Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current Wuhan, China, outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. The rapid accumulation of many new cases in Wuhan City during the months of December 2019 and January and February 2020, combined with evidence of spread to persons from other nearby provinces in central China and reports of acute infection in healthcare workers, point to facile human-to-human transmission of COVID-19 as the key factor responsible for continued propagation of the outbreak.

Education Category: Infection Control / Internal Medicine
Release Date: 02/01/2020
Expiration Date: 01/31/2023


This outbreak is ongoing. As the situation evolves, the course is being revised to reflect new information. The last update was done June 5, 2020.


This course is designed for physicians, nurses, and other healthcare professionals who may identify or educate patients regarding coronavirus infection.

Accreditations & Approvals

In support of improving patient care, NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. State and provincial regulatory boards have the final authority to determine whether an individual course may be accepted for continuing education credit. NetCE maintains responsibility for this course. NetCE is accredited by the International Association for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 2 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 2 ANCC contact hour(s). NetCE designates this continuing education activity for 2.4 hours for Alabama nurses. Social workers participating in this intermediate to advanced course will receive 2 Clinical continuing education clock hours. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 2 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE designates this activity for 2 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-20-067-H04-P. This home study course is approved by the Florida Board of Nursing Home Administrators for 2 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 2 hour(s) of continuing education credit - NHAP#1622002-7685/P. California NHAs may only obtain a maximum of 10 hours per course. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.2 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through November 21, 2021); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2021; South Carolina, Provider #50-2405. South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190; Texas State Board of Social Worker Examiners, Approval #3011;

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide physicians, nurses, and other healthcare professionals an overview of the emerging human coronavirus (SARS-CoV-2) outbreak, including background epidemiology, clinical features, mode of transmission, epidemic potential, and the clinical and public health measures recommended to limit the spread of infection and control the outbreak.

Learning Objectives

Upon completion of this course, you should be able to:

  1. Outline the background of coronaviruses.
  2. Describe the response to the 2019–2020 novel coronavirus disease (COVID-19) outbreak.


John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Table of Contents

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#94150: The Coronavirus Disease (COVID-19) Pandemic

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Coronaviruses (a subfamily of Coronaviridae) are enveloped, single-stranded RNA viruses that are broadly distributed among humans, other mammals, and birds. Under electron microscopy, the outer envelope of the virion shows club-like surface projections that confer a crown-like appearance to the virus, which accounts for the name given to this family of viruses. The nucleocapsid is a long, folded strand that tends to spontaneous mutations and frequent recombination of the genome, which may account, in part, for changes in transmissibility and pathogenicity that permit a new (novel) form of coronavirus infection in humans.

In addition to four specific subtypes of coronavirus commonly found in humans, other strains have been detected in many different species of animals, including bats, cats, camels, and cattle. On rare occasions, an animal coronavirus is responsible for zoonotic infection in humans, meaning that a novel coronavirus is transmitted from an animal host to one or more humans, producing clinical illness that may result in secondary spread among persons in close contact. The wide distribution, genetic diversity, and frequent shifts in the genome, combined with unique human-animal interface activities, are considered important factors in the periodic emergence of new coronavirus outbreaks in human populations [1,2].


Common Strains

Human coronavirus (HCoV) was first identified in 1965, isolated from a patient with what was described as the common cold [3]. Subsequently, four types of HCoV have been detected commonly in respiratory secretions of children and adults in scattered regions of the globe, labeled HCoV-229E, -NL63, -OC43, and -HKU1. These agents are a common cause of mild-to-moderate upper respiratory illness, such as the common cold, bronchitis, bronchiolitis in infants and children, and asthma exacerbation. On occasion, as with influenza, HCoVs can cause serious lower respiratory tract infection (viral pneumonia), a complication more common to persons with underlying cardiopulmonary disease or weakened immune systems.

Novel Coronavirus Outbreaks

In addition to the seasonal infections caused by the ambient, adaptive HCoVs described, widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the 2019–2020 Wuhan, China, outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale [1,4]. The common epidemiologic feature of these outbreaks is an initial point source cluster of zoonotic infection followed by secondary spread of the virus via human-to-human transmission. Among the factors thought to be conducive to the emergence of such outbreaks are the following: genomic recombination in an animal CoV capsid that renders the virus better adapted to human infection (and perhaps more virulent); and dietary practices and cultural determinants that bring humans into close contact with livestock or raw meat and carcasses of wild animals and birds, thereby facilitating transmission from an infected animal host to humans. After infection is established, secondary viral transmission occurs through close person-to-person contact by way of droplet nuclei propelled into the air during coughing and sneezing. The first two known novel coronavirus outbreaks, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, are considered to be zoonotic in origin and were associated with serious, sometimes fatal illness.

Severe Acute Respiratory Syndrome (SARS-CoV)

Infection with SARS-CoV was first recognized in China in November 2002, and signs of an outbreak in Asia were evident by February 2003 [3]. Epidemiologic investigation found that early cases of SARS-CoV represented zoonotic infection involving transmission from civet cats to humans. Over the next several months, SARS-CoV spread to countries in North America, South America, Europe, and other parts of Asia before the global outbreak was contained later in the same year.

SARS-CoV infection began with fever, headache, malaise, and arthralgia/myalgia followed in two to seven days by cough, shortness of breath, and in most patients, signs of pneumonia [3].

According to the World Health Organization (WHO), the 2002–2003 outbreak caused 8,098 probable cases of SARS worldwide and 774 deaths. Just eight cases were identified in the United States. Since 2004, there have been no additional known cases of SARS-CoV infection reported anywhere in the world [3].

In response to the 2003 global SARS outbreak, the Centers for Disease Control and Prevention (CDC), working in concert with the WHO, developed a strategy for controlling the epidemic that included the following elements [3]:

  • Activated the Emergency Operations Center to provide around-the-clock coordination and response.

  • Committed more than 800 medical experts and support staff to work on the SARS response and to assist with ongoing investigations around the world.

  • Provided assistance to state and local health departments in investigating possible cases of SARS in the United States.

  • Conducted extensive laboratory testing of clinical specimens from patients with SARS to identify the cause of the disease.

  • Initiated a system for distributing health alert notices to travelers who may have been exposed to cases of SARS.

This experience provided a blueprint for responding to the 2019–2020 coronavirus outbreak in China.

Middle East Respiratory Syndrome (MERS-CoV)

MERS-CoV was first reported in Saudi Arabia in 2012, and all cases to date have been linked to countries in or near the Arabian Peninsula. Travel-associated MERS-CoV infection has been reported from many countries around the world, including two imported cases diagnosed in the United States in 2014 involving unlinked healthcare providers who had recently lived and worked in Saudi Arabia. There is epidemiologic evidence for two modes of transmission: zoonotic infection from an animal reservoir to humans (with camels acting as the intermediate host), and person-to-person transmission via close contact with an index case, as described in association with a family case cluster and a nosocomial outbreak [5,6,7].

Most persons with confirmed MERS-CoV infection have had moderately severe respiratory illness manifest by fever, cough, and shortness of breath, often complicated by pneumonia and respiratory failure. The case-fatality rate approaches 40%. Most deaths have been in patients with pre-existing chronic conditions such as diabetes, cancer, or heart, lung, or renal disease. Sporadic cases of MERS-CoV continue to appear in various parts of the Middle East [3].


In December 2019, Chinese physicians in Hubei Province, China, began an investigation of a cluster of cases of severe viral pneumonia in area hospitals linked to exposure to a large seafood and live animal wholesale market in Wuhan City. In the weeks following, it became evident that a large outbreak of respiratory illness was rapidly emerging within Wuhan City and nearby communities, reaching the thousands by mid-January.

On January 24, Chinese scientists reported the results of viral diagnostic studies conducted on bronchoalveolar lavage specimens obtained from three Wuhan City patients hospitalized in December with severe bilateral interstitial, alveolar pneumonia [2]. The investigation identified a viral genome matched to lineage B of the genus betacoronavirus, showing more than 85% match with a SARS-like CoV genome previously described in bats. Ultrathin sections of infected human airway epithelial cells showed inclusion bodies filled with virus particles in membrane-bound vesicles in the cytoplasm. On electron microscopy, the observed morphology of the virion is consistent with the Coronaviridae family.

This newly identified coronavirus is now known to be the etiologic agent responsible for the Wuhan, China, outbreak and is named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The resultant disease is referred to as COVID-19. Like SARS-CoV and MERS-CoV, SARS-CoV-2 is a betacoronavirus that likely has its origin in bats, with one or more animals serving as the intermediate host for zoonotic infection in humans. According to CDC reports, virus sequences from imported cases in this country are similar to the one initially posted by China, suggesting a likely single, recent emergence of this virus from an animal reservoir [12].

The rapid accumulation of many new cases in Wuhan City during the months of December 2019 and January and February 2020, combined with evidence of spread to persons from other nearby provinces in central China and reports of acute infection in healthcare workers, point to facile human-to-human transmission of SARS-CoV-2 as the key factor responsible for continued propagation of the COVID-19 outbreak.


Extrapolating from epidemiologic information and what is known from previous novel coronavirus outbreaks (SARS and MERS), the incubation period of SARS-CoV-2 is estimated to be 5 to 7 days on average, with a range of 2 to 14 days. One study reported that 97.5% of persons with COVID-19 who develop symptoms will do so within 11.5 days of infection [15,18]. The onset and progression of illness is variable, with most patients experiencing some combination of fever, cough, fatigue, anorexia, myalgias, and shortness of breath. Atypical presentations have been described, and older adults and persons with medical comorbidities may have delayed presentation of fever and respiratory symptoms [15]. Headache, confusion, rhinorrhea, sore throat, hemoptysis, vomiting, and diarrhea have been reported but are less common (<10%). Some persons with COVID-19 have experienced gastrointestinal symptoms such as diarrhea and nausea prior to developing fever and lower respiratory tract signs and symptoms. Anosmia or ageusia preceding the onset of respiratory symptoms has been anecdotally reported, but more information is needed to understand its role in identifying COVID-19.

Although most symptomatic patients with COVID-19 experience a mild-to-moderate illness with slow convalescence, there is substantial risk of progression to bilateral pneumonia complicated by respiratory failure and death. Based on official case reports through the month of January 2020, the mortality rate for confirmed cases of COVID-19 reported from China was approximately 3%. Based on worldwide reported cases and deaths through April, the case fatality rate in the United States and other heavily affected areas is approximately 6% [8]. However, there is significant variability among various countries and localities.

The first report describing the clinical features of hospitalized patients with COVID-19-related pneumonia in Wuhan City was published online January 24, 2020 [9]. As of January 2, 41 admitted patients had been identified as having laboratory-confirmed 2019-nCoV infection; 30 (73%) were men and 27 (66%) had been exposed to the open-air Huanan Seafood Market. The median age was 49 years, and fewer than half of the patients had a history of underlying chronic disease. Common symptoms at onset of illness were fever (98%), cough (76%), and myalgia or fatigue (44%). Dyspnea developed in 22 patients (55%), with a median time from illness onset to dyspnea of eight days. Common laboratory abnormalities included leukopenia, lymphopenia, and mild hepatic enzyme elevations. All 41 patients were reported to have pneumonia, and all save one had radiographic evidence of bilateral involvement. The typical findings on chest computed tomography (CT) images of intensive care unit (ICU) patients were bilateral multilobar and segmental areas of consolidation. Acute respiratory distress syndrome developed in 12 (32%) patients, 13 (32%) were admitted to an ICU, and 6 died (15%).

A larger retrospective study examined the clinical characteristics of COVID-19 in a cohort of 1,099 hospitalized patients in China during the first two months of the outbreak [17]. The most common symptoms were fever (43.8% on admission, 88.7% during hospitalization), cough (67.8%), and fatigue (38.1%) [17]. The most common patterns on chest CT were ground-glass opacification (36.4%) and bilateral patchy shadowing (51.8%). Some degree of radiographic or CT abnormality was evident in 82% of patients with nonsevere disease and 97% of patients with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Sixty-seven patients (6.1%) were admitted or transferred to the ICU, 2.3% required mechanical ventilation, and 1.4% died [17].

In a summary of 72,314 cases reported to the Chinese Center for Disease Control and Prevention, the majority of cases (81%) were characterized as mild, with no or mild pneumonia [23]. Of the remaining cases, 14% were severe and 5% were critical. The overall case-fatality rate was 2.3%, with higher rates among patient subgroups. Specifically, the case-fatality rate was 49% among critical patients, and all reported deaths occurred in critical patients [23].

Risk factors for severe disease include advanced age, obesity, and comorbidities such as hypertension, diabetes, cardiovascular disease, cancer, and chronic lung disease. Among more than 70,000 cases reported in China through February 11, 2020, 87% occurred in persons 30 to 79 years of age [23]. The proportion of case fatalities among patients 70 to 79 years of age was 8%, and among those 80 years of age or older, the rate was 14.8%. Case fatality for patients with comorbidities was elevated as well, specifically for those with cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6%), and cancer (5.6%). Only 2% of cases were in persons younger than 20 years of age, and no deaths were reported in those younger than 10 years of age.


At the cellular level, infection by a virus requires some affinity of the virion for the host cell, a mechanism that facilitates attachment and entry into the cell. Cell entry of SARS-CoV-2 depends on binding of the viral surface spike protein to angiotensin-converting enzyme (ACE2) receptors and activation of the spike protein by host cell transmembrane protease serine 2 [30]. ACE2 is highly expressed by epithelial cells in the nasopharynx and type II alveolar cells in the lung. ACE2 is also expressed in the heart, kidney, vascular endothelium, and intestinal epithelium, which may explain, in part, the propensity for multiorgan dysfunction and vascular complications increasingly recognized in patients with severe COVID-19. In an autopsy series of 27 patients reported from Germany, SARS-CoV-2 was detected in multiple organs, including the lungs, pharynx, kidney, heart, liver, and brain [31]. In a further analysis of renal involvement, SARS-CoV-2 viral load was detected in all kidney compartments examined, with preferential targeting of glomerular cells. Based upon recent reports from clinical centers caring for a high volume of hospitalized patients, renal and cardiac complications are relatively common in severe COVID-19. In a retrospective study from China, 251 of 333 (75%) hospitalized patients with COVID-19 pneumonia exhibited some degree of renal involvement, as evidenced by proteinuria or hematuria, and 35 (10%) met criteria for acute kidney injury [32]. In another case series of 138 hospitalized COVID-19 patients, 7% overall and 22% of those admitted to the ICU developed elevated troponin levels or electrocardiogram abnormalities indicative of myocarditis or cardiac injury some time during hospitalization [33]. Myocardial injury is estimated to affect more than one-quarter of COVID-19 cases classified as critical and presents in two patterns: acute myocardial injury and dysfunction on presentation, and myocardial injury that develops as illness severity intensifies [34].


Hospitalized patients with advanced COVID-19 often exhibit laboratory signs of a coagulopathy and are at increased risk for arterial and venous thromboembolic complications [15,39,40]. The pathogenesis is unknown but may involve some combination of systemic inflammation, endothelial dysfunction, platelet activation, immobility, and stasis of blood flow [40]. The early and most consistent abnormalities are elevated D-dimer levels and mild thrombocytopenia, followed by increased fibrin degradation products and prolongation of the prothrombin time as disease progresses. Laboratory measure of coagulation factors in a patient hospitalized with COVID-19 can provide an indication of disease severity. The presence of an elevated D-dimer on admission carries a poor prognosis and has been associated with increased risk of requiring mechanical ventilation, ICU admission, and mortality [40,41]. The most frequently reported complications of COVID-19 coagulopathy are deep venous thrombosis (DVT) and pulmonary emboli (PE). In a prospective study of 150 critically ill patients from two centers in France, 25 patients developed PE and 3 developed DVT despite prophylactic anticoagulation [42]. In a report of 184 patients with severe COVID-19 from three centers in the Netherlands, the cumulative incidence of venous thromboembolism was 27%, including PE in 80% of the cases affected [43]. Other centers have reported lower rates. Among 393 patients from New York, venous thromboembolism was diagnosed in only 13 patients (3.3%), 10 of whom were on mechanical ventilation [44]. These differences point to the need for studies that control for clinical severity, underlying comorbidities, prophylactic regimen, and COVID-19-related therapies. At present, there are limited data available to inform clinical management around prophylaxis or treatment of venous thromboembolic complications in patients with COVID-19 [15]. One source of interim guidance recommends regularly monitoring hemostatic markers—namely D-dimer, prothrombin time, and platelet count—in all patients presenting with COVID-19 and prophylactic use of low-molecular-weight heparin in all hospitalized patients, unless there are contraindications [40]. The National Institutes of Health has developed guidelines for antithrombotic therapy in patients with COVID-19 available at https://covid19treatmentguidelines.nih.gov/antithrombotic-therapy.


The CDC provides information for pediatric healthcare providers and guidance for the evaluation and care of neonates at risk for COVID-19 [45]. Acute SARS-CoV-2 infection in childhood tends to be asymptomatic or relatively mild, consisting of transient fever, cough, and other signs common to an upper respiratory viral syndrome. Severe manifestations of COVID-19 have been reported in children of all ages, though the incidence is far less common than in adults and fatalities following acute childhood infection are rare. According to data from more than 2,000 pediatric cases in China, 4% were asymptomatic, 51% had mild symptoms, 39% were moderately ill with some evidence of pneumonia, and 5% were severely ill with dyspnea, hypoxia, and central cyanosis [45]. Only 0.6% developed respiratory failure, shock, or multi-organ dysfunction. In the United States, about 2% of confirmed cases of COVID-19 are among persons younger than 18 years of age, and data from the New York State Department of Health show that only 1% of patients hospitalized with COVID-19 were younger than 20 years of age [46].


Reports from the United Kingdom, Italy, and New York describe a serious inflammatory disorder in children linked to COVID-19 with many features common to Kawasaki disease and toxic shock syndrome [46,47,48]. The term applied to this condition is multisystem inflammatory syndrome in children (MIS-C). Kawasaki disease is an acute vasculitis of unknown cause that affects infants and young children, first described in Japan and thought to involve an aberrant immune response to an unidentified pathogen in persons with a genetic predisposition [47]. Children with COVID-related MIS-C present with signs of a diffuse inflammatory disorder, including persistent fever, abdominal complaints, rash, leukocytosis, elevated C-reactive protein, and evidence of single or multiple organ dysfunction [49]. Hypotension on presentation is common, and myocarditis and other cardiovascular changes (e.g., mitral regurgitation, coronary artery dilatation) may be seen. The majority of patients have tested positive for recent SARS-CoV-2 infection by molecular diagnostic and/or antibody testing. The onset of MIS-C may come days or weeks after what appears to have been an asymptomatic or mild case of COVID-19.

During a 10-day period in mid-April 2020, pediatricians at an intensive care hospital in England noted an unprecedented cluster of eight children with hyperinflammatory shock and other clinical features similar to atypical Kawasaki disease [47]. All had been previously well, and five of the children were boys. Four of the children had known family exposure to SARS-CoV-2. Clinical presentations were similar, with unrelenting fever, variable rash, conjunctivitis, peripheral edema, and warm shock refractory to volume repletion and eventually requiring vasopressors. There was no clinical or virologic evidence of lower respiratory involvement. All patients were treated with IV immunoglobulin; seven recovered and one died following arrhythmia, shock, and cerebral infarction. During the course of the COVID-19 epidemic in northern Italy, physicians in Bergamo observed 10 children (median age: 7.5 years) in the span of two months with a severe form of Kawasaki-like disease, a 30-fold increase in incidence when compared to the previous five years [48]. All were positive for recent SARS-CoV-2 infection. As of June 3, 2020, the New York State Department of Health was investigating 195 reported cases of MIS-C and 3 deaths in children. Of these patients, 28% are younger than 5 years of age and 69% are between 5 and 19 years of age [46]. Of the 195 cases, 93% have tested positive for COVID-19.

Early recognition of MIS-C and prompt referral to an inpatient unit of care is essential. Clinical evaluation should include inquiry as to recent COVID-19 illness or known exposure to persons with COVID-19. There are currently no published guidelines or CDC recommendations regarding treatment for MIS-C and no studies comparing efficacy of various treatment options. Based on published reports, principles of care include close observation, correction of hemodynamic instability, diagnostic evaluation to exclude serious bacterial infection (e.g., streptococcal or staphylococcal sepsis, toxic shock syndrome), and consideration of treatment with IV immunoglobulin. The CDC recommends that patients younger than 21 years of age meeting MIS-C criteria be reported to local, state, and territorial health departments. The CDC case definition for MIS-C is [49]:

  • An individual younger than 21 years of age presenting with fever (>38.0°C for at least 24 hours), laboratory evidence of inflammation (including, but not limited to, one or more of the following: an elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or interleukin-6, elevated neutrophils, reduced lymphocytes, and low albumin), and evidence of clinically severe illness requiring hospitalization, with multisystem (at least two) organ involvement; AND

  • No alternative plausible diagnoses; AND

  • Positive for current or recent SARS-CoV-2 infection or exposure to a suspected or confirmed COVID-19 case within the four weeks prior to the onset of symptoms

All individuals should be reported if they meet the case definition for MIS-C, regardless of whether they fulfill criteria for Kawasaki disease. In addition, MIS-C should be considered in any pediatric death with evidence of SARS-CoV-2 infection.


A real-time reverse transcription-polymerase chain reaction (rRT-PCR) test, based on genomic sequencing of the virus in China and at the CDC, can be used to diagnose SARS-CoV-2 in respiratory and serum samples from clinical specimens. On January 24, 2020, the CDC publicly posted the assay protocol for this test. As of March 16, 2020, testing for this virus in the United States can be done at state and local public health laboratories in all states and at the CDC [16]. Detection of SARS-CoV-2 viral RNA is better in nasopharynx samples compared with throat samples [15]. Viral RNA shedding may persist over longer periods in older persons and those who had severe illness requiring hospitalization (median range of viral shedding: 12 to 20 days) [15]. Information on specimen collection, handling, and storage is available online at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html. The CDC's recommendations for diagnostic testing are discussed in detail later in this course.


There is no established antiviral therapy of proven efficacy for the treatment of COVID-19 and, as yet, no vaccine for prevention of SARS-CoV-2 infection. Care is supportive and, for the purposes of limiting spread, should be carried out in a controlled environment under Isolation Precautions.

According to a National Institutes of Health briefing reported by the Infectious Disease Society of America, research efforts are underway to develop better diagnostics, treatments, and vaccines [10]. As noted, the CDC has already developed a diagnostic test based on genetic sequencing of the virus shared by Chinese investigators. Two antiviral agents—remdesivir, a drug tried unsuccessfully in the Ebola outbreak, and lopinavir/ritonavir (Kaletra), a combination antiviral used for treatment of human immunodeficiency virus (HIV)—were provided on a compassionate use basis in China. However, one study of hospitalized patients with COVID-19 in China found no difference in time to clinical improvement and no difference in eventual outcome with lopinavir/ritonavir treatment [20].

An accelerated effort is underway in the United States and other countries to develop a vaccine against SARS-CoV-2 utilizing the genetic sequencing shared by China as well as genetic material derived from viral isolates obtained in the West [10]. Preliminary trials to assess vaccine safety began in the first quarter of 2020 to be followed by trials to determine vaccine effectiveness, which would require additional months for completion.


Antiviral Therapy


Remdesivir, an investigational antiviral drug that inhibits viral RNA polymerases, has been shown to have in-vitro activity against SARS-CoV-2 [15]. A recent report describes the clinical outcomes for a cohort of patients with COVID-19 who were treated with a 10-day course of intravenous remdesivir as part of a compassionate use program [26]. The study enrolled patients from the United States, Canada, Europe, and Japan who were hospitalized with confirmed SARS-CoV-2 infection and signs of lower respiratory tract disease severe enough to require some degree of oxygen supplementation and/or ventilatory support. Of 53 patients with sufficient data for analysis, 32 (68%) showed significant improvement in oxygen support status with use of remdesivir; the overall mortality was 13% over a median follow-up of 18 days, including 18% among those who were receiving invasive ventilation and 5% among those who were receiving noninvasive oxygen support. The authors observed that while there was no randomized control group and the patients in this study are not directly comparable, the observed mortality was considerably less than that reported contemporaneously in other COVID-19 case series and reports [26]. An NIH adaptive randomized controlled clinical trial of investigational therapeutics for hospitalized patients with COVID-19 in the United States was approved by the U.S. Food and Drug Administration (FDA); the first investigational therapeutic to be studied is remdesivir.

On April 29, 2020, the NIH reported an interim data analysis from a multicenter randomized controlled trial of remdesivir involving 1,063 hospitalized patients with advanced COVID-19 and lung involvement [35]. Preliminary results showed that patients who received remdesivir had a 31% faster time to recovery than those who received placebo. The median time to recovery was 11 days for patients in the remdesivir group, compared with 15 days for those in the placebo group. Recovery in this study was defined as well enough for hospital discharge or return to normal activity. The data also indicated a trend toward survival benefit, with a mortality rate of 8.0% for the remdesivir group versus 11.6% for the placebo group.


In-vitro studies show that chloroquine phosphate and hydroxychloroquine sulphate (commonly used to treat malaria) interfere with the replication cycle of coronaviruses, including SARS-CoV-2 and thus may offer some therapeutic efficacy for treatment of COVID-19 [21]. Randomized controlled clinical trials of hydroxychloroquine are underway in the United States. Based on reports of possible efficacy, many clinicians have been inclined to administer hydroxychloroquine to patients with COVID-19 who are so ill as to require hospitalization and having risk factors for severe disease (i.e., age older than 65 years, underlying medical conditions, and/or signs of viral pneumonia). On March 28, 2020, the FDA authorized use of chloroquine phosphate or hydroxychloroquine sulphate for the treatment of COVID-19 when clinical trials are not available or participation is not feasible [36]. If used, hydroxychloroquine sulphate is generally preferred as it is better tolerated. The suggested dosage regimen is hydroxychloroquine administered orally in a loading dose of 400 mg twice daily (for one day) then 200 mg twice daily for four days [22]. Potential adverse effects include cardiac conduction QT-prolongation and a number of drug-drug interactions.

A recently published observational study examined the association between hydroxychloroquine use and clinical outcomes, analyzing data from 1,376 consecutive patients with COVID-19 admitted to a clinical center in New York City between March 7 and April 8, 2020 [37]. To assess potential benefit or detrimental effect, the primary end point selected was a composite of intubation or death in a time-to-event analysis, comparing outcomes in patients who received hydroxychloroquine with those who did not. A total of 811 patients (59%) were treated with hydroxychloroquine for a median of five days, 60% of whom also received azithromycin. After adjusting for severity of illness, the investigators found no significant difference in the rate of the composite end point of intubation or death over a median follow-up of 22.5 days. These results show that the risk of intubation or death was not significantly different among hospitalized patients with COVID-19 who received hydroxychloroquine than among those who did not [37]. The results of randomized controlled trials, stratified for stage of infection and severity of illness, are needed to define more clearly what role, if any, hydroxychloroquine has in the management of COVID-19.

Approaches to Disease Modification

Death from COVID-19 is often preceded by progressive viral pneumonia and signs of a hyperimmune inflammatory response ("cytokine storm") that leads to ARDS, multi-organ dysfunction, and circulatory collapse. Laboratory markers of heightened inflammation include elevated C-reactive protein, ferritin, and interleukin-6. Novel approaches to disease management are being explored in the effort to modify disease progression, prevent or ameliorate pulmonary and systemic complications of cytokine storm, and thus reduce mortality from COVID-19. One such approach is passive immunization with transfused plasma (or administration of immune globulin derived from the plasma) of persons recently recovered from SARS-CoV-2 infection. In a preliminary, uncontrolled case series of five critically ill Chinese patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in clinical status, including resolution of ARDS in four patients at 12 days after transfusion [27].

The FDA website provides information and directions for donation of convalescent COVID-19 plasma [28]. People who have fully recovered from COVID-19 for at least two weeks are encouraged to consider donating plasma, which may help save the lives of other patients. COVID-19 convalescent plasma can only be collected from recovered individuals if they are eligible to donate blood. A potential donor must have had a prior diagnosis of COVID-19 documented by a laboratory test and meet other donor criteria. Complete resolution of symptoms for at least 28 days is required before an individual may donate plasma, or alternatively have had no symptoms for at least 14 days prior to donation and have a negative lab test for active COVID-19 disease [28]. Persons interested in becoming donors should contact the American Red Cross or ask the local blood center about options to donate convalescent plasma in their area.

On April 10, 2020, the FDA granted emergency use authorization for an extracorporeal blood purification system to treat adult patients with COVID-19 admitted to an ICU with confirmed or imminent respiratory failure [29]. This device filters the blood for removal of cytokines and other inflammatory mediators associated with cytokine storm, then returns filtered blood to the patient.



Beginning in January 2020, and in association with travel to and from China, cases of confirmed SARS-CoV-2 infection began to be reported from multiple countries around the world, including the United States. The WHO monitors developments and tracks the progress of the epidemic, providing daily Situation Reports at its website [8]. In an effort to curb the spread of infection, the WHO and national agencies have developed clinical criteria to guide the evaluation and management of persons with significant exposure and/or compatible illness.

In the initial weeks of the outbreak, cases reported in countries outside China were occurring primarily in returning travelers who had visited Wuhan City or nearby locales in central China. With time, the extent of person-to-person spread unrelated to travel has become increasingly clear; local transmission and community spread is now evident in most countries. As of June 4, 2020, there were 6,416,828 confirmed cases and 382,867 deaths globally [8]. More than 150 countries have been impacted. The Americas is the region most severely impacted, and the United States is by far the country with the greatest number of cases with 1,823,220 confirmed cases reported to the WHO.

Advice to the Public

The WHO has posted standard recommendations for the general public designed to reduce exposure to, and transmission of SARS-CoV-2 [11]. In addition, the CDC has developed guidelines for the public on how to best protect themselves and others [24]:

  • Wash hands often with soap and water for at least 20 seconds, especially after having been in a public place or after coughing, sneezing, or blowing your nose. If soap and water are not readily available, a hand sanitizer that contains at least 60% alcohol may be used.

  • Avoid touching eyes, nose, and mouth with unwashed hands.

  • Avoid close contact with people who are sick, and stay home as much as possible

  • Put distance (at least 6 feet) between yourself and other people.

  • Cover your mouth and nose with a cloth face cover when around others (i.e., in public). Note: This recommendation does not apply to children younger than 2 years of age, persons with breathing difficulties, or those who are unable to remove the mask unassisted.

  • Cover coughs and sneezes.

  • Clean and disinfect frequently touched surfaces daily, including tables, doorknobs, light switches, countertops, handles, desks, phones, keyboards, toilets, faucets, and sinks.

CDC guidance on the use of a face covering, whether by prefabricated mask or fashioned from cloth, is predicated on the growing evidence that asymptomatic and presymptomatic individuals infected with SARS-CoV-2 can transmit the virus to others in close proximity by coughing, sneezing, or speaking [54]. Therefore, anyone out in public should consider that he or she could, unwittingly, be an agent of transmission to others. The face covering serves as a means of source control, and although the primary function is to prevent inadvertent transmission to others, it may also provide a degree of barrier protection for the one wearing it. The CDC recommends wearing cloth face coverings in public settings in which other social distancing measures are difficult to maintain (e.g., grocery stores, pharmacies), especially in areas experiencing significant community-based transmission. Detailed guidance on the construction, proper usage, and cleaning of cloth face coverings is provided on the CDC website [12].

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