Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. In response to a 13-fold increase in the number of reported cases within the span of two weeks and active cases in more than 100 countries, the WHO reached a decision that the COVID-19 outbreak should be characterized as a pandemic.

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

Table of Contents


This outbreak is ongoing. As the situation evolves, the course is being revised to reflect new information. The last update was done May 28, 2021.


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 by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. 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. This course, The Coronavirus Disease (COVID-19) Pandemic, Approval #201004-1358, provided by NetCE, is approved for continuing education by the New Jersey Social Work Continuing Education Approval Collaborative, which is administered by NASW-NJ. CE Approval Collaborative Approval Period: June 1, 2020 through August 31, 2022. New Jersey social workers will receive 2 Non-Clinical CE credits for participating in this course. NetCE is accredited by the International Accreditors 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. NetCE designates this activity for 2 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-21-029-H04-P. 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. Social workers participating in this intermediate to advanced course will receive 2 Clinical continuing education clock hours. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 2 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 2 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to satisfy the Lifelong Learning requirements for the American Board of Ophthalmology's Maintenance of Certification program. It is the CME activity provider's responsibility to submit learning completion information to ACCME for the purpose of granting MOC credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. 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. NetCE is authorized by IACET to offer 0.2 CEU(s) for this program. AACN Synergy CERP Category A.

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 July 29,2025); 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 12/31/2023; 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;

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 2019–2020 global outbreak of novel human coronavirus (SARS-CoV-2) infection, 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. Differentiate between the common, ubiquitous strains of human coronavirus and novel (outbreak) strains with respect to epidemiology, modes of transmission, spectrum of illness, and public health implications.
  2. Characterize the clinical and public health experience gained from the two prior novel human coronavirus epidemics, SARS and MERS, and how that informs our understanding and response to the current pandemic.
  3. Recognize the clinical manifestations of COVID-19 and systemic complications associated with a dysregulated immune response, and discuss the dynamics of transmission and advise patients regarding prevention of infection, with special attention to those with risk factors for severe disease.
  4. Access and implement guideline recommendations for clinical assessment, diagnostic testing, appropriate isolation precautions, and monitoring of a patient with recent exposure to, suspected infection with, or newly diagnosed COVID-19.


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.

Technical Requirements

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



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. 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 were 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, the etiologic agent responsible for the Wuhan outbreak, is named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease caused by the infection 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. The precise origin and timing of initial human infection is unclear. According to CDC reports, virus sequences from imported cases in this country are similar to the one initially posted by China, indicating emergence of this virus from a point-source in Wuhan, China [12].

The rapid accumulation of many new COVID-19 cases in Wuhan City during the months of December 2019 and January/February 2020, combined with evidence of spread to nearby provinces in central China and reports of acute infection in healthcare workers, indicated that facile human-to-human transmission of SARS-CoV-2 was the key factor responsible for propagation of the outbreak. This has been proven true throughout the pandemic. During the first six months of 2020, outbreaks of COVID-19 spread to countries in every part of the world.


The incubation period of SARS-CoV-2 infection is 5 to 7 days on average, with a range of 2 to 14 days. It is estimated 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. Less common presenting symptoms include rhinorrhea, sudden loss of smell (anosmia) and/or taste (ageusia), and sore throat. Atypical presentations have been described whereby some patients experience diarrhea or nausea and vomiting prior to the onset of fever and respiratory symptoms and signs. As with other infections, elderly persons may present with weakness and confusion. Older adults and persons with medical comorbidities may have delayed onset of fever and respiratory symptoms [15].

In a study designed to better characterize the symptom profiles of patients with COVID-19 in the United States, especially among nonhospitalized patients, the CDC used an optional questionnaire to collect detailed information from a sample of confirmed COVID-19 cases reported from 16 participating states [60]. Among 164 symptomatic patients with onset of illness between January 14 and April 4, 2020, a total of 158 (96%) reported fever, cough, or shortness of breath. Of 57 hospitalized adult patients, 39 (68%) reported all three of these symptoms, compared with 25 (31%) of the 81 nonhospitalized adult patients. Each of the following symptoms was reported by more than half of patients: cough (84%), fever (80%), myalgia (63%), chills (63%), fatigue (62%), headache (59%), and shortness of breath (57%). Gastrointestinal symptoms were relatively common, most frequently diarrhea (38%) and least frequently vomiting (13%). Shortness of breath was more common in patients who required hospitalization (82%) than in nonhospitalized patients (38%). Anosmia and ageusia were reported by a higher percentage of nonhospitalized patients (22%) than hospitalized patients (7%) [60].

An array of cutaneous symptoms and signs has been described in patients with COVID-19. Although the exact frequency remains unknown, reports have ranged from 0.2%, early in the pandemic, to as high as 20.4% [15]. In addition to the exanthems common to many viral infections, pernio-like lesions have been described [105]. Pernio (chilblains) is a superficial inflammatory vascular response that occurs on acral skin, usually after cold exposure. In patients with COVID-19, these lesions appear as discolored edematous plaques on the toes and fingers. An international registry was organized early in the pandemic to characterize the diversity of dermatologic manifestations. In a study of 171 registry patients with confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%) [106]. Morbilliform rashes were often pruritic and involved the trunk. Pernio morphologies were often painful/burning and involved the hands/feet. Pernio-like lesions were generally observed in patients with mild disease, whereas retiform purpura was seen exclusively in critically ill patients. Cutaneous manifestations usually appeared at the onset of or after other COVID-19 symptoms. However, in 12% of cases skin lesions occurred before other COVID-19 symptoms or signs [106]. Images of cutaneous findings are available from the American Academy of Dermatology at https://www.aad.org/public/diseases/coronavirus/covid-toes.

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. In February 2020, the overall case fatality rate for confirmed cases of COVID-19 reported from China was approximately 3%. As the pandemic has progressed, reported case fatality rates have varied considerably among countries and regions, ranging from 3% to as high as 14%. Multiple factors account for this variance, including available health resources and access to care, differences in public health mitigation strategies, lack of uniformity in the way deaths are attributed to COVID, and the extent to which testing and contact tracing identifies asymptomatic infections. Based on reported cases and attributable deaths through mid-July, the COVID-19 case fatality rate in the United States is 3.6% [8].


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 severity of illness ranged from mild to critical with approximately the following distribution [15,23]:

  • Mild to moderate (mild symptoms up to mild pneumonia): 81%

  • Severe (dyspnea, hypoxia or >50% lung involvement on imaging): 14%

  • Critical (respiratory failure, shock, or multiorgan dysfunction): 5%

The majority of cases (81%) were characterized as mild, with no or mild pneumonia [23]. 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

Risk factors for severe disease include advanced age, obesity (body mass index ≥30), 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.

In June 2020, the CDC issued an epidemiologic report on 1,320,488 laboratory-confirmed COVID-19 cases in the United States and territories, reported to CDC between January 22 and May 30, 2020 [55]. Cumulative incidence (403.6 cases per 100,000 persons) was similar among males (401.1) and females (406.0), highest among persons 80 years of age or older (902.0), and lowest among children younger than 9 years of age (51.1). Among 599,636 cases with known information on both race and ethnicity, 36% of persons were non-Hispanic white, 33% were Hispanic, 22% were black, 4% were Asian, and 1.3% were American Indian or Alaska Native. Among 287,320 cases with sufficient data on underlying health conditions, the most frequently reported were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Overall, 184,678 (14%) patients were hospitalized, 29,837 (2%) were admitted to an ICU, and 71,116 (5%) died. The hospitalization rate was six times higher among patients with a reported underlying condition (45.4%) than among those without reported underlying conditions (7.6%). The mortality rate was 12 times higher among patients with reported underlying conditions (19.5%) compared with those with none reported (1.6%). Approximately 4% of reported cases were asymptomatic. Among 373,833 cases with data on individual symptoms, 70% noted fever, cough, or shortness of breath; 36% reported muscle aches; and 34% reported headache. Overall, 31,191 (8%) persons reported loss of taste or smell [55].

During the course of the COVID-19 pandemic in the United States, obesity has emerged as an important independent risk factor for severe disease, especially among adult patients younger than 60 years of age. Multiple reports, ranging from single-center studies to analyses of records from large patient care networks, have consistently found that severe obesity (body mass index >35) is associated with higher rates of hospitalization, respiratory failure, and mortality from COVID-19 [77,78]. The risk varies directly with degree of obesity and is independent of obesity-associated comorbidities. The impact is more striking among men than women. There are multiple mechanisms by which obesity may contribute to adverse outcomes in patients with COVID-19. In addition to obstructive pulmonary physiology and sleep apnea, severe obesity is associated with immune dysfunction (depression of anti-inflammatory signaling and increased pro-inflammatory signaling), alterations in vascular endothelium, and renin-angiotensin stimulation, which together may worsen lung inflammation and alveolar damage [78].

Although the absolute risk of severe COVID-19 is low among people of child-bearing age, pregnant women have a higher risk of severe illness and complications than nonpregnant women. Evidence for this comes from an analysis of 409,462 women (15 to 44 years of age) with symptomatic COVID-19 reported to the CDC between January 22 and October 3, 2020 [107]. Of the total, 23,434 women (5.7%) were pregnant at the time of infection. Pregnant women were admitted to an ICU more frequently than nonpregnant women (10.5 versus 3.9 per 1,000 cases) and were more likely to receive invasive ventilation (2.9 versus 1.1 per 1,000 cases) or extracorporeal membrane oxygenation (ECMO) (0.7 versus 0.3 per 1,000 cases). The mortality rate was 1.5 per 1,000 cases for pregnant women compared with 1.2 per 1,000 cases for nonpregnant women. Older pregnant women (35 to 44 years of age) with symptomatic COVID-19 were nearly four times more likely to require invasive ventilation and twice as likely to die than were nonpregnant women of the same age [107].


At the cellular level, infection by a virus requires some affinity of the virion for the host cell combined with 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].

While headache and confusion are seen in some patients presenting with severe COVID-19 there is no evidence that SARS-CoV-2 causes primary infection of the central nervous system (e.g., encephalitis). In an autopsy series of 18 consecutive patients who died 0 to 32 days after onset of COVID-19 histopathologic examination of brain specimens did not show encephalitis or other specific brain changes referable to the virus [56].


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.


Convalescence following SARS-CoV-2 infection follows a variable course, and symptomatic recovery from severe COVID-19 may take weeks to months. A report from Italy describes a cohort of 143 patients with moderate-to-severe COVID-19, 87% of whom had persistent symptoms two months or more after discharge from hospital [68]. The mean duration of hospitalization was 13.5 days; 73% had evidence of interstitial pneumonia, 15% received noninvasive respiratory support, and 5% required mechanical ventilation. Follow-up clinical assessment was conducted a mean of 60 days after onset of the first COVID-19 symptom. At evaluation, 18 (13%) were symptom free; of the remaining participants, 32% had one or two symptoms and 55% had three or more symptoms. The most common persistent symptoms were fatigue (53%), dyspnea (43%), joint pain (27%), and chest pain (22%). None had fever or signs of acute illness. Of the total, 44% reported persistence of the decline in quality of life imposed by COVID-19.

A multistate survey conducted by the CDC found that persistent symptoms three weeks after diagnosis of SARS-CoV-2 infection was common among outpatients with milder illness [69]. Of 270 respondents who were symptomatic at diagnosis, 95 (35%) had not returned to their usual state of health 14 to 21 days from the test date, including 26% of those 18 to 34 years of age and 47% of those older than 50 years of age. Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview [69]. A cohort study of long-term symptoms among healthcare professionals found that after mild COVID-19, 26% of participants reported at least one moderate-to-severe symptom lasting two months and 15% reported at least one moderate-to-severe symptom lasting eight months [108]. The most common symptoms were anosmia, fatigue, ageusia, and dyspnea. These studies show that low-risk adults with mild COVID-19 commonly experience a slow convalescence with diverse long-term symptoms that may disrupt work and social activity.


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 (IVIG); 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. A targeted surveillance for MIS-C in pediatric health centers across the United States identified 186 cases in 26 states during a five-week period between March and May [61]. The median age was 8.3 years, 165 (62%) were male, and 131 (70%) tested positive for SARS-CoV-2 infection by rT-PCR or serologic antibody test. The clinical features in the MIS-C cases investigated by the New York Department of Health have been reported [62]. Of 191 patients in the study, all presented with fever and tachycardia, 80% were admitted to the ICU, and 62% required vasopressor support. Abdominal complaints and gastrointestinal symptoms were common (62%), as was rash (60%), conjunctival injection (56%), and mucosal changes (27%). Laboratory markers of inflammation included elevated levels of C-reactive protein in all patients, positive D-dimer (91%), and elevated troponin (71%). Evidence of myocarditis was present in 53% of patients. At least one echocardiogram was obtained for 93 patients (94%); 51 (52%) had some degree of ventricular dysfunction, 32 (32%) had pericardial effusion, and 9 (9%) had a documented coronary artery aneurysm. The majority of patients were treated with IVIG and/or glucocorticoids in addition to vasopressors. The median duration of hospitalization was six days. Two patients died. As in Italy, MIS-C cases in New York followed the peak of the COVID-19 epidemic in that state and nearly all patients tested seropositive for recent SARS-CoV-2 infection [62].

Early recognition of MIS-C and prompt referral to an inpatient unit of care is essential. Approximately 50% to 60% of children and adolescents with MIS-C present with signs of cardiovascular involvement leading to warm shock and a need for vasopressor support, compared with about 5% of children with Kawasaki’s disease [61,62]. Cardiac abnormalities are common, including a 9% incidence of coronary artery aneurysm. Echocardiography is recommended in all patients presenting with MIS-C, and until more is known about long-term cardiac sequelae of MIS-C, providers should consider follow-up imaging at one to two weeks and four to six weeks after treatment [61]. 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 IVIG. 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.


There are two types of diagnostic tests for determining active SARS-CoV-2 infection: molecular tests that use the real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect viral RNA, and antigen tests that detect specific proteins on the surface of the virion. The most widely used and reliable of these is RT-PCR, which can be applied to mucus specimens from the upper or lower respiratory tracts and to serum samples. SARS-CoV-2 viral RNA can be detected more readily in secretions taken by swab from the nasopharynx than in samples obtained by throat swab [15]. RT-PCR testing of deep nasopharyngeal swab specimens has become the standard procedure for the laboratory diagnosis of active SARS-CoV-2 infection [79,80]. This test is highly accurate and results can be obtained within one or two days. Antigen tests for the diagnosis of active SARS-CoV-2 infection are also performed on nasal or throat swab specimens and have the advantage of providing results much faster than the RT-PCR test (often less than one hour) [80]. However, antigen tests are less sensitive than molecular tests, which detect viral nucleic acids, and the amount of antigen in a sample decreases as the duration of illness increases. Specimens collected after day 7 of illness are considered more likely to be negative compared to a RT-PCR assay [80]. Thus, a positive antigen test result is highly reliable, but a negative test may need to be confirmed with RT-PCR.

The availability of safe, reliable, and timely SARS-CoV-2 diagnostic testing is essential for effective public health measures to control the COVID-19 pandemic. The nasopharyngeal swab specimen collection method involves close interaction between healthcare workers and patients, requires personal protective equipment, and entails a measure of discomfort for the test subject—all disadvantages to community drive-through diagnostic testing and contact tracing. Self-collected saliva could prove to be a simple, less expensive alternative that alleviates the need for personal protective equipment. There is growing evidence that the molecular test detection rate in saliva specimens from symptomatic and asymptomatic SARS-CoV-2 infected individuals is comparable to deep nasopharyngeal swab specimens. Yale investigators found that among 70 inpatients with confirmed COVID-19 and 495 asymptomatic healthcare workers, the use of self-collected saliva specimens for SARS-CoV-2 molecular diagnostic testing compared favorably with nasopharyngeal swab specimens collected by personnel [81]. In another study of 354 patients presenting to a drive-through testing center with at least one symptom consistent with COVID-19, the SARS-CoV-2 positivity rate was 22.6% for nasopharyngeal swab specimens compared with 22.9% for salivary specimens [82]. Between nasopharyngeal swab specimens and salivary specimens, the positive percent agreement was 93.8% and the negative percent agreement 97.8%.

COVID-19 diagnostic testing in the United States is available at all state and local public health laboratories and at commercial laboratories authorized by the U. S. Food and Drug Administration (FDA) [16,80]. Although in some cases viral nucleic acid can be detected in nasopharyngeal specimens for weeks after infection, studies show that SARS-CoV-2 viral cultures are usually negative within 8 to 10 days after onset of infection. Shedding of live virus may persist longer in severely ill, hospitalized patients (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.


SARS-CoV-2 antibody assays are useful for epidemiologic investigation of prevalence in the general population and to identify groups at risk for infection. Unlike RT-PCR and antigen detection tests that identify acute infection, antibody tests determine whether there is evidence of prior infection, even if the person being tested never developed symptoms. The FDA has not authorized the use of serology to detect active SARS-CoV-2 infection, and the CDC does not recommend antibody testing for routine diagnosis of acute infection [79]. However, antibody testing in conjunction with viral RT-PCR may be used to support clinical assessment of persons who present late in the course of COVID-19, or a patient suspected of having a post-infectious syndrome caused by recent SARS-CoV-2 infection (e.g., MIS-C).

Following SARS-CoV-2 infection, IgM and IgG antibodies appear almost simultaneously in the serum within two to three weeks after symptom onset, at which time infectiousness likely is greatly decreased and some degree of immunity from future infection has developed [83]. Thus, early IgM assay without IgG testing is of little value. The duration of detectable antibody is unknown, and the absence of detectable IgM or IgG antibodies does not necessarily rule out previous infection. Several commercially marketed serologic assays for SARS-CoV-2 have emergency use authorization (EUA) by the FDA, which has independently reviewed their performance. A list of all tests authorized for emergency use under EUA is maintained on the FDA website [84]. All currently authorized tests are qualitative (providing a result that is positive, negative, or indeterminate) rather than quantitative (providing a quantitative assessment of antibody levels). It is important to minimize false-positive test results by choosing an assay with high specificity and by testing individuals with an elevated likelihood of previous exposure to SARS-CoV-2 [83].


There is no established antiviral therapy of proven efficacy for the treatment of COVID-19. Care is supportive and should be provided in a controlled environment under Isolation Precautions. Effective vaccines for prevention of SARS-CoV-2 began distribution at the end of 2020.

After China published the viral genome on a public database in mid-January 2020, the National Institutes of Health immediately began research efforts to improve diagnostics, identify effective treatments, and develop vaccines against SARS-CoV-2 [10]. The CDC and commercial laboratories has already developed a reliable diagnostic test based on genetic sequencing of the virus. 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 or outcome with lopinavir/ritonavir treatment [20].

Following successful development and clinical trials of vaccines against SARS-CoV-2 in the summer and fall of 2020, an accelerated effort was launched in the United States and other countries to implement an immunization strategy against COVID-19.


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]. An early report described 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].

On October 22, 2020, the FDA approved remdesivir for use in adult and pediatric patients 12 years of age and older (weighing at least 40 kg) for the treatment of COVID-19 when hospitalization is required [90]. The approval was supported by an analysis of three randomized, controlled clinical trials that showed remdesivir shortens the time to recovery and decreases progression of respiratory illness in adult patients hospitalized with COVID-19 [90]. The data analysis included final results from an NIH-sponsored study, a double-blind, placebo-controlled remdesivir trial involving hospitalized patients with moderate-to-severe COVID-19 [35]. In this study, a total of 1,062 patients were randomized to receive intravenous remdesivir or placebo for 10 days. The primary outcome was time to recovery, defined by discharge from hospital or resolution of need for clinical care (hospitalization for infection-control purposes only). The median time to recovery was 10 days for the remdesivir group, compared with 15 days for the placebo group. In an analysis of secondary outcomes, patients who received remdesivir were more likely than those who received placebo to have clinical improvement at day 15. The proportion of serious adverse events related to respiratory failure and the need for higher levels of respiratory support were lower among patients in the remdesivir group. Kaplan-Meier estimates of mortality showed a trend in favor of the treatment group: 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% versus 15.2% by day 29 [35].

As of October 9, 2020, the NIH Treatment Guidelines Panel (NIH Panel) recommends remdesivir for treatment of COVID-19 in hospitalized patients with SpO2 <94% on ambient air or those who require supplemental oxygen, and in patients who need any form of mechanical ventilatory support [57]. The recommended duration of treatment and the advisability of combining remdesivir with a glucocorticoid vary in relation to severity of illness and level of ventilatory support. For patients who require supplemental oxygen but have no need for delivery of oxygen through a high-flow device, the recommended regimen is remdesivir 200 mg IV for one day, followed by 100 mg daily for four days or until hospital discharge, whichever comes first. The duration of remdesivir therapy may be extended up to 10 days when there is no substantial clinical improvement by day 5.


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 issued an EUA that allowed chloroquine phosphate or hydroxychloroquine sulphate to be used for the treatment of patients hospitalized with COVID-19 when clinical trials are not available or participation is not feasible [36]. However, this letter was revoked in June 2020 [58]. 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.

An 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. Thus, 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].

Randomized, controlled clinical trials to assess efficacy of hydroxychloroquine in patients hospitalized with COVID-19 have not shown a benefit. A multicenter study of hospitalized patients with mild-to-moderate COVID-19 found that hydroxychloroquine, alone or in combination with azithromycin, was no more effective than standard care in improving clinical status at 15 days [70]. Preliminary analysis of data from a multicenter, randomized trial in the United Kingdom found no reduction in 28-day mortality among those treated with hydroxychloroquine when compared with the control group [71]. Hydroxychloroquine use was associated with increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation. An NIH-sponsored, controlled clinical trial was halted (after the fourth interim analysis) because hydroxychloroquine was found unlikely to be beneficial to hospitalized patients with COVID-19 [72]. Whether hydroxychloroquine has a role in outpatient treatment of mild COVID-19, or would be effective as primary or secondary prophylaxis against SARS-CoV-2 infection, remains to be determined by randomized controlled trials designed to assess these possibilities.

On June 15, 2020, the FDA revoked the EUA that allowed for chloroquine and hydroxychloroquine donated to the Strategic National Stockpile to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was not available or feasible [58]. This decision was based on an ongoing analysis of emerging data indicating that these drugs are unlikely to be effective for patients hospitalized with COVID-19. As of July 2020, the NIH Panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 except in a clinical trial [57].

Approaches to Disease Modification

Severe SARS-Cov-2 infection results in progressive interstitial-alveolar pneumonia and respiratory failure. The disease process is closely linked to activation of the innate immune system and dysregulation of adaptive immune responses, with release of proinflammatory cytokines and chemokines. Death from COVID-19 is often preceded by 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 seek to modify disease progression and prevent or ameliorate pulmonary and systemic complications of cytokine storm, in hope of reducing mortality from COVID-19.

COVID-19 Convalescent Plasma

Passive immunization with plasma obtained from surviving patients has been used in the past to treat life-threatening infections absent specific therapy. There is emerging evidence that intravenous transfusion of convalescent plasma with high-titer antibody directed against SARS-CoV-2 is effective in reducing mortality in hospitalized patients with COVID-19 pneumonia. 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].

Convalescent plasma treatment has been widely utilized in the United States since early April 2020 under the Mayo Clinic's Expanded Access Protocol (EAP). A report from the Mayo EAP involving 35,322 registered patients found that plasma infusion is relatively safe and may reduce COVID-19 mortality when administered early after hospitalization [76]. A subset analysis showed a gradient of mortality in relation to IgG antibody levels in transfused plasma. The risk of dying from COVID-19 was lower among patients who received convalescent plasma units containing high titer anti-SARS-CoV-2 antibody than among those who received plasma containing low antibody levels. The pooled relative risk reduction among patients transfused with high antibody level plasma units versus low-level antibody plasma was 35% at 7 days and 23% at 30 days. The Mayo EAP report is an analysis of registry data and not a randomized controlled study.

On August 23, 2020, the FDA granted an EUA to COVID-19 convalescent plasma for treatment of patients hospitalized with COVID-19 [73]. This decision was based on historical evidence derived from the use of plasma in prior outbreaks of respiratory virus infection, small case series, and non-randomized clinical trials conducted during the current outbreak. As of December 2020, the only double-blind, placebo-controlled clinical trial of convalescent plasma did not demonstrate a reduction in mortality or improvement in other clinical outcomes [93]. In this study, 333 patients with severe COVID-19 pneumonia were randomized in a 2:1 ratio to receive convalescent plasma (228 subjects) or placebo (105 subjects). Of the total, 68% were men and 65% had a coexisting condition at entry into the trial. The median time from onset of COVID-19 symptoms to enrollment was eight days. More than 90% were receiving oxygen and glucocorticoids at the time of entry into the trial. The infused convalescent plasma had a median titer of 1:3,200 of total SARS-CoV-2 antibodies. At 30 days, the clinical status of patients in the convalescent plasma group did not differ significantly from that of patients in the placebo group. The proportion of ICU admissions and invasive ventilatory support requirements were similar in both groups. Overall mortality was 11.43% in the placebo group and 10.96% in the convalescent plasma group. In a subset analysis, no differences favoring convalescent plasma were noted in a group of 39 patients who received the intervention within 72 hours of symptom onset [93]. Of note, all patients in this study had signs of severe pneumonia; thus, no firm conclusion can be drawn as to the potential efficacy of COVID-19 convalescent plasma initiated earlier in the disease. At present, IDSA and NIH guidelines recommend that convalescent plasma therapy be used only in the context of a clinical trial [10,57].

Although convalescent plasma therapy has no clear benefit for hospitalized patients with COVID-19 pneumonia, treatment with high-titer convalescent plasma early in the course of illness has been shown to reduce the risk of progression to severe disease. Evidence for this comes from a randomized, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 administered to older adults within 72 hours after onset of mild COVID-19 symptoms. In the cohort of patients who received high-titer plasma therapy, 13 of 80 (16%) patients progressed to severe respiratory disease, compared with 25 of 80 patients (31%) who received placebo [109]. This corresponds to a relative risk reduction of 48%. The study population consisted of adults 75 years of age or older, or between 65 and 74 years of age with at least one coexisting condition.

The FDA provides a COVID-19 convalescent plasma fact sheet with guidance for healthcare providers [73]. Patients recovering from COVID-19 who wish to donate convalescent plasma can also find information at the FDA website [28]. Persons who have fully recovered from COVID-19 are candidates for plasma donation. 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 EUA 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.

Monoclonal Antibody to SARS-CoV-2

Modern immunologic techniques enable the identification of pathogen-specific memory B cells and recovery of immunoglobulin genes that can be expressed to produce monoclonal antibodies [85]. The clinical application of monoclonal antibodies has been relatively safe, and FDA-approved monoclonal antibody products are available to treat or prevent respiratory-syncytial virus, anthrax, and Clostridioides difficile. Several laboratories have used B cells from patients recovering from COVID-19 to produce neutralizing monoclonal antibodies to SARS-CoV-2. These antibodies are directed against surface spike glycoprotein, preventing entry of virus into host cells. Passive immunization with monoclonal antibodies has potential for prevention of COVID-19 in vulnerable people and for early augmentation of the immune response (to block disease progression) in COVID-19 patients at risk for severe illness. Given the long half-life of immunoglobulin (approximately three weeks), a single infusion of monoclonal antibodies to SARS-CoV-2 should suffice for either prevention or treatment of COVID-19 [85]. In a phase 2 randomized clinical trial involving outpatients with mild or moderate COVID-19, a single infusion of bamlanivimab (a monoclonal neutralizing antibody) was associated with rapid decline in viral load and reduced need for further medical attention [94]. Subsequent COVID-related hospitalization or visit to an emergency room was required in 1.6% of patients in the monoclonal antibody group, compared with 6.3% in the placebo group.

Two monoclonal antibody preparations, bamlanivimab and combination casirivimab plus imdevimab, have received FDA authorization (EUA) for use in adults and children older than 12 years of age with mild-to-moderate COVID-19 who are at high risk of progressing to severe disease and/or hospitalization. In general, this is an outpatient therapy reserved for at-risk symptomatic patients and should be administered soon after confirmation of SARS-CoV-2 infection and within 7 to 10 days of symptom onset. Patients with symptomatic COVID-19 who meet one of the following criteria are eligible for treatment:

  • Body mass index >35

  • Diabetes

  • Chronic kidney disease

  • Immunosuppressive disease or current immunosuppressive treatment

  • Age 65 years or older or 55 years or older with underlying cardiovascular disease, hypertension, or chronic lung disease

Fact sheets for healthcare providers, including patient selection criteria, authorized dosage, and treatment initiation, are provided at the FDA website [95,96].


Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been used to mitigate cytokine storm syndrome associated with COVID-19. A retrospective cohort study of hospitalized patients who required ICU support found that treatment with tocilizumab was associated with reduced mortality [74]. Of 630 patients selected for analysis, 358 (57%) died—102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. The primary multivariable Cox regression analysis showed an association between receiving tocilizumab and decreased hospital-related mortality. This association was also noted among subgroups requiring mechanical ventilation and with baseline C-reactive protein of 15 mg/dL or higher. In contrast to findings from this and other observational studies of COVID-19 pneumonia, randomized clinical trials have not reported a mortality benefit from tocilizumab therapy [91]. Tocilizumab has been reported to reduce the requirement for mechanical ventilation in some patient populations, thereby alleviating the demand on ICU-level care for management of severe COVID-19. A published editorial assessment concluded that newly released randomized trials suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy [91]. As of October 2020, the NIH Panel recommends against the use of tocilizumab for COVID-19 except in the context of a clinical trial [57].


Preliminary results of a large multicenter therapeutic trial show that dexamethasone (a glucocorticoid) improves survival in patients hospitalized with COVID-19 who require some degree of respiratory support [63]. In this ongoing study platform, patients are randomly assigned to a group of different therapies and efficacy is assessed using a single end-point: mortality within 28 days after randomization. A total of 2,104 patients were assigned to receive dexamethasone at a dose of 6 mg daily, and 4,321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1,110 patients (25.7%) in the usual care group died within 28 days after randomization. The observed differences in mortality varied according to the level of respiratory support patients required upon entry to the study. Among patients receiving mechanical ventilation, the 28-day mortality was significantly lower in the dexamethasone group (29.3%) than that in the usual care group (41.4%). Among patients receiving supplemental oxygen without mechanical ventilation, the observed benefit was less pronounced but also significant, 23.3% in the dexamethasone group and 26.2% in the usual care group. There was no demonstrable benefit from dexamethasone treatment in patients who did not require oxygen. In light of this report, the NIH Panel recommends using dexamethasone (at a dose of 6 mg per day for up to 10 days) for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who require supplemental oxygen but not mechanical ventilation [57].

If dexamethasone is not available, equivalent doses of another glucocorticoid may be used, such as prednisone 40 mg/day or methylprednisolone 32 mg/day. Dexamethasone is the preferred glucocorticoid to use in pregnant women with COVID-19 who require respiratory support, because of the potential benefit of decreased maternal mortality and the known low risk of fetal adverse effects associated with short-course maternal dexamethasone therapy [57]. Patients receiving dexamethasone at the time of hospital discharge should be given a prescription to complete the specified 10-day course. The Panel recommends against using dexamethasone for the treatment of COVID-19 in patients who do not require supplemental oxygen.

Potential adverse effects of glucocorticoid use include hyperglycemia and opportunistic infection. Clinicians should be aware that Strongyloides hyperinfection syndrome has been reported as a complication of modest-dose and short-duration dexamethasone regimens [75]. Patients who may be at risk are those who have previously resided in South America, the Caribbean, the Middle East, Africa, or Asia. Clinical clues to subclinical or unrecognized Strongyloides infection include peripheral eosinophilia and unexplained gram-negative bacteremia [75].


The effort to develop vaccines against coronavirus began following the 2002–2004 SARS outbreak, but was halted when SARS-CoV began to disappear from the human population. These earlier preclinical studies did clarify the antigenic target for coronavirus and laid the groundwork for current SARS-CoV-2 vaccine development. Coronaviruses encode for one large surface glycoprotein, the spike protein, which is responsible for receptor binding and membrane fusion [97]. As noted, SARS-CoV-2 spike protein binds to ACE2 receptors on host cells and facilitates release of the viral genome into the cytoplasm for replication of new virions. Antibodies that bind to the spike protein prevent attachment and neutralize the virus [97]. On the basis of these observations, the spike protein is an antigenic target for development of vaccines against SARS-CoV-2.

As of December 2020, more than 180 potential vaccines were in preclinical studies worldwide, and several candidate vaccines had entered into clinical trials designed to assess immunogenicity and safety. The range of vaccine platforms includes inactivated-virus and live-virus vaccines, recombinant protein vaccines, vectored vaccines, and novel RNA and DNA vaccines [97]. Three vaccines showed promising early results and were advanced to phase 3 clinical trials in August 2020; two are messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna, and the third is an adenovirus-vectored vaccine developed by Astra-Zeneca and the University of Oxford. Pfizer and the German company BioNTech have reported preliminary results of an ongoing phase 1 mRNA vaccine trial in 45 healthy adults 18 to 55 years of age. Participants received one of three vaccine doses (25, 100, or 250 mcg) given as two inoculations 28 days apart [64]. All participants developed an immune response. Following the second dose, antibody titers increased and serum neutralizing antibody activity was comparable to levels measured in a control panel of SARS-CoV-2 convalescent serum. Adverse events such as fatigue, myalgia, feverishness, and pain at injection site were reported in half the participants, more commonly after the second injection and at the highest dose. The study group concluded that immunogenicity and safety findings supported expansion of the trial to include older adults and advancement of this vaccine to later-stage clinical trials. In a follow-up report of 40 older adults (50% 56 to 70 years of age and 50% older than 70 years of age) administered the mRNA vaccine, the safety profile and immunogenicity were comparable to results in the younger cohort of participants [86]. Enrollment in a phase 3 trial began in late July 2020.

A report from the University of Oxford described early results of a clinical trial using a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCov-19) that expresses a full-length version of the SARS-CoV-2 spike protein [65]. In a phase 1/2 randomized controlled trial, 1,077 healthy adults received either the candidate vaccine or a meningococcal conjugate vaccine as control. Following a single dose, ChAdOx1 nCoV-19 elicited spike-specific T-cell responses that peaked on day 14 and measurable anti-spike IgG antibody by day 28. Strong humoral and cellular immune responses persisted at day 56 of the ongoing trial. Neutralizing antibody was detected in 32 (91%) of 35 participants after a single dose, and in 10 (100%) of 10 participants who received a booster dose. Adverse events such as discomfort at injection site, fever, malaise, and headache were common but mild or moderate and self-limiting. There were no serious adverse reactions. Progression into phase 2 and 3 trials is underway, recruiting older age groups with comorbidities, healthcare workers, and those at higher risk for SARS-CoV-2 exposure [65].

COVID-19 mRNA Vaccine Availability

COVID-19 mRNA vaccine represents a new vaccine technology that has important public health advantages. The vaccine can be produced completely in vitro, which enables facile purification and rapid production of individual vaccine doses. The COVID-19 mRNA vaccine consists of a nucleoside-modified messenger RNA inside a lipid-laden nanoparticle. The vaccine mRNA encodes for SARS-CoV-2 surface spike protein. The lipid envelope not only facilitates vaccine delivery into host cells but also enhances stability and may augment the immune response. Following intramuscular inoculation, host myocytes utilize vaccine mRNA to express SARS-CoV-2 antigen on cell surfaces, which in turn elicits neutralizing antibody and cellular immune responses to SARS-CoV-2. The vaccine mRNA does not enter the host cell nucleus and cannot become part of the vaccinee’s own DNA.

Preliminary results of phase 3 clinical trials demonstrate that both the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines are safe and 94% to 95% effective [98,99]. In the Pfizer-BioNTech vaccine trial, 43,448 adults were randomized to receive vaccine (21,720 participants) or placebo (21,728 participants) in two doses 21 days apart [98]. The primary outcomes were safety and the incidence of symptomatic COVID-19 at least seven days after the second dose. The interim analysis included the first 170 cases of symptomatic COVID-19 diagnosed in the study population and covered a median of two months of safety data. Of the total, eight cases of COVID-19 were observed in the vaccine group and 162 cases in the placebo group. This corresponds to a vaccine efficacy of 95.0%. Vaccine efficacy was similar across subgroups defined by age, sex, race, body mass index, and coexisting medical conditions. Ten cases of severe COVID-19 occurred with onset after the first dose, of which nine were in placebo recipients. Post-vaccination reactions included mild-to-moderate localized pain at the injection site and transient systemic reactions such as fatigue, fever, and headache. Systemic reactions occurred more commonly in younger vaccine recipients (16 to 55 years of age) and after the second dose [98]. The Moderna phase 3 vaccine trial results were equally favorable [99]. In this trial, 30,420 adult participants were randomly assigned to receive either two doses of vaccine or placebo 28 days apart. Of 196 confirmed cases of symptomatic COVID-19 with onset at least 14 days after the second inoculation, 185 cases were in the placebo group and 11 in the vaccine group, a vaccine efficacy of 94.1%. Severe COVID-19, including one fatality, occurred in 30 participants, all of whom were in the placebo group. Transient local and systemic post-vaccination reactions occurred commonly; no safety concerns were identified [99]. In mid-December 2020, following independent verification of safety and efficacy data, the FDA issued an EUA to the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines for use in adults and older adolescents.

COVID-19 mRNA Vaccine Availability

In February 2021, Johnson and Johnson (Janssen Pharmaceuticals) received an EUA for use of the Janssen COVID-19 vaccine in adults [110]. This is a recombinant, replication-incompetent adenovirus vector vaccine encoded for the SARS-CoV-2 prefusion spike glycoprotein. Based on interim data from an international phase 3 clinical trial, a single dose of Janssen COVID-19 vaccine is highly effective in preventing COVID-19-associated hospitalization and death [110]. The phase 3 study enrolled 43,783 participants across three regions, 44% from United States, 41% from Latin America, and 15% from South Africa. One-third of the participants were older than 60 years of age and 41% had underlying chronic health conditions. At 14 days following vaccination, the Janssen vaccine was 66% effective in preventing symptomatic COVID-19. After 28 days, the vaccine was 85% effective against severe disease and 93% effective in preventing hospitalization. Among participants in South African, where 95% of COVID-19 cases were caused by the B.1.351 variant, vaccine efficacy against severe disease was 89%. There were no COVID-19 deaths in the vaccine group compared with seven in the placebo group. Vaccine administration side effects were mild-to-moderate, and adverse events were rare and manageable; no anaphylaxis was encountered [110].

Vaccine Distribution

Because initial supplies of vaccine are limited, the Advisory Committee on Immunization Practices and the CDC have provided interim recommendations for allocation of COVID-19 vaccines, updated January 1, 2021 [100]. The recommended plan calls for prioritization of vaccine distribution based upon risk of exposure to SARS-CoV-2 and potential for severe illness. In Phase 1a, healthcare workers and residents and staff of long-term care facilities are to be offered vaccination. The next priority group (Phase 1b) consists of front-line essential workers (e.g., first-responders, teachers, Postal Service employees, grocery workers) and people older than 75 years of age. In Phase 1c, vaccine should be offered to persons 65 to 74 years of age and 14 to 64 years of age with high-risk conditions, and other essential workers. Phase 2 includes all other persons 16 years of age and older who were not offered the vaccine in Phase 1.

The ACIP has issued interim considerations for the use of Pfizer-BioNTech, Moderna, and Janssen (Johnson & Johnson) COVID-19 vaccines, available at the CDC website [101]. This guidance includes vaccine dose, timing of second inoculation, contraindications, anticipated side effects, and COVID-19 vaccination of pregnant persons and those with underlying medical conditions. Adolescents 16 to 17 years of age are included among those eligible to receive the Pfizer-BioNTech COVID-19 vaccine under the EUA. Providers should counsel vaccine recipients to expect local reactions (e.g., injection site pain, swelling, erythema, localized axillary lymphadenopathy) and systemic symptoms such as fever, fatigue, headache, or myalgias. Most post-vaccination symptoms are mild-to-moderate and resolve within one to three days of onset.

Data from clinical trials indicate that it is safe to offer vaccination to persons with evidence of a prior SARS-CoV-2 infection, and the CDC recommends doing so 90 days or more after infection [101]. Interestingly, the natural immunity that follows SARS-CoV-2 infection is greatly enhanced by vaccination. In one study, anti-spike antibody titers increased more than 140-fold from peak pre-vaccine levels following a single dose of mRNA vaccine [111]. In a small cohort of persons previously infected, a single dose of vaccine was also shown to substantially increase neutralizing activity against the important SARS-CoV-2 variants circulating in the United States [112].

COVID-19 Vaccines and Pregnancy

As noted, observational data demonstrate that pregnant persons have an increased risk of severe illness and complications from COVID-19, including ICU admission and mechanical ventilation [107]. Related concerns include the possibility of increased risk for adverse pregnancy outcomes (e.g., pre-eclampsia, coagulopathy, preterm birth) [101]. Any of the currently authorized COVID-19 vaccines can be administered to pregnant or lactating people; the ACIP does not state a product preference [101]. Data on the safety of COVID-19 vaccines in pregnant people are limited. Based on current knowledge, experts believe that COVID-19 vaccines are unlikely to pose a risk to pregnant persons or the fetus because the currently authorized COVID-19 vaccines are non-replicating vaccines and cannot cause infection in either the mother or fetus [101]. No reproductive, fetal developmental, or safety concerns were demonstrated in preclinical vaccine studies in animals, nor were any adverse pregnancy-related outcomes, including fetal outcomes, determined to be related to previous use of an adenovirus vector platform in a large-scale Ebola virus vaccine trial [101]. Clinical trials to evaluate the safety and efficacy of COVID-19 vaccines in pregnant people are underway, and surveillance programs are in place to monitor outcomes in pregnant persons who choose to receive vaccination.

Pregnant people may choose to receive a COVID-19 vaccine. A conversation between the patient and clinical team may assist with decisions about the use of a COVID-19 vaccine, though a discussion with a healthcare provider is not required before vaccination [101]. When making a decision, patient and provider should consider the level of SARS-CoV-2 community transmission, the patient’s personal risk of contracting COVID-19, the risks of COVID-19 to the patient and potential risks to the fetus, the efficacy and side effects of the vaccine, and the limited data about the vaccine use during pregnancy [101]. Pregnant persons who choose to receive COVID-19 vaccine are encouraged to enroll in the CDC's v-safe tool, a registry established to follow outcomes among people who are vaccinated [113]. As of April 12, 2021, no specific safety signals have been observed among pregnant vaccine recipients included in the v-safe registry.

Adverse Reactions to COVID-19 mRNA Vaccines

Immediate allergic reactions to vaccination were not observed during clinical trials, in part because potential participants who had experienced reactions to vaccines were excluded. However, according to a review of SARS-CoV-2 vaccine safety, several cases of anaphylaxis associated with the Pfizer mRNA vaccine have been reported following vaccination of 2 million healthcare workers in the United States [102]. Vaccine-associated anaphylaxis has been a rare event, at about one case per million injections, for most known vaccines. Anaphylaxis associated with use of the Pfizer mRNA vaccine is approximately 1 in 100,000 inoculations—10 times higher [102]. The explanation for this is unclear. One component unique to mRNA vaccines is a polyethylene glycol (PEG) 200 lipid conjugate used to stabilize the nanoparticle carrier system. PEG is a stabilizing compound commonly used in medications and other products and has been implicated in IgE-mediated reactions and recurrent anaphylaxis [102]. This has raised concern that individuals sensitized by past exposure to PEG (or its polysorbate derivative) in commercial products may be at risk of anaphylactic reactions from mRNA vaccination. Anaphylaxis is an acute allergic reaction that can lead to upper airway obstruction, bronchospasm, and circulatory collapse. Prompt recognition and treatment with epinephrine is necessary to prevent life-threatening complications.

A detailed discussion of contraindications and precautions to be observed with mRNA vaccine administration is included in the guidance provided by the CDC [101]. The history of any one of the following reactions is considered a contraindication to vaccination with either the Pfizer-BioNTech or Moderna COVID-19 vaccines [101]:

  • Severe allergic reaction (e.g., anaphylaxis) after a previous dose of an mRNA vaccine or any of its components

  • Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG)

  • Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with the vaccine ingredient PEG)

Persons with an immediate allergic reaction to the first dose of an mRNA vaccine should not receive additional doses of either of the mRNA COVID-19 vaccines [101]. Healthcare providers who participate in mRNA vaccine administration should be familiar with signs and symptoms of hypersensitivity reactions and have access to medications and supplies needed for assessing and managing anaphylaxis. The CDC has provided interim guidance on preparation for the potential management of anaphylaxis after COVID-19 vaccination [103].

Delayed-onset local reactions have been reported after mRNA vaccination in some individuals beginning a few days through the second week after the first dose [101,114]. The suspected cause is delayed-type or T-cell-mediated hypersensitivity, and reactions resolve within a few days. In a small series report, the recurrence rate following the second dose was less than 50% [114]. Vaccinees with only a delayed-onset local reaction (e.g., erythema, induration, pruritis) around the injection site do not have a contraindication or precaution to the second dose of vaccine. The CDC recommends these individuals receive the second dose using the same vaccine product as the first dose at the recommended interval, preferably in the opposite arm [101].

Immune Thrombotic Thrombocytopenia and Adenovirus-Vectored Vaccines

On April 13, 2021, after more than 6.8 million doses of the Janssen COVID-19 vaccine had been administered in the United States. the FDA placed a pause on use of this vaccine while the CDC investigated six reports of severe intravascular clotting events that occurred within two weeks following vaccination [127]. In these cases, a rare form of blood clot (cerebral venous sinus thrombosis) combined with thrombocytopenia was observed between the 6th and 13th day after vaccination. All cases were women 18 to 48 years of age, one of whom died. The pause was for purposes of further analysis and so health professionals could become familiar with the diagnostic and management implications. Treatment of this type of clotting disorder is different from treatment that might typically be administered to patients with thrombosis. Usually, the anticoagulant drug heparin is used to treat blood clots. However, in this setting the administration of heparin may be dangerous, and alternative therapies are needed [127]. The risk of cerebral venous thrombosis following Jenssen COVID-19 vaccination is approximately 1 in 1,000,000 vaccinees. AstraZenica COVID-19 vaccine, the other primate adenovirus-vectored vaccine used in Europe, has also been linked to thrombotic events in vaccinees. In two separate reviews (11 cases from Germany and Austria, and 5 cases from Norway), patients presented 5 to 16 days after vaccination with thrombocytopenia and signs of vascular thrombosis at unusual sites [128; 129]. In patients with one or more thrombotic events, there were 13 instances of cerebral venous thrombosis, 4 of splanchnic-vein thrombosis, 2 of pulmonary embolism, and 4 involving other sites. The patient age range was 22 to 54 years, and 13 of 16 cases were women. The timing of events and character of clinical features were considered similar to severe autoimmune heparin-induced thrombocytopenia, suggesting an antibody-mediated thrombotic thrombocytopenia triggered by the vaccine. All patients in each series had high levels of antibodies directed against antigenic complexes of platelet factor 4 (PF4). None of the patients had previously received heparin. This disorder is thought to represent vaccine-induced immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4 [128; 129].

These reports, and the action taken by the FDA and the CDC, have important implications for health professionals. The few cases among millions of vaccine doses administered indicates the incidence is rare and the risk low. The risk may be highest in women younger than 50 years of age. Vaccinees who are beyond three weeks from date of vaccination are not considered at risk for thrombotic complications. Individuals who develop any of the following new-onset symptoms within three weeks of vaccination should be evaluated for severe headache, abdominal pain, swelling or pain in the leg, chest pain, or shortness of breath. The evaluation should include a platelet count and imaging studies appropriate to clinical exam findings. Patients with thrombocytopenia and suspicion of a thrombotic event should not be treated initially with a heparin product. A diagnostic screening immunoassay for antibodies against PF[4]-heparin, or an enzyme-linked immunosorbent assay for antibodies against PF4-polyanion should be ordered. Hematology consultation is advisable. Potential treatment options include high-dose immunoglobulins and certain non-heparin anticoagulants [128,130].


One year into the COVID-19 pandemic, there is limited information on duration of immunity following SARS-CoV-2 infection. Despite the scope of the pandemic and burgeoning number of COVID-19 cases, there are few reports of reinfection. According to one source, 71 well-documented cases of SARS-CoV-2 reinfection have been reported, 12 of which occurred in the United States [115]. For the large majority of those infected, natural immunity to SARS-CoV-2 appears to be quite durable.

As with most viral infections, pathogen-specific IgG antibody assays in the weeks following onset of COVID-19 are useful for diagnostic purposes but not for measuring the durability of immunity provided by (unmeasured) neutralizing antibody and memory T-cell immune responses, which often persist for months to years. In a population-based study designed to assess durability of humoral immune responses following SARS-CoV-2 infection, serum samples from 1,107 seropositive persons were tested up to four months after the diagnosis of COVID-19. Antiviral Ig-antibody titers increased during the first two months after infection and had not declined at four months after infection [116]. In a longitudinal study of healthcare workers at the University of Oxford Hospitals undergoing periodic SARS-CoV-2 testing, the presence of antibodies in persons with previous asymptomatic or symptomatic COVID-19 substantially reduced the risk of reinfection [117]. Workers were offered nasopharyngeal SARS-CoV-2 PCR testing every two weeks and antibody testing at two-month intervals. Among 11,364 workers who were initially seronegative, 223 subsequently acquired SARS-CoV-2 infection, evidenced by a positive PCR. Among 1,265 workers who were seropositive, 2 subsequently developed an asymptomatic reinfection, evidenced by a positive PCR. During eight months surveillance, no symptomatic SARS-CoV-2 reinfections were detected among workers who had serologic evidence of prior SARS-CoV-2 infection [117]. Population-based studies also indicate that reinfection with SARS-CoV-2 is uncommon and occurs in less than 1% of individuals who have previously tested positive by SARS-CoV-2 PCR. Using a PCR-test data set from 4 million inhabitants of Denmark, researchers analyzed infection rates across separate surges of COVID-19 to estimate the degree of protection afforded by natural immunity against SARS-CoV-2 reinfection more than seven months later [118]. Among 11,068 persons who tested PCR-positive during the first COVID-19 surge (March to May 2020), 72 (0.65%) tested positive again during the second surge (September to December 2020). By comparison, the rate of infection among uninfected persons who became PCR-positive during the second surge was 3.27%. Thus, the estimate of protection against SARS-CoV-2 reinfection was 80.5%. However, protection against reinfection among persons older than 65 years of age was lower (47%). The authors note the limitations of this study, including absence of information about severity of infection and the possibility individuals infected during the first COVID-19 surge may have altered subsequent behavior affecting exposure risk. These estimates of protection do highlight the importance of administering SARS-CoV-2 vaccines to previously infected individuals, especially the elderly [118].

Durable protective immunity after infections or vaccinations consists of a repertoire of immune responses referred to collectively as "immunological memory" [119]. Measurable components of immune memory can include antibody, memory B cells, CD4+ T cells, and/or memory CD8+ T cells. Immune memory against SARS-CoV-2 provides the basis of protection against reinfection and determines the quality and duration of vaccine efficacy. In a study of 254 blood samples from 188 COVID-19 cases, including some samples up to eight months after infection, substantial immune memory involving all four types of immune response was retained in 95% of subjects over the six- to eight-month period of observation [119]. Antibodies against SARS-CoV-2 spike and receptor binding domains declined moderately over eight months, and memory B cell activity increased between one month and eight months after infection. Circulating antibody titers were not predictive of T cell memory. The authors concluded that simple serologic tests for SARS-CoV-2 antibodies do not reflect the quality and durability of immune memory to the virus [119]. Furthermore, studies show that vaccine-induced immunity may be more robust and durable than the natural immunity that follows mild and asymptomatic SARS-CoV-2 infection.



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. 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. Soon, however, the extent of person-to-person transmission unrelated to travel became increasingly clear from contact tracing and rapid community spread. By May 2021, 224 countries and territories around the world had been impacted by the COVID-19 pandemic, SARS-CoV-2 infections were on the increase in 58 countries, and the global case report total exceeded 135 million, with more than 3 million deaths [120].

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 public health measures and clinical criteria to guide the evaluation and management of persons with significant exposure and/or compatible illness.

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.

WHO and 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 [54]. The simple act of coughing, sneezing, talking, singing, or forceful breathing can release virus-laden droplets and respiratory particles into the air and onto nearby environmental surfaces. Multi-layered cloth masks block 50% to 70% of fine droplets and particles and limit the forward spread of those not captured [104]. Although the primary function of a face covering is to prevent inadvertent transmission to others ("source control"), 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].

As public health restrictions are lifted, professional and social interactions in the community present more opportunities for spread of SARS-CoV-2. The risk of transmission varies in proportion to how closely a person interacts with an infected individual and for how long. In a scientific brief updated November 20, 2020, the CDC summarized the experimental and epidemiologic data supporting community masking to reduce the spread of SARS-CoV-2 and concluded that the prevention benefit of masking is derived from the combination of source control and personal protection for the mask wearer [104]. Studies confirm that wearing face masks or double-layer cloth face coverings reduces the risk of transmission for medical personnel, patients, and the general public when in social and community settings, especially when social distancing is not possible [66,67,68]. A CDC report of a contact investigation involving a hair salon where universal face covering was practiced is illustrative. Two stylists with COVID-19 symptoms had worked closely with 139 clients over an eight-day period before learning of the COVID-19 diagnosis, yet there was no evidence of secondary transmission [67]. None of the clients developed COVID-19 symptoms and of 67 individuals tested for SARS-CoV-2, all were negative. Both stylists and 98% of of the clients interviewed had followed posted company policy and city ordinance requiring face coverings by employees and clients in businesses providing personal care services.

The CDC issued an order, effective February 1, 2021, requiring passengers to wear a mask on all public conveyances (e.g., airplanes, ships, ferries, subways, buses, taxis, ride-shares) when traveling into, within, or out of the United States [121]. Masks are required upon entering or while on the premises of a transportation hub and when waiting, boarding, and disembarking from public conveyances. People must wear masks that completely cover the mouth and nose.

In May 2021, the CDC recommended that all persons who are fully vaccinated (i.e., two weeks following the last dose) could safely cease use of face coverings regardless of the setting [131]. Following this announcement, several states rescinded their face covering mandates; however, requirements vary widely by state and individual businesses.


The rapidity with which the outbreak spread locally in China provided early evidence that human-to-human transmission from close contact with persons having mild, nonspecific symptoms is the primary means by which SARS-CoV-2 spreads within the community. Epidemiologic studies suggest that infected droplet nuclei expelled during coughing, sneezing, loud talking, or singing is the primary mode of transmission. Sustained close personal contact (being within 6 feet for at least 15 minutes) with an infected person increases the risk of transmission. Limiting the time and lengthening the distance reduces the risk [87]. Recovery of replication-competent virus from the upper respiratory tract begins to decline after onset of symptoms. For patients with mild-to-moderate COVID-19, replication-competent virus has not been recovered after 10 days following symptom onset [88]. Recovery of replication-competent virus between 10 and 20 days after symptom onset has been documented in some patients with severe COVID-19.

Unlike the 2003 SARS-CoV, whereby replication occurs primarily in the lower respiratory tract and shedding is temporally associated with symptom onset, SARS-CoV-2 is characterized by high levels of replication and shedding in the upper respiratory tract, even during the pre-symptomatic phase of infection [38]. Newly infected individuals are most infectious one to two days before and for a few days after the onset of symptoms. This means that persons with asymptomatic and pre-symptomatic SARS-CoV-2 infection may have high viral loads in nasopharyngeal secretions that render them efficient vectors of person-to-person transmission, and a strategy for prevention that relies solely on symptom-based detection and isolation of COVID-19 cases is likely to have limited effectiveness. In a study of skilled nursing facility residents infected with SARS-CoV-2 from a healthcare worker, half were asymptomatic or pre-symptomatic at the time of contact tracing evaluation and testing [15].

These considerations have important public health implications. Close personal contact implies touching and the sharing of common utensils; it is also defined by a proximity of 6–8 feet—the distance respiratory droplets travel after coughing or sneezing. As noted, the risk of infection is greatest for persons who have prolonged, unprotected close contact (i.e., within 6 feet for 15 minutes or longer) with someone recently diagnosed with SARS-CoV-2 infection, regardless of whether the patient has symptoms [89]. A CDC contact investigation demonstrated that even brief periods of unprotected close contact, if repeated and cumulative (exceeding 15 minutes) over the course of a day, significantly increases the risk [92]. This highlights the importance of avoiding congregate settings (e.g., assisted living facilities, college dormitories, family gatherings, indoor dining and bars) because of the increased likelihood of repetitive or sustained close contact. People can reduce the community spread of SARS-CoV-2 by practicing social distancing, wearing face coverings in public, and washing their hands.

On October 21, 2020, the CDC definition of "close contact" was revised for purposes of contact investigation [59]. Close contact describes someone who was within 6 feet of an infected person for a cumulative total of 15 minutes within a 24-hour period starting from two days before illness onset (or, for asymptomatic patients, two days prior to test specimen collection) until the time the patient is isolated. The cumulative 15-minute exposure refers to any combination of individual exposures (e.g., three 5-minute exposures) over a 24-hour period. Factors to consider when assessing close contact include proximity, duration of exposure, whether the individual has symptoms (as the period around onset of symptoms is associated with highest levels of viral shedding), whether the infected person was likely to generate aerosols (e.g., was coughing, shouting, singing), and other environmental factors (e.g., crowding, adequacy of ventilation, whether exposure was indoors or out of doors) [59].

Several emerging reports and epidemiologic studies indicate that children younger than 10 years of age may play only a small role in transmission of SARS-CoV-2. An investigation of 36 childhood COVID-19 cases in China found that 89% acquired the infection from exposure to an older household family member [50]. A population-based surveillance study in Iceland, drawing from a nationwide random sample, found that of 848 children younger than 10 years of age, none tested positive for SARS-CoV-2, whereas 100 of 12,232 (0.8%) adolescents and adults tested positive [51]. Contact tracing in relation to a cluster of COVID-19 among family and friends in France revealed that despite several days of potential exposure to a symptomatic pediatric case, there was no evidence of secondary transmission among 172 school contacts [52]. One possible explanation for these observations is the finding that gene expression of ACE2 in nasal epithelium is age-dependent; it is significantly lower in young children and increases as one develops into adulthood [53]. Lower ACE2 expression in children relative to adults could impact transmission dynamics and may help explain why COVID-19 is less prevalent in children.

The stability of SARS-CoV-2 on environmental surfaces (fomites) has been studied in an effort to assess whether surface contamination could play a role in virus transmission. After application of aerosols containing a standard dose of SARS-CoV-2, viable virus was detected up to 72 hours on plastic and stainless steel, though the virus titer was greatly reduced; on cardboard, no viable SARS-CoV-2 was measured after 24 hours [19]. These data should be interpreted with caution, as it is unclear to what extent environmental detection of virus in much reduced titer at a given interval, experimentally, can be equated with actual risk of transmission from common environmental surfaces. In an April 2021 scientific brief, a CDC analysis of quantitative microbial risk assessment studies concluded the risk of SARS-CoV-2 infection via the fomite transmission route is less than 1 in 10,000, which means that each contact with a contaminated surface has less than a 1 in 10,000 chance of causing an infection [122].

The public health strategy of mitigation (preventing spread within communities) has become paramount in order to decisively limit spread and blunt the COVID-19 epidemic curve, pending development and distribution of effective vaccines. These measures include the following: suspension or cancellation of events having large public gatherings, such as cinema, theatre, concerts, and collegiate and professional sports competition; closure of schools and cancellation of classes at colleges and universities; the practice of social distancing in smaller venues such as restaurants and churches; the wearing of masks or cloth face coverings at indoor commercial venues and social gatherings. By slowing the degree and pace of virus transmission, effective mitigation helps to protect those most vulnerable and to ensure that the clinical case load does not overwhelm local hospital and critical care resources.


In fall 2020, variant strains of SARS-CoV-2 began to appear in some countries with high COVID-19 case rates. Widespread circulation combined with spontaneous mutations in the viral genome increases the likelihood that a mutation affecting virus transmission will lead to emergence of a variant strain. The most important SARS-CoV-2 variants, designated by country of origin and genetic lineage, are United Kingdom (B.1.1.7), South Africa (B.1.351), and Brazil (P.1). All three variants are circulating in the United States. The B.1.1.7 strain, which has about 50% increased transmission, accounts for the large majority of variant SARS-CoV-2 cases reported in this country [123].

In response to concerns raised about the potential of variants to circumvent COVID-19 countermeasures, a SARS-CoV-2 Interagency Group (SIG) was established to characterize emerging variants and monitor their impact on viral transmission, disease severity, risk of reinfection, and potential to evade vaccine-induced immunity. The CDC’s national genomic surveillance program identifies SARS-CoV-2 variants by genetic sequencing and tracks the proportion and distribution of COVID-19 cases caused by variants [123,124]. Sequences with similar genetic changes associated with important epidemiologic and biological events are grouped into viral lineages defined by the founding variant and its descendants. The proportion of lineages circulating in the United States are tracked and characterized as variants of concern (VOC) or variants of interest (VOI).

As of May 2021, B.1.1.7, B.1.351, P.1, and California (B.1.427/429) are classified as VOC [123]. The important attributes of these variants include increased transmission (B.1.1.7), possibly increased severity (B.1.1.7), moderate impact on neutralization by monoclonal antibody therapeutics (P.1, B.1.351, 427/429), and reduced neutralization by convalescent and post-vaccination sera (P.1, B.1.351, and B.1.427/429). Approximately 27.2% of COVID-19 cases in the United States are caused by SARS-CoV-2 variant B.1.1.7. The proportion of cases caused by other VOC are estimated at 13.4% for B.1.427/429 and 0.5% for both P.1 and B.1.351 variants [124].

The emergence of SARS-CoV-2 variants could impact disease severity, risk of reinfection, and vaccine efficacy. At issue is the extent to which adaptive immunity (CD4+ and CD8+ T cell responses) from COVID-19 convalescent subjects and recipients of COVID-19 vaccines recognize (target) conserved epitopes on SARS-CoV-2 variants of concern. Fortunately, studies have demonstrated that SARS-CoV-2 T cell epitopes are not appreciably affected by the mutations found in newly described variants [125,126]. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in VOC presently circulating in the United States.


As of May 2021, nearly 33 million cases and more than 587,000 deaths from COVID-19 have been reported in the United States and territories [12]. Ethnic populations appear to be disproportionately affected [12]. The CDC monitors COVID-19 epidemiologic data and provides updated clinical guidance for healthcare providers, laboratories, health facilities, and public health professionals [12]. Included are recommendations for the evaluation of persons/patients under investigation, laboratory specimen transport, and protection of healthcare workers. Recommendations for patient assessment and care in hospitals and other healthcare facilities emphasize the importance of strict adherence to patient isolation and barrier precautions, including the proper use of personal protective equipment (PPE).

Selected materials from the CDC website, including recommendations for travelers, interim guidance for healthcare professionals, infection control, and healthcare worker safety, are reproduced in the following sections. Please note that language and/or cultural barriers may impede assessment and education on the topic, and interpreters and translated materials are recommended, when appropriate.

COVID-19 Data Tracker

The CDC website maintains a COVID-19 Data Tracker and Weekly Review [124]. This site reviews reported cases of SARS-COV-2 infection in the United States, prevalence of variant strains, rates of COVID-19 hospitalization, and vaccination status of the population. As of May 23, 2021, the seven-day moving average of daily new cases was 27,789 (19.5% decrease). Rates of hospitalization in adults older than 65 years of age decreased by more than 70% from the first of February to the first of April. The seven-day moving average of daily new deaths decreased 10.5% over the prior week and 88% compared with the highest peak on January 7, 2021. Overall, about 279.4 million vaccine doses have been administered and about 160.2 million people (48.2% of the population) have received at least one dose. Vaccination trends by age group show that 84.9% of people 65 or older have received at least one dose and 73.2% are fully vaccinated.

CDC Guidance on Travel During COVID-19

The CDC provides updated information and guidance on domestic and international travel based on SARS-CoV-2 vaccination status [13]. The CDC recommends delaying travel until fully vaccinated. Both vaccinated and unvaccinated individuals who must travel should observe the following precautions[13]:

  • Avoid contact with sick people.

  • Avoid touching your eyes, nose, or mouth with unwashed hands.

  • Wash hands often with soap and water for at least 20 seconds or use an alcohol-based hand sanitizer that contains at least 60% to 85% alcohol.

  • Avoid traveling if you are sick.

  • Wear a cloth face covering in terminals and other public venues.

  • Cover coughs and sneezes.

  • Pick up food at drive-throughs, curbside restaurant service, or stores.

Unvaccinated persons should get a SARS-CoV-2 nasopharyngeal swab test one to three days before the trip, repeat the viral test three to five days after travel and self-quarantine for seven days after travel (or 10 days if testing is omitted). Returning travelers from any destination are encouraged to observe standard precautions, monitor health, and follow state, territorial, tribal, and local recommendations or requirements after travel [13].

As of April 2, 2021, the CDC recommends that fully vaccinated people can travel at low risk to themselves and others [13]. A person is considered fully vaccinated two weeks after receiving the last recommended dose of vaccine. Such persons can travel safely within the United States without the need for pre-travel testing or post-travel self-quarantine if they continue to take COVID-19 precautions while traveling.

Recommended Criteria to Guide Evaluation of Patients Under Investigation for COVID-19

CDC guidance specifies who should be tested for COVID-19 and encourages clinicians to use clinical judgment in determining whether a patient with signs and symptoms compatible with COVID-19 should be tested [14]. Symptoms to be considered include fever, chills, cough, sore throat, muscle aches, shortness of breath, new loss of taste or smell, and vomiting or diarrhea. As noted, SARS-CoV-2 can cause asymptomatic, pre-symptomatic, and minimally symptomatic infection, leading to virus shedding that may result in transmission to others who are particularly vulnerable to severe disease and death. Special attention should be paid to older adults and to patients with underlying conditions or immunosuppressed states. Even mild signs and symptoms of COVID-19 should be evaluated among potentially exposed healthcare personnel because of their extensive contact with vulnerable patients in healthcare settings.

The CDC has established priorities for COVID-19 diagnostic testing [14]. High priority for testing applies to hospitalized patients with compatible clinical features, healthcare facility workers and those who work in congregate living settings with symptoms, and residents in long-term care facilities (including prisons and shelters) with symptoms. Priority designation for testing applies to any person in the community with symptoms of potential COVID-19. In addition, persons without symptoms may be prioritized by health departments or clinicians for reasons such as public health monitoring, sentinel surveillance, or screening purposes.

Clinicians should work with their local and state health departments to coordinate testing through public health laboratories or work with commercial or clinical laboratories using SARS-CoV-2 diagnostic tests granted an Emergency Use Authorization by the FDA. Patients should be evaluated and discussed with public health departments on a case-by-case basis if their clinical presentation or exposure history is equivocal.

Other considerations that may guide testing include epidemiologic factors (e.g., close contact with an individual who in the past 14 days has tested positive for SARS-CoV-2) and the occurrence of local transmission or a cluster of COVID-19 within a specific community setting (e.g., nursing home, manufacturing facility) [14]. Close contact is defined as one of the following:

  • Being within approximately 6 feet (2 meters), or within the room or care area, of a novel coronavirus case for a prolonged period of time while not wearing recommended personal protective equipment or PPE (e.g., gowns, gloves, certified disposable N95 respirator, eye protection); close contact can include caring for, living with, visiting, or sharing a healthcare waiting area or room with a novel coronavirus case.

  • Having direct contact with infectious secretions of a novel coronavirus case (e.g., being coughed on) while not wearing recommended personal protective equipment.

Any patient with fever and severe acute lower respiratory illness (e.g., pneumonia, ARDS) requiring hospitalization and without alternative explanatory diagnosis (e.g., influenza) should be evaluated for COVID-19, even if no source of exposure has been identified [14].

A symptomatic patient should be provided a surgical mask and placed on respiratory isolation, preferably in an airborne isolation negative pressure room. Caregivers should observe enhanced precautions (i.e., wear gloves, gown, eye protection device [other than prescription eye glasses], and N95 respirator). For information on the management of patients with COVID-19, see https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html.

Diagnostic Testing

The CDC recommends that healthcare providers should immediately notify both infection control personnel at their healthcare facility and their local or state health department in the event of a newly diagnosed or a suspected case of COVID-19.

Confirmation of COVID-19 is performed using the rRT-PCR assay for SARS-CoV-2 on respiratory specimens (which can include nasopharyngeal or oropharyngeal aspirates or washes, nasopharyngeal or oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirates, or sputum) and serum. The FDA has worked to expedite the availability of tests through emergency authorization of commercial laboratories that have developed SARS-CoV-2 testing capability. Information on specimen collection, handling, and storage is available at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html. After initial confirmation of COVID-19, additional testing of clinical specimens can help inform clinical management, including discharge planning. Additional guidance for collection, handling, and testing of clinical specimens is available at the CDC website [12].

Infection with both SARS-CoV-2 and with other respiratory viruses has been reported, and detection of another respiratory pathogen does not rule out COVID-19 [15].

Interim Clinical Guidance for Management of Patients with Confirmed COVID-19

Interim clinical guidance and additional resources for clinicians caring for patients with COVID-19 is provided and updated at the CDC website, selected aspects of which are reproduced in this section [15].

As noted, the clinical presentation of COVID-19 can range from asymptomatic to critically ill, and older patients and those with comorbidities are considered at greater risk for more severe disease. Among patients who developed severe disease, the median time to dyspnea was 5 to 8 days, the median time to ARDS was 8 to 12 days, and the median time to ICU admission was 10 to 12 days. Clinicians should be aware of the potential for some patients to rapidly deteriorate one week after illness onset. Among all hospitalized patients, 26% to 32% of patients were admitted to the ICU [15]. Only 3% to 17% of all patients with COVID-19 develop ARDS, but this increases to 20% to 42% for hospitalized patients and 67% to 85% for patients admitted to the ICU. Mortality among patients admitted to the ICU ranges from 39% to 72%, depending on the study [15]. The median length of hospitalization among survivors was 10 to 13 days.

Remdesivir is the only FDA-approved antiviral therapy for COVID-19 currently available, though multiple trials involving a variety of therapeutic agents are being conducted at many clinical centers throughout the United States. Clinical management includes prompt implementation of recommended infection prevention and control measures and supportive management of complications, including advanced organ support if indicated [15]. The NIH and the Infectious Diseases Society of America provide updated COVID-19 management guidelines, including specific recommendations for the use of remdesivir and dexamethasone in hospitalized patients [10,57].

Healthcare personnel should care for patients in an airborne infection isolation room. Isolation Precautions should be used when caring for the patient. For more detailed recommendations, see the CDC's Interim Infection Prevention and Control Recommendations for Patients with Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings at https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html.

Patients with a mild clinical presentation may not initially require hospitalization [15]. However, clinical signs and symptoms may worsen with progression to lower respiratory tract disease in the second week of illness; all patients should be monitored closely. As noted, possible risk factors for progressing to severe illness may include, but are not limited to, older age, obesity (body mass index >35), and underlying chronic medical conditions (e.g., lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, pregnancy).

The CDC advises that the decision to monitor a patient in the inpatient or outpatient setting should be made on a case-by-case basis. This decision will depend not only on the clinical presentation, but also on the patient's ability to engage in monitoring and the risk of transmission in the patient's home environment. For more information, see the CDC's Criteria to Guide Evaluation of Patients Under Investigation (PUI) for COVID-19 at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-criteria.html.

The CDC recommends that for most patients with confirmed SARS-CoV-2 infection the decision to discontinue transmission-based precautions should be made using a symptom-based strategy [25]. In general, patients with mild-to-moderate COVID-19 who are not immunocompromised may discontinue isolation once 10 days have passed since onset of illness, respiratory symptoms have improved, and at least 24 hours have passed since resolution of fever (without the use of fever-reducing medications). For patients who were asymptomatic throughout their infection, precautions may be discontinued when at least 10 days have passed since the date of their first positive viral diagnostic test. Additional considerations apply to patients who have sustained severe or critical illness and to those who are significantly immunocompromised [25].

Summary of the CDC Response to the COVID-19 Outbreak

The CDC is working with the WHO and state and local public health partners to respond to this emerging public health threat. The goal of the ongoing U.S. public health response is to contain this outbreak and prevent sustained spread of COVID-19 in this country.

The CDC and Customs and Border Protection (CBP) continue to conduct enhanced entry screening of travelers who have been in an affected area within the past 14 days at 20 designated U.S. airports. Passengers having symptoms compatible with COVID-19 and a history of travel to an affected area are being referred to CDC staff for evaluation.

As of May 2021, the CDC has produced more than 80 guidance documents on infection control, hospital preparedness assessments, PPE supply planning, and clinical evaluation and management for the outbreak.


CDC Information for Healthcare Professionals about Coronavirus (COVID-19)
CDC Information for Healthcare Professionals about COVID-19 Vaccination
CDC Coronavirus Disease 2019 (COVID-19) Resources for Health Departments
World Health Organization Coronavirus Disease 2019 (COVID-19) Pandemic
Johns Hopkins University and Medicine Coronavirus Resource Center
NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines
Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

Works Cited

1. Periman S. Another decade, another coronavirus. N Engl J Med. 2020;382:760-762.

2. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727-733.

3. Centers for Disease Control and Prevention. Coronavirus: Resources and References. Available at https://www.cdc.gov/coronavirus/resources.html. Last accessed May 23, 2021.

4. Munster VJ, Koopmans M, van Doremalen N, et al. A novel coronavirus emerging in China: key questions for impact assessment. N Engl J Med. 2020;382:692-694.

5. Azhar EI, El-Kafrawy SA, Farraj SA, et al. Evidence for camel-to-human transmission of MERS Coronavirus. N Engl J Med. 2014;370:2499-2505.

6. Drosten C, Meyer B, Muller MA, et al. Transmission of MERS-Coronavirus in household contacts. N Engl J Med. 2014;371:828-835.

7. Assiri A, McGeer A, Peri TM, et al. Hospital outbreak of Middle East Respiratory Syndrome Coronavirus. N Engl J Med. 2013;369:407-416.

8. World Health Organization. Coronavirus Disease (COVID-19) Pandemic. Available at https://www.who.int/emergencies/diseases/novel-coronavirus-2019. Last accessed May 23, 2021.

9. Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

10. Infectious Disease Society of America. COVID-19 Resource Center. Available at https://www.idsociety.org/covid-19-real-time-learning-network. Last accessed May 23, 2021.

11. World Health Organization. Coronavirus Disease (COVID-19) Advice for the Public. Available at https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public. Last accessed May 23, 2021.

12. Centers for Disease Control and Prevention. Coronavirus Disease (COVID-19). Available at https://www.cdc.gov/coronavirus/2019-ncov/index.html. Last accessed May 23, 2021.

13. Centers for Disease Control and Prevention. Travel During the COVID-19 Pandemic. Available at https://www.cdc.gov/coronavirus/2019-ncov/travelers/travel-during-covid19.html. Last accessed May 23, 2021.

14. Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html. Last accessed May 23, 2021.

15. Centers for Disease Control and Prevention. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html Last accessed May 23, 2021.

16. U.S. Food and Drug Administration. FDA Takes Significant Step in Coronavirus Response Efforts, Issues Emergency Use Authorization for the First 2019 Novel Coronavirus Diagnostic. Available at https://www.fda.gov/news-events/press-announcements/fda-takes-significant-step-coronavirus-response-efforts-issues-emergency-use-authorization-first. Last accessed May 23, 2021.

17. 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.

18. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (COVID-19) in China. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(2):145-151.

19. van Doremalen N, Bushmaker T, Morris DH, et al. To the editor: aerosolized and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382:1564-1567.

20. 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.

21. 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). Clin Infect Dis. 2020;71(15):732-739.

22. Devaux CA, Rolain JM, Colson P, et al. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5):105938.

23. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242.

24. Centers for Disease Control and Prevention. How to Protect Yourself and Others. Available at https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Last accessed May 23, 2021.

25. Centers for Disease Control and Prevention. Discontinuation of Transmission-Based Precautions and Disposition of Patients with COVID-19 in Healthcare Settings (Interim Guidance). Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html. Last accessed May 23, 2021.

26. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020;382:2327-2336.

27. Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020;323(16):1582-1589.

28. U.S. Food and Drug Administration. Donate COVID-19 Plasma. Available at https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma. Last accessed May 23, 2021.

29. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Blood Purification Device to Treat COVID-19. Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-blood-purification-device-treat-covid-19. Last accessed May 23, 2021.

30. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.

31. Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383:590-592.

32. Pei G, Zhang Z, Peng J, et al. Renal involvement and early prognosis in patients with COVID-19 pneumonia. J Am Soc Neph. 2020;31(6):1157-1165.

33. 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.

34. Clerkin KJ, Fried JA, Raikhelkar J, et al. Coronavirus disease 2019 (COVID-19) and cardiovascular disease. Circulation. 2020;141:1648-1655.

35. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19: final report. N Engl J Med. 2020;383:1813-1826.

36. U.S. Food and Drug Administration. Emergency Use Authorization for Use of Chloroquine Phosphate or Hydroxychloroquine Sulphate for Treatment of 2019 Coronavirus Disease. Available at https://www.fda.gov/media/136534/download. Last accessed May 23, 2021.

37. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;382:2411-2418.

38. Gandhi M, Yokie DS, Havlir DV. Asymptomatic transmission, the Achilles' heel of current strategies to control Covid-19. N Engl J Med. 2020;382:2158-2160.

39. Cannegieter S, Klok FA. COVID-19-associated coagulopathy and thromboembolic disease: commentary on an interim expert guidance. Res Pract Thromb Haemost. 2020;4(4):439-445.

40. COVID-19 coagulopathy: an evolving story. Lancet. 2020;7(6):E425.

41. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847.

42. Helms J, Tacquard C, Severac F, et al. for the CRICS TRIGGERSEP Group. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098.

43. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020;191:145-147.

44. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of COVID-19 in New York City. N Engl J Med. 2020;382:2372-2374.

45. Centers for Disease Control and Prevention. Information for Pediatric Healthcare Providers. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html. Last accessed May 23, 2021.

46. New York State Department of Health. Childhood Inflammatory Disease Related to COVID-19. Available at https://coronavirus.health.ny.gov/childhood-inflammatory-disease-related-covid-19. Last accessed May 23, 2021.

47. Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):P1607-P1608.

48. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicenter of the SARS-CoV-2 epidemic: an observational study. Lancet. 2020;395(10239):P1771-P1778.

49. Centers for Disease Control and Prevention. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). Available at https://www.cdc.gov/mis-c/hcp. Last accessed October 28, 2020.

50. Qui H, Wu J, Hang L, et al. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational study. Lancet. 2020;20(6):P689-P696.

51. Gudbjartsson D, Helgason A, Jonsson H, et al. Spread of SARS-CoV-2 in the Icelandic population. N Engl J Med. 2020;382:2302-2315.

52. Danis K, Epaulard O, Bénet T, et al. Cluster of coronavirus disease 2019 (Covid-19) in the French Alps, 2020. Clin Infect Dis. 2020;71(15):825-832.

53. Bunvavanich S, Do A, Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA. 2020;323(23):2427-2429.

54. Centers for Disease Control and Prevention. Considerations for Wearing Masks. Available at https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/cloth-face-cover.html. Last accessed May 23, 2021.

55. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States, January 22–May 30, 2020. MMWR. 2020;69(24):759-765.

56. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of Covid-19. N Engl J Med. 2020;383:989-992.

57. National Institutes of Health. COVID-19 Treatment Guidelines: Therapeutic Management of Patients with COVID-19. Available at https://www.covid19treatmentguidelines.nih.gov/therapeutic-management. Last accessed May 23, 2021.

58. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and-hydroxychloroquine. Last accessed May 23, 2021.

59. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): Health Departments, Appendices. Available at https://www.cdc.gov/coronavirus/2019-ncov/php/contact-tracing/contact-tracing-plan/appendix.html. Last accessed May 23, 2021.

60. Burke RM, Killerby ME, Newton S, et al. Symptom profiles of a convenience sample of patients with COVID-19—United States, January–April 2020. MMWR. 2020;69:904-908.

61. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383:334-346.

62. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York state. N Engl J Med. 2020;383:347-358.

63. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med. 2020;2021;384:693-704.

64. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med. 2020;383:1920-1931.

65. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomized controlled trial. Lancet. 2020;396(10249):P467-P478.

66. Brooks JT, Butler JC, Redfield RR. Universal masking to prevent SARS-CoV-2 transmission—the time is now. JAMA. 2020;324(7):635-637.

67. Hendrix MJ, Wade C, Findley K, Trotman R. Absence of transmission of SARS-CoV-2 after exposure at a hair salon with universal face mask policy—Springfield, Missouri. MMWR. 2020;69(28):930-932.

68. Carfi A, Bernabei R, Landi F, et al. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324:603-605.

69. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR. 2020;69:993-998.

70. Cavalcanti AB, Zampieri FG, Rosa RC, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383:2041-2052.

71. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-center, randomized, controlled trial. Available at https://www.medrxiv.org/content/10.1101/2020.07.15.20151852v1. Last accessed May 23, 2021.

72. National Institutes of Health. NIH Halts Clinical Trial of Hydroxychloroquine. Available at https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine. Last accessed May 23, 2021.

73. U.S. Food and Drug Administration. Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) of COVID-19 Convalescent Plasma for Treatment of COVID-19 in Hospitalized Patients. Available at https://www.fda.gov/media/141478/download. Last accessed May 23, 2021.

74. Biran N, Andrew I, Ahn J, et al. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicenter observational study. Lancet Rheumatology. 2020;2(10):e603-e612.

75. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related Strongyloides hyperinfection. JAMA. 2020;324(7):623-624.

76. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. Available at https://www.medrxiv.org/content/10.1101/2020.08.12.20169359v1. Last accessed May 23, 2021.

77. Tartof SY, Qian L, Hong V, et al. Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care system. Ann Int Med. 2020; [Epub ahead of print].

78. Kass DA. COVID-19 and obesity: a big problem? Ann Int Med. 2020; [Epub ahead of print].

79. Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2 (COVID-19). Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html. Last accessed May 23, 2021.

80. U. S. Food and Drug Administration. Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization for Medical Devices: In Vitro Diagnostics EUAs. Available at https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/vitro-diagnostics-euas#individual-antigen. Last accessed May 23, 2021.

81. Fournier J, Casanovas-Massana A, Campbell M, et al. To the editor: Saliva or nasopharyngeal swab specimens for detection of SARS-CoV-2. N Engl J Med. 2020;383:1283-1286.

82. Hanson KE, Barker AP, Hillyard DR, et al. Self-collected anterior nasal and salivary specimens versus healthcare worker-collected nasopharyngeal swabs for the molecular detection of SARS-CoV-2. J Clin Microbiol. 2020;58(11):e01824-e01830.

83. Centers for Disease Control and Prevention. Interim Guidelines for COVID-19 Antibody Testing. Available at https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html. Last accessed May 23, 2021.

84. U.S. Food and Drug Administration. Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization for Medical Devices: EUA Authorized Serology Test Performance. Available at https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/eua-authorized-serology-test-performance. Last accessed May 23, 2021.

85. Marovich M, Mascola JR, Cohen MS. Monoclonal antibodies for prevention and treatment of COVID-19. JAMA. 2020;324:131-132.

86. Anderson EJ, Rouphael NG, Widge AT, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med. 2020;383:2427-2438.

87. Chu DK, Aki EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systemic review and meta-analysis. Lancet. 2020;395:1973-1987.

88. Centers for Disease Control and Prevention. Duration of Isolation and Precautions for Adults with COVID-19. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html. Last accessed May 23, 2021.

89. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) Frequently Asked Questions: COVID-19 Risk. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html#COVID-19-Risk. Last accessed May 23, 2021.

90. U.S. Food and Drug Administration. FDA Approves First Treatment for COVID-19. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19. Last accessed May 23, 2021.

91. Parr JB. Time to reassess tocilizumab's role in COVID-19 pneumonia. JAMA Intern Med. 2020;2021;181(1):12-15.

92. Pringle JC, Leikauskas J, Ransom-Kelly S, et al. COVID-19 in a correctional facility employee following multiple brief exposures to persons with COVID-19—Vermont, July–August 2020. MMWR. 2020;69(43):1569-1570.

93. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2020;2021;384:619-629.

94. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2020;2021;384:229-237.

95. U.S. Food and Drug Administration. Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Bamlanivimab. Available at https://www.fda.gov/media/143603/download. Last accessed May 23, 2021.

96. U.S. Food and Drug Administration. Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Casirivimab and Imdevimab. Available at https://www.fda.gov/media/143892/download. Last accessed May 23, 2021.

97. Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020;586:516-527.

98. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603-2615.

99. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384:403-416.

100. Dooling K, Marin M, Wallace M, et. al. The Advisory Committee on Immunization Practices' updated interim recommendation for allocation of COVID-19 vaccine—United States, December 2020. MMWR. 2021;69:1657-660.

101. Centers for Disease Control and Prevention. COVID-19 Vaccination: Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. Available at https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html. Last accessed May 23, 2021.

102. Castells MC, Phillips EJ. Maintaining safety with SARS-CoV-2 vaccines. N Engl J Med. 2021;384:643-649.

103. Centers for Disease Control and Prevention. COVID-19 Vaccination, Interim Considerations: Preparing for the Potential Management of Anaphylaxis after COVID-19 Vaccination. Available at https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/anaphylaxis-management.html. Last accessed May 23, 2021.

104. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) Scientific Brief: Community Use of Cloth Masks to Control the Spread of SARS-CoV-2. Available at https://www.cdc.gov/coronavirus/2019-ncov/more/masking-science-sars-cov2.html. Last accessed May 23, 2021.

105. Freeman EE, McMahon DE, Lipoff JB, et al. Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries. J Am Acad Dermatol. 2020;83:486-492.

106. Freeman EE, McMahon DE, Lipoff JB, et al. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. J Am Acad Dermatol. 2020;83:1118-1129.

107. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3, 2020. MMWR. 2020;69:1641-1647.

108. Havervall S, Rosell A, Phillipson M. Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers. JAMA. 2021;325(19):2015-2016.

109. Libster R, Marc GP, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384:610-618.

110. Oliver SE, Gargano JW, Scobie H, et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Janssen COVID-19 vaccine—United States, February 2021. MMWR. 2021;70:329-332.

111. Manisty C, Otter AD, Treibel TA, et al. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet. 2021;397:1057-1058.

112. Lustig Y, Nemer I, Kliker L, et al. Neutralizing response against variants after SARS-CoV-2 infection and one dose of BNT162b2. N Engl J Med. 2021; [Epub ahead of print].

113. Centers for Disease Control and Prevention. V-Safe After Vaccination Health Checker. Available at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html. Last accessed May 23, 2021.

114. Blumenthal KG, Freeman EE, Saff RR, et al. Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2. N Engl J Med. 2021;384:1273-1277.

115. BNO News. COVID-19 Reinfection Tracker. Available at https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker. Last accessed May 23, 2021.

116. Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral immune response to SARS-CoV-2 in Iceland. N Engl J Med. 2020;383:1724-1734.

117. Lumley SF, O’Donnell D, Stoesser NE, et al. Antibody status and incidence of SARS-CoV-2 infection in health care workers. N Engl J Med. 2021;384:533-540.

118. Hansen CH, Michlmayr D, Gubbels SM, et al. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-positive individuals in Denmark in 2020: a population-level observational study. Lancet. 2021;397(10280):1204-1212.

119. Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed up to 8 months after infection. Science. 2021;371(6529):eabf4063.

120. Reuters. COVID-19 Global Tracker. Available at https://graphics.reuters.com/world-coronavirus-tracker-and-maps. Last accessed May 23, 2021.

121. Centers for Disease Control and Prevention. Federal Register Notice: Wearing of Face Masks While on Conveyances and at Transportation Hubs. Available at https://www.cdc.gov/quarantine/masks/mask-travel-guidance.html. Last accessed May 23, 2021.

122. Centers for Disease Control and Prevention. COVID-19 Science Brief: SARS-CoV-2 and Surface (Formite) Transmission for Indoor Community Environments. Available at https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/surface-transmission.html. Last accessed May 23, 2021.

123. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and Definitions. Available at https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html. Last accessed May 23, 2021.

124. Centers for Disease Control and Prevention. COVID Data Tracker Weekly Review. Available at https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html. Last accessed May 23, 2021.

125. Tarke A, Sidney J, Methot N, et al. Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv. 2021; [Epub ahead of print].

126. Redd AD, Nardin A, Kared H, et al. CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants. Open Forum Infectious Diseases. 2021; [Epub ahead of print].

127. U. S. Food and Drug Administration. Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine. Available at https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine. Last accessed May 23, 2021.

128. Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021; [Epub ahead of print].

129. Schultz NH, Sorvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021; [Epub ahead of print].

130. Hunter PR. Editorial: thrombosis after covid-19 vaccination. BMJ. 2021;373:n958.

131. Centers for Disease Control and Prevention. Interim Public Health Recommendations for Fully Vaccinated People. Available at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated-guidance.html. Last accessed May 23, 2021.

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