Short-term moderate-dose corticosteroid plus immunoglobulin effectively reverses COVID-19 patients who have failed low-dose therapy [preprint].
        Preprints. 2020; : 2020030065
      11. Zhou YH, Qin YY, Lu YQ, et al. Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial [e-pub before print]. Chin Med J https://doi.org/10.1097/CM9.0000000000000791.

      12. Brown C, Carson G, Chand M, Dunning J, Zambon M. Treatment of MERS-CoV: information for clinicians clinical decision-making support for treatment of MERS-CoV patients. London: 2014, Public Health England.

        • Mair-Jenkins J.
        • Saavedra-Campos M.
        • Baillie J.K.
        • et al.
        The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.
        J Infect Dis. 2015; 211: 80-90
      13. China National Health Commission. The clinical guideline of convalescent plasma treatment (trial version 2). 2020. Available at: http://www.chinadaily.com.cn/a/202002/16/WS5e48cbf6a310128217277d72.html. Accessed February 16, 2020.

      14. Zhang Y, Wang X. 32 recovered patients donate plasma to others with coronavirus infection. China Daily 2020 Feb 16. Available at: https://www.chinadaily.com.cn/a/202002/16/WS5e48cbf6a310128217277d72.html. Accessed February 16, 2020.

        • Xiang Y.
        Clinical trial registration information analysis of COVID-19 in China.
        Chin J Clin Pharmacol Ther. 2020; 25: 135-140
        • Lin L.
        • Lu L.
        • Cao W.
        • Li T.
        Hypothesis for potential pathogenesis of SARS-CoV-2 infection—a review of immune changes in patients with viral pneumonia.
        Emerg Microbes Infect. 2020; 9: 727-732
      15. Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2–mediated inflammatory responses: from mechanisms to potential therapeutic tools [e-pub before print]. Virol Sin, https://doi.org/10.1007/s12250-020-00207-4.

        • Gu M.
        • Shi N.
        • Li X.
        • et al.
        Analysis of property and efficacy of traditional Chinese medicine in staging prevention and treatment of corona virus disease 2019.
        Zhongguo Zhong Yao Za Zhi. 2020; 45 ([in Chinese]): 1253-1258
      16. Yan Y-M, Shen X, Cao Y-K, Zhang J-J, Wang Y, Cheng Y-X. Discovery of anti–2019-nCoV agents from 38 Chinese patent drugs toward respiratory diseases via docking screening. Preprints 2020:2020020254.

        • Expert Team of Chinese Medical Association Nephrology Branch
        Expert consensus on diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infection with acute kidney injury.
        Chin J Nephrol. 2020; : 242-246
        • Li L.
        Translation: Expert consensus on the application of artificial liver blood purification system in the treatment of severe and critical COVID-19: National Clinical Research Center for Infectious Diseases.
        State Key Laboratory for Diagnosis and Treatment of Infectious Diseases. 2020; : 10
        • Hu L.
        • Chen S.
        • Fu Y.
        • et al.
        Risk factors associated with clinical outcomes in 323 COVID-19 patients in Wuhan, China [e-pub before print].
        Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa539
      17. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention [e-pub before print]. JAMA, doi:10.1001/jama.2020.2648.

      18. First vaccine clinical trials begin in the United States. March 17, 2020.
        (Available at:) (Accessed March 17, 2020)
      19. China has successfully developed recombination vaccines of SARS-CoV-2. Available at: https://news.qudong.com/2020/0317/653095.shtml. Accessed March 17, 2020.

        • Guerin C.
        • Reignier J.
        • Richard J.C.
        • et al.
        Prone positioning in severe acute respiratory distress syndrome.
        N Engl J Med. 2013; 368: 2159-2168
        • Xu Y.
        • Deng X.
        • Han Y.
        • et al.
        A multicenter retrospective review of prone position ventilation (PPV) in treatment of severe human H7N9 avian flu.
        PLoS One. 2015; 10e0136520
      20. Nursing Department of Tongji Hospital Affiliated to Tongji Medical College Hust; Nursing Department of Peking Union Medical College Hospital; Intensive Care Professional Committee of the Chinese Nursing Association; Writing Committee Members; Wang H, Zeng T, Wu X, Sun H. Holistic care for patients with severe coronavirus disease 2019: an expert consensus. Int J of Nurs Sci 2020;7:128-34.

        • Tang S.
        • Hu W.
        • Niu L.
        • et al.
        Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer.
        J Thorac Oncol. 2020; 15: 700-704
      21. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:P420-2.

        • Yang P.
        • Shao F.
        • Wang G.
        Two cases of increased positive rate of SARS-CoV-2 nucleic acid test by aerosol inhalation to induce sputum excretion.
        Chin J Tuberc Respir Dis. 2020; : E018
        • Infectious Disease Group, Respiratory Disease Branch, Chinese Medical Association
        Guidelines for the diagnosis and treatment of hospital-acquired pneumonia and ventilator-associated pneumonia in adult in China (2018 edition).
        Chin J Tuberc Respir Dis. 2018; 4: 255-280
        • Chinese Society of Cardiology of Chinese Medical Association; Editorial Board of Chinese Journal of Cardiovascular Disease
        [Expert consensus on principal of clinical management of patients with severe emergent cardiovascular diseases during the epidemic period of COVID-19].
        Zhonghua Xin Xue Guan Bing Za Zhi. 2020; 48 ([in Chinese]): 189-194
        • Deng P.
        • Zhong D.
        • Yu K.
        • et al.
        Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans.
        Antimicrob Agents Chemother. 2013; 57: 1743-1755
        • Wrapp D.
        • Wang N.
        • Corbett K.S.
        • et al.
        Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.
        Science. 2020; 367: 1260-1263
        • Monteil V.
        • Prado P.
        • Hagelkrüys A.
        • et al.
        Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.
        Cell. 2020; 181 (905‐913.e7)
        • Jing Z.-C.
        • Zhu H.-D.
        • Yan X.-W.
        • et al.
        Recommendations from the Peking Union Medical College Hospital for the management of acute myocardial infarction during the COVID-19 outbreak.
        Eur Heart J. 2020; 41: 1791-1794
        • Zhang L.
        • Fan Y.
        • Lu Z.
        Experiences and lesson strategies for cardiology from the COVID-19 outbreak in Wuhan, China, by “on the scene” cardiologists.
        Eur Heart J. 2020; 41: 1788-1790
      22. COVID-19: too little, too late? [editorial]. Lancet 2020;395(10266):755.

        • Tian H.
        • Liu Y.
        • Li Y.
        • et al.
        The impact of transmission control measures during the first 50 days of the COVID-19 epidemic in China [preprint].
        medRxiv. 2020; (01.30.20019844)
        • China National Health Commission
        Covid-19 prevention and control scheme.
        (Available at:) (Accessed March 7, 2020)
      23. Comprehensive Office of the Leading Group for the Prevention and Control of New Coronavirus Pneumonia in Chongqing, Chongqing Municipal People’s Government. [Chongqing COVID-19 epidemic area classification and classification prevention and control implementation scheme].
        (Available at:) (Accessed February 19, 2020)
        • Yi Jiang Y.
        • Lu X.
        • Jin R.
        • et al.
        Diagnosis, treatment and prevention of 2019 novel coronavirus infection in children: experts' consensus statement (Second Edition). [J].
        Chinese Journal of Applied Clinical Pediatrics. 2020; 35: 143-150