Coronavirus Disease 2019 (COVID-19)

Updated: Oct 26, 2020
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Overview

Practice Essentials

Coronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; formerly called 2019-nCoV), which was first identified amid an outbreak of respiratory illness cases in Wuhan City, Hubei Province, China. [1] It was initially reported to the WHO on December 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency. [2, 3] On March 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza a pandemic in 2009. [4]

Illness caused by SARS-CoV-2 was termed COVID-19 by the WHO, the acronym derived from "coronavirus disease 2019." The name was chosen to avoid stigmatizing the virus's origins in terms of populations, geography, or animal associations. [5, 6] On February 11, 2020, the Coronavirus Study Group of the International Committee on Taxonomy of Viruses issued a statement announcing an official designation for the novel virus: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). [7]

The Centers for Disease Control and Prevention (CDC) has estimated that SARS-CoV-2 entered the United States in late January or early February, establishing low-level community spread before being noticed. [8] Since that time, the United States has experienced widespread infections, with over 224,000 deaths reported as of October 26, 2020.

On April 3, 2020, the CDC issued a recommendation that the general public, even those without symptoms, should begin wearing face coverings in public settings where social-distancing measures are difficult to maintain in order to abate the spread of COVID-19. [9]

The CDC had postulated that this situation could result in large numbers of patients requiring medical care concurrently, resulting in overloaded public health and healthcare systems and, potentially, elevated rates of hospitalizations and deaths. The CDC advised that nonpharmaceutical interventions (NPIs) will serve as the most important response strategy in attempting to delay viral spread and to reduce disease impact. [10]

The feasibility and implications of strategies for suppression and mitigation have been rigorously analyzed and are being encouraged or enforced by many governments in order to slow or halt viral transmission. Population-wide social distancing of the entire population plus other interventions (eg, home self-isolation, school and business closures) was strongly advised. These policies may be required for long periods to avoid rebound viral transmission. [11]

According to the CDC, individuals at high risk of infection include persons in areas with ongoing local transmission, healthcare workers caring for patients with COVID-19, close contacts of infected persons, and travelers returning from locations where local spread has been reported. [10]

Person-to-person spread of SARS-CoV-2 has been reported in the United States. [12, 13] Individuals who believe they may have been exposed to SARS-CoV-2 should contact their healthcare provider.

The CDC has also provided recommendations for individuals who are at high risk of COVID-19–related complications, including older adults and persons who have serious underlying health conditions (eg, heart disease, diabetes, lung disease). Such individuals should consider the following precautions: [14]

  • Stock up on supplies.
  • Avoid close contact with sick people.
  • Wash hands often.
  • Stay home as much as possible in locations where COVID-19 is spreading.
  • Develop a plan in case of illness.

Healthcare personnel are also referred to Medscape’s Novel Coronavirus (COVID-19) Resource Center for the latest news, perspective, and resources.

Signs and symptoms

Presentations of COVID-19 have ranged from asymptomatic/mild symptoms to severe illness and mortality. Symptoms may develop 2 days to 2 weeks following exposure to the virus. [15] A pooled analysis of 181 confirmed cases of COVID-19 outside Wuhan, China, found the mean incubation period to be 5.1 days and that 97.5% of individuals who developed symptoms did so within 11.5 days of infection. [16]

Wu and McGoogan reported that, among 72,314 COVID-19 cases reported to the Chinese Center for disease Control and Prevention (CCDC), 81% were mild (absent or mild pneumonia), 14% were severe (hypoxia, dyspnea, >50% lung involvement within 24-48 hours), 5% were critical (shock, respiratory failure, multiorgan dysfunction), and 2.3% were fatal. [17]

The following symptoms may indicate COVID-19: [18]

  • Fever or chills
  • Cough
  • Shortness of breath or difficulty breathing
  • Fatigue
  • Muscle or body aches
  • Headache
  • New loss of taste or smell
  • Sore throat
  • Congestion or runny nose
  • Nausea or vomiting
  • Diarrhea

Other reported symptoms have included the following:

  • Sputum production
  • Malaise
  • Respiratory distress
  • Neurologic (eg, headache, altered mentality)

The most common serious manifestation of COVID-19 appears to be pneumonia.

A complete or partial loss of the sense of smell (anosmia) has been reported as a potential history finding in patients eventually diagnosed with COVID-19. [19] A phone survey of outpatients with mildly symptomatic COVID-19 found that 64.4% (130 of 202) reported any altered sense of smell or taste. [20]

For information regarding how the infection affects children, see Coronavirus Disease 2019 (COVID-19) in Children.

See Clinical Presentation.

Diagnosis

COVID-19 should be considered a possibility in (1) patients with respiratory tract symptoms and newly onset fever or (2) in patients with severe lower respiratory tract symptoms with no clear cause. Suspicion is increased if such patients have been in an area with community transmission of SARS-CoV-2 or have been in close contact with an individual with confirmed or suspected COVID-19 in the preceding 14 days.

Microbiologic (PCR) testing is required for definitive diagnosis. At present, such testing is of limited availability.

Patients who do not require emergency care are encouraged to contact their healthcare provider over the phone. Patients with suspected COVID-19 who present to a healthcare facility should prompt infection-control measures. They should be evaluated in a private room with the door closed (an airborne infection isolation room is ideal) and asked to wear a surgical mask. All other standard contact and airborne precautions should be observed, and treating healthcare personnel should wear eye protection. [21]

See Workup.

Management

As of October 22, 2020, remdesivir, an antiviral agent, is the only drug approved for treatment of COVID-19. It is indicated for treatment of COVID-19. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. [22] An emergency use authorization (EUA) remains in place for treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [23]   

An EUA for convalescent plasma was announced on August 23, 2020. [24]

In addition, infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases. [25]

No vaccine is approved in the US for SARS-CoV-2; however, several vaccine candidates have moved into phase 3 testing. Avoidance is the principal method of deterrence.

Numerous collaborative efforts to discover and evaluate effectiveness of antivirals, immunotherapies, monoclonal antibodies, and vaccines have rapidly emerged. Guidelines and reviews of pharmacotherapy for COVID-19 have been published. [26, 27, 28, 29, 30]

For more information on investigational drugs and biologics being evaluated for COVID-19, see Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies.

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Background

Coronaviruses comprise a vast family of viruses, 7 of which are known to cause disease in humans. Some coronaviruses that typically infect animals have been known to evolve to infect humans. SARS-CoV-2 is likely one such virus, postulated to have originated in a large animal and seafood market.

Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are also caused by coronaviruses that “jumped” from animals to humans. More than 8,000 individuals developed SARS, nearly 800 of whom died of the illness (mortality rate of approximately 10%), before it was controlled in 2003. [31] MERS continues to resurface in sporadic cases. A total of 2,465 laboratory-confirmed cases of MERS have been reported since 2012, resulting in 850 deaths (mortality rate of 34.5%). [32]

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Route of Transmission

The principal mode by which people are infected with SARS-CoV-2 is through exposure to respiratory droplets carrying infectious virus (generally within a space of 6 feet). Additional methods includes contact transmission (eg, shaking hands) and airborne transmission of droplets that linger in the air over long distances (usually greater than 6 feet). [33, 34, 35] Virus released in respiratory secretions (eg, during coughing, sneezing, talking) can infect other individuals via contact with mucous membranes.

On July 9, 2020, the World Health Organization issued an update stating that airborne transmission may play a role in the spread of COVID-19, particularly involving “super spreader” events in confined spaces such as bars, although they stressed a lack of such evidence in medical settings. Thus, they emphasized the importance of social distancing and masks in prevention. [35]

The virus can also persist on surfaces to varying durations and degrees of infectivity, although this is not believed to be the main route of transmission. [33] One study found that SARS-CoV-2 remained detectable for up to 72 hours on some surfaces despite decreasing infectivity over time. Notably, the study reported that no viable SARS-CoV-2 was measured after 4 hours on copper or after 24 hours on cardboard. [36]

Oran and Topol estimate asymptomatic persons account for approximately 40-45% of SARS-CoV-2 infection. These asymptomatic carriers can transmit infection to others for an extended period, perhaps more than 14 days, and therefore, contribute to substantial spread of the disease. [37]  

Transmission of SARS-CoV-2 from 12 young children who acquired COVID-19 at childcare facilities to family members has been reported. Findings showed 25% of their close contacts became infected — most often mothers or siblings. Three of the children were asymptomatic, 2 of whom likely infected their contacts, including a mother who required hospitalization. One mildly symptomatic child too young for face masks (age 8 months) likely infected both parents. [38]  

In a separate study, Chin et al studied the stability of SARS-CoV-2 in different environmental conditions, using viral culture as a measure of infectivity (rather than PCR), indicating detection of replication-capable virus. They found that the virus was very susceptible to high heat (70°C). At room temperature and moderate (65%) humidity, no infectious virus could be recovered from printing and tissue papers after a 3-hour incubation period or from wood and cloth by day two. On treated smooth surfaces, infectious virus became undetectable from glass by day 4 and from stainless steel and plastic by day 7. “Strikingly, a detectable level of infectious virus could still be present on the outer layer of a surgical mask on day 7 (~0.1% of the original inoculum).” [39] At present, contact with fomites is thought to be less significant than person-to-person spread as a means of transmission. [33]

Wölfel et al reported that, in a small group of patients with mild COVID-19, nasopharyngeal/oropharyngeal swabs collected during the first week of illness showed infectious virus but not after this period despite high detected rates of SARS-CoV-2 RNA from these sites. [40]

The duration of viral shedding varies significantly and may depend on severity. Among 137 survivors of COVID-19, viral shedding based on testing of oropharyngeal samples ranged from 8-37 days, with a median of 20 days. [41] A different study found that repeated viral RNA tests using nasopharyngeal swabs were negative in 90% of cases among 21 patients with mild illness, whereas results were positive for longer durations in patients with severe COVID-19. [42] In an evaluation of patients recovering from severe COVID-19, Zhou et al found a median shedding duration of 31 days (range, 18-48 days). [43] These studies have all used PCR detection as a proxy for viral shedding. The Korean CDC, investigating a cohort of patients who had prolonged PCR positivity, determined that infectious virus was not present. [44]

In a 2020 study on the efficacy of facemasks in preventing acute respiratory infection, surgical masks worn by patients with such infections (rhinovirus, influenza, seasonal coronavirus [although not SARS-CoV-2 specifically]) were found to reduce the detection of viral RNA in exhaled breaths and coughs. Specifically, surgical facemasks were found to significantly decreased detection of coronavirus RNA in aerosols and influenza virus RNA in respiratory droplets. The detection of coronavirus RNA in respiratory droplets also trended downward. Based on this study, the authors concluded that surgical facemasks could prevent the transmission of human coronaviruses and influenza when worn by symptomatic persons and that this may have implications in controlling the spread of COVID-19. [45]

In a 2016 systematic review and meta-analysis, Smith et al found that N95 respirators did not confer a significant advantage over surgical masks in protecting healthcare workers from transmissible acute respiratory infections. [46]

Bae et al, in a letter to Annals of Internal Medicine, reported that surgical and cotton masks were ineffective at containing cough droplets of SARS CoV-2 in a study conducted in two hospitals in Seoul, South Korea. Although the study methods were somewhat questionable in terms of mimicking natural transmission (the patients were asked to cough on culture plates placed 20 cm from their mouths), the results may indicate the value of maintaining social distancing even while a mask is worn. [47]

SARS-CoV-2 has also been found in the semen of men with acute infection, as well as in some male patients who have recovered. [48]

Asymptomatic/presymptomatic SARS-CoV-2 infection and its role in transmission

Data have suggested that asymptomatic patients are still able to transmit infection. This raises concerns for the effectiveness of isolation. [49, 50]

Oran and Topol published a narrative review of multiple studies on asymptomatic SARS-CoV-2 infection. Such studies and news articles reported rates of asymptomatic infection in several worldwide cohorts, including resident populations from Iceland and Italy, passengers and crew aboard the cruise ship Diamond Princess, homeless persons in Boston and Los Angeles, obstetric patients in New York City, and crew aboard the U.S.S Theodore Roosevelt and Charles de Gaulle aircraft carrier, among several others. They found that approximately 40%-45% of SARS-CoV-2 infections were asymptomatic. [37]

Data from 90 passengers and staff aboard the Diamond Princess Cruise ship with asymptomatic (not presymptomatic) SARS-CoV-2 were analyzed. The median age of these individuals was 59.5 years (range, 9-77 years). Twenty-four had underlying medical conditions (eg, hypertension [20%], diabetes [9%]). The median time from the first positive PCR result to infection resolution (two serial negative results) was 9 days (range, 3-21 days). Delayed resolution correlated with increasing age. [51]

Zou et al followed viral expression through infection via nasal and throat swabs in a small cohort of patients. They found increases in viral loads at the time that the patients became symptomatic. One patient never developed symptoms but was shedding virus beginning at day 7 after presumed infection. [52]

Xi et al modeled the infectiousness of SARS-CoV-2 and estimated that 44% (CI, 25%-69%) of secondary cases were infected by a person in the presymptomatic stage of infection. They found that the highest viral load occurred at the time of initial symptom onset and inferred that infectiousness began 2.3 days before symptom onset and peaked 0.7 days before symptom onset. [53]

Recent news stories have reported on the high prevalence of asymptomatic SARS-CoV-2 infections. In France, more than 1000 crewmembers aboard the Charles de Gaulle aircraft carrier were found to be infected with SARS-CoV-2, approximately half of whom were asymptomatic. [54] In the United States, nearly the entire crew of the USS Theodore Roosevelt underwent SARS-CoV-2 testing. Of the 660 crewmembers who tested positive for the virus (of approximately 4800 personnel), more than 350 (53%) were found to be asymptomatic. [55] In Boston, Massachusetts, 408 homeless individuals were tested for SARS-CoV-2 infection, and 147 tested positive, most (87.8%) of whom were asymptomatic. [56, 57]

Universal screening of 215 pregnant women admitted for delivery at New York–Presbyterian Allen Hospital and Columbia University Irving Medical Center showed that 33 (15%) had SARS-CoV-2 infection, 29 (88%) of whom had no symptoms of the infection. [58]

A population survey conducted in Iceland found that 57% of persons who tested positive for SARS-CoV-2 infection reported symptoms. [59]

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Epidemiology

Coronavirus outbreak and pandemic

As of October 26, 2020, confirmed COVID-19 infections number over 42.9 million individuals worldwide and has resulted in over 1.1 million deaths. More than 220 countries have reported laboratory-confirmed cases of COVID-19 on all continents except Antarctica. [60]

In the United States, over 8.6 million cases of COVID-19 have been confirmed as of October 26, 2020, resulting in over 224,000 deaths, making it the third leading cause of death after heart disease and cancer. [61, 62, 63]  Beginning in late March 2020, the United States had more confirmed infections than any other country in the world. [64]  The US also has the most confirmed deaths in the world, followed by Brazil and India. [60]

An interactive map of confirmed cases can be found here.

CDC estimates of COVID-19 epidemiology parameters

In late May 2020, the CDC and the Office of the Assistant Secretary for Preparedness and Response (ASPR) released parameter values intended to support public health preparedness and planning for the COVID-19 pandemic. Their “best estimates” for viral transmissibility, disease severity, and presymptomatic and asymptomatic disease transmission of COVID-19 based on current data are as follows: [65]

  • Basic reproduction number (R 0 or R-naught): 2.5
  • Asymptomatic SARS-CoV-2 infection rate: 40%
  • Infectiousness of asymptomatic individuals relative to symptomatic individuals: 75%
  • Percentage of transmission occurring prior to symptom onset: 50%
  • Time from exposure to symptom onset: Mean of 6 days 
  • Time from symptom onset in an individual and symptom onset of a second person infected by that individual: Mean of 6 days
  • Ratio of estimated infections to reported case counts: Mean of 11 

Infection fatality ratio (IFR)

IFR is the number of individuals who die of the disease among all infected individuals (symptomatic and asymptomatic)

  • 19 years or younger: 0.00003
  • 20-49 years: 0.002
  • 40-69 years: 0.005
  • 70 years or older: 0.054

Healthcare usage parameters [65] (Open Table in a new window)

Parameter Age 18-49 y Age 50-64 y Older than 65 y
Median days from symptom onset to test in patients testing positive 3 3 3
Median days from symptom onset to hospitalization 6 6 4
Median days hospitalized (not admitted to ICU) 3 4 6
Median days hospitalized (admitted to ICU) 11 14 12
Percent of those hospitalized admitted to ICU 23.8% 36.1% 35.3%
Percent on mechanical ventilation (non-ICU and ICU) 12% 22.1% 21.1%
Percent that die among those hospitalized (non-ICU and ICU) 2.4% 10% 26.6%
Median days on mechanical ventilation 6 6 6
Median days from symptom onset to death 15 17 13
Median days from death to reporting 19 21 19

 

United States incidence

A total of 8,617,002 cases of COVID-19 have been confirmed were reported in the United States as of October 26, 2020, resulting in 224,601 deaths, making it the third leading cause of death. [61, 63] The following data were derived from analysis of case surveillance from January 22 thorugh May 30, 2020. [66]

Sex-based incidence was as follows: [66]

  • Females: 406 cases per 100,000 persons
  • Males: 401.1 cases per 100,000 persons

The median age was 48 years. Age-based incidence was as follows: [66]

  • Adults aged 80 years or older: 902 cases per 100,000 population (8.7% of overall cases)
  • Adults aged 70-79 years: 464.2 cases per 100,000 population (8% of overall cases)
  • Adults aged 60-69 years: 478.4 cases per 100,000 population (13.6% of overall cases)
  • Adults aged 50-59 years: 550.5 cases per 100,000 population (17.9% of overall cases)
  • Adults aged 40-49 years: 541.6 cases per 100,000 population (16.6% of overall cases)
  • Adults aged 30-39 years: 491.6 cases per 100,000 population (16.3% of overall cases)
  • Adults aged 20-29 years: 401.6 cases per 100,000 population (13.8% of overall cases)
  • Persons aged 10-19 years: 117.3 cases per 100,000 population (3.7% of overall cases)
  • Children aged 9 years or younger: 51.1 cases per 100,000 population (1.4% of overall cases)

Race-based incidence was as follows: [66]

  • Non-Hispanic white: 36% of cases
  • Hispanic or Latino: 33% of cases
  • Black: 22% of cases
  • Non-Hispanic Asian: 4% of cases
  • Non-Hispanic American Indian or Alaska Native: 1.3% of cases
  • Non-Hispanic Native Hawaiian or other Pacific Islander: < 1% of cases

Reported outcomes were as follows: [66]

  • Hospitalization: 14% of cases (6 times more common among patients with underlying conditions)
  • ICU admission: 2% of cases
  • Mortality: 5% of cases (12 times more common among patients with underlying conditions)
  • Rates of hospitalization, ICU admission, and mortality were higher in men than in women: (16% vs 12%, 3% vs 2%, 6% vs 5%, respectively)

Mortality rates by age were as follows: [66]

  • Patients aged 80 years or older: 49.7% with underlying conditions; 29.8% without underlying conditions
  • Patients aged 70-79 years: 31.7% with underlying conditions; 10.2% without underlying conditions
  • Patients aged 60-69 years: 16.7% with underlying conditions; 2.4% without underlying conditions
  • Patients aged 50-59 years: 7.8% with underlying conditions; 0.9% without underlying conditions
  • Patients aged 40-49 years: 4.5% with underlying conditions; 0.4% without underlying conditions
  • Patients aged 30-39 years: 2.8% with underlying conditions; 0.1% without underlying conditions
  • Patients aged 20-29 years: 1.4% with underlying conditions; 0.1% without underlying conditions
  • Patients aged 10-19 years: 0.8% with underlying conditions; 0.1% without underlying conditions
  • Children aged 9 years or younger: 0.6% with underlying conditions; 0.1% without underlying conditions

Reported underlying health conditions were as follows: [66]

  • Cardiovascular disease (32.2%)
  • Chronic pulmonary disease (17.5%)
  • Renal disease (7.6%)
  • Diabetes (30.2%)
  • Liver disease (1.4%)
  • Immunocompromise (5.3%)
  • Neurologic/Neurodevelopmental disability (4.8%)

Reported symptoms were as follows: [66]

  • Fever (43.1%)
  • Cough (50.3%)
  • Shortness of breath (28.5%)
  • Myalgia (36.1%)
  • Runny nose (6.1%)
  • Sore throat (20%)
  • Headache (34.4%)
  • Nausea/vomiting (11.5%)
  • Abdominal pain (7.6%)
  • Diarrhea (19.3%)
  • Loss of smell or taste (8.3%)

New York City regional incidence March-April 2020

Data on presenting characteristics, comorbidities, and outcomes among patients with COVID-19 in and around New York City were issued in late April 2020. Among the 5,700 patients for whom data was collected, outcome data was assessed in 2,634 patients who had been discharged or died (study endpoints). Of these, 373 (14.2%) were admitted to the ICU, 320 (12.2%) required invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. The overall mortality rate among the 282 patients who required mechanical ventilation was 88.1%, which increased to 97.2% in patients older than 65 years. [67]

In mid-April 2020, a separate population-based surveillance study reported findings among 1,482 US patients hospitalized with COVID-19 from March 1 to March 30, 2020, from 14 states. Over half of these patients were male (54.4%), and 74.5% were aged 50 years or older. Data concerning underlying conditions were available for 178 (12%) of adult patients, 89.3% of whom had one or more underlying conditions. The following were most common: [68]

  • Hypertension (49.7%)
  • Obesity (48.3%)
  • Chronic lung disease (34.6%)
  • Diabetes mellitus (28.3%)
  • Cardiovascular disease (27.8%)

A prospective study on the epidemiology, clinical course, and outcomes among critically ill adults with COVID-19 in New York City found high rates of morbidity and mortality. Of the 257 critically ill patients studied, the median age was 62 years, 67% were men, and 82% had at least one chronic underlying illness (hypertension in 63%, obesity in 46%, and diabetes in 36%). As of April 28, 2020, 39% of the had patients died after a median of nine days in the hospital, 83% of whom had received invasive mechanical ventilation. [69]

Yang et al published an estimation of the infection-fatality risk of SARS-CoV-2 in New York City during the spring 2020 pandemic. From March 1 to June 6, 2020, 205,639 people had a laboratory-confirmed infection with SARS-CoV-2 and 21,447 confirmed and probable COVID-19-related deaths occurred among residents of New York City. The overall estimated infection-fatality risk was 1.39%. [70]  

This risk varied by age as follows: [70]  

  • 25-44 years: 0.116%
  • 45-64 years: 0.939%
  • 65-74 years: 4.87%; 6.72% (weekly IFR)
  • 75 years or older: 14.2%; 19.1% (weekly IFR)

Incidence in China

COVID-19–related deaths in China have mostly involved older individuals (≥60 years) and persons with serious underlying health conditions. [71]

An initial report of 425 patients with confirmed COVID-19 in Wuhan, China, attempted to describe the epidemiology. Many of the initial cases were associated with direct exposure to live markets, while subsequent cases were not. This further strengthened the case for human-to-human transmission. The incubation time for new infections was found to be 5.2 days, with a range of 4.1-7 days. The longest time from infection to symptoms seemed to be 12.5 days. At this point, the epidemic had been doubling approximately every 7 days, and the base reproductive number was 2.2 (meaning every patient infects an average of 2.2 others). [72] Further data will likely better define the clinical course, incubation time, and duration of infectivity.

On March 10, 2020, Dr. Zunyou Wu of the CCDC delivered a report at the Conference on Retroviruses and Opportunistic Infections (CROI) meeting detailing data from China, including updates on epidemiology and clinical presentation. COVID-19 was reported to be most severe in older adults, but a marked male predominance was no longer found. At presentation, approximately 40% of the cases were “mild” with no pneumonia symptoms. Another 40% were “moderate” with symptoms of viral pneumonia, 15% were severe, and 5% critical. During the course of the illness, 10%-12% of cases that initially presented as mild or moderate illness progressed to severe, and 15%-20% of severe cases eventually became critical. The mean time from exposure to symptoms was 5-6 days. Patients with mild cases seem to recover within 2 weeks, while patients with severe infections may take 3-6 weeks to recover. Deaths were observed from 2-8 weeks following symptom onset. Interestingly, completely asymptomatic infection was rare (< 1%) after detailed symptom assessments. Analysis of the virology data does suggest that patients can shed virus 1-2 days before symptoms appear, raising concern for asymptomatic spread.

In an initial report of 41 patients infected in Wuhan, China, Huang et al reported a 78% male predominance, with 32% of all patients reporting underlying disease. [73]

Young Adults

Outcomes from COVID-19 disease in young adults have been described by Cunningham et al. Of 3200 adults aged 18-34 years hospitalized in the US with COVID-19, 21% were admitted to the ICU, 10% required mechanical ventilation, and 3% died. Comorbidities included obesity 33% (25% overall were morbidly obese), diabetes 18%, and hypertension 16%. Independent predictors of death or mechanical ventilation included hypertension, male gender, and morbid obesity. Young adults with multiple risk factors for poor outcomes from COVID-19 compared similarly to middle-aged adults without such risk factors. [74]  

COVID-19 in children

Data continue to emerge regarding the incidence and how children are affected by COVID-19, especially for severe disease. A severe multisystem inflammatory syndrome linked to COVID-19 infection has been described in children. [75, 76, 77]

The American Academy of Pediatrics reports children represent 10.7% of all cases in the 49 states reporting by age, over 741,000 children have tested positive in the US since the onset of the pandemic as of October 15, 2020. This was a 13% increase over 2 weeks (October 1-15). This represents an overall rate of 986 cases per 100,000 children. Children were 1-3.6% of total reported hospitalizations (25 states and NYC reported), and between 0.5-7.2% of all child COVID-19 cases resulted in hospitalization. [78]  

 In September 2020, the CDC published the demographics of SARS-CoV-2-associated deaths among persons aged 21 years and younger. At the time of publication, approximately 6.5 million cases of SARS-CoV-2 infection and 190,000 associated deaths were reported in the US. Persons aged younger than 21 years constitute 26% of the US population. [79]  Characteristics of the 121 COVID-related deaths among this population reported between February 12 to July 31, 2020 include:  

  • Male: 63%
  • Younger than 1 year: 10%
  • Aged 1-9 years: 20%
  • Aged 10-20 years: 70%
  • Hispanic: 45%
  • Black: 29%
  • Native American or Alaska persons: 4%
  • Underlying conditions: 75%
  • Died after hospital admission: 65%
  • Died at home or emergency department: 32%

Clinical characteristics and outcomes of hospitalized children and adolescents aged 1 month to 21 years with COVID-19 in the New York City area have been described. These observations alerted clinicians to rare, but severe illness in children. Of 67 children who tested positive for COVID-19, 21 (31.3%) were managed as outpatients. Among 46 hospitalized patients, 33 (72%) were admitted to the general pediatric medical unit and 13 (28%) to the pediatric intensive care unit (PICU). Obesity and asthma were highly prevalent, but not significantly associated with PICU admission (P = .99). Admission to the PICU was significantly associated with higher C-reactive protein, procalcitonin, and pro-B type natriuretic peptide levels and platelet counts (P < .05 for all). Patients in the PICU were more likely to require high-flow nasal cannula (P = .0001) and were more likely to have received remdesivir through compassionate release (P < .05). Severe sepsis and septic shock syndromes were observed in 7 (53.8%) patients in the PICU. ARDS was observed in 10 (77%) PICU patients, 6 of whom (46.2%) required invasive mechanical ventilation for a median of 9 days. Of the 13 patients in the PICU, 8 (61.5%) were discharged home, and 4 (30.7%) patients remain hospitalized on ventilatory support at day 14. One patient died after withdrawal of life-sustaining therapy associated with metastatic cancer. [80]

A case series of 91 children who tested positive for COVID-19 in South Korea showed 22% were asymptomatic during the entire observation period. Among 71 symptomatic cases, 47 children (66%) had unrecognized symptoms before diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. Twenty-two children (24%) had lower respiratory tract infections. The mean (SD) duration of the presence of SARS-CoV-2 RNA in upper respiratory samples was 17.6 (6.7) days. These results lend more data to unapparent infections in children that may be associated with silent COVID-19 community transmission. [81]  

Dong et al presented data on 2,143 children younger than 18 years infected in Wuhan, China, between January 16 and February 8, 2020. The median age was 7 years, (interquartile range [IQR], 2-13 years) and 56.6% were male. Less than 10% were severe or critical cases. Younger age (especially infancy) increased the risk of severe illness. The proportion of severe and critical cases was 10.6% for children younger than 1 year, 7.3% for children aged 1-5 years, 4.2% for children aged 6-10 years, 4.1% for children aged 11-15 years, and 3% for children aged 16 years or older. [82]

Similarly, Qiu and colleagues retrospectively analyzed data from patients with COVID-19 (n=36) younger than 17 years (mean age, 8.3 [SD, 3.5] years) in Zhejiang, China, from January 17 to March 1, 2020. Most children were believed to be infected via close contact with family members. Clinically, 19 (53%) patients had a moderate presentation with pneumonia; 7 (19%) had a mild presentation with upper respiratory infection, and 10 (28%) were asymptomatic. Common symptoms upon admission included fever (13 [36%]) and dry cough (7 [19%]). The authors raised concerns about the large number of asymptomatic infections being a reservoir of transmission. [83]

Similar outcomes were noted by Jiehao et al. [84]

Neonatal fever [85] and late-onset neonatal sepsis [86] have been reported as unexpected manifestations of COVID-19 in case reports. Both children recovered.

An Expert Consensus Statement has been published that discusses diagnosis, treatment, and prevention of COVID-19 in children.

Multisystem inflammatory syndrome in children

Media reports and a health alert from the New York State Department of Health drew attention to a newly recognized multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. As of June 2020, more than 26 states are investigating potential cases of MIS-C in children with a wide range of ages. [87, 88]  For more information, see the American Academy of Pediatrics interim guidance for multisystem inflammatory syndrome in children (MIS-C).

Symptoms are reminiscent of Kawasaki disease, atypical Kawasaki disease, or toxic shock syndrome. All patients had persistent fevers, and more than half had rashes and abdominal complaints. Interestingly, respiratory symptoms were rarely described. Many patients did not have PCR results positive for COVID-19, but many had strong epidemiologic links with close contacts who tested positive. Furthermore, many had antibody tests positive for SARS-CoV-2. These findings suggest recent past infection, and this syndrome may be a postinfectious inflammatory syndrome.

Riphagen et al described 8 children (aged 4-14 years) in the United Kingdom who had severe inflammation and shock. The authors noted significant cardiac involvement. The patients also developed effusions that were consistent with an inflammatory process. [89] Verdoni et al compared 19 patients (7 boys, 12 girls; average age, 3 years [SD, 2.5]) diagnosed with Kawasaki disease between 2015 and February 2020 in Bergamo, Italy, with 10 patients (7 boys, 3 girls; average age, 7.5 years [SD, 3.5]) diagnosed between February 18 and April 20, 2020, during the COVID-19 outbreak. The COVID-19–exposed group demonstrated a greater incidence, were older, and had significantly more cardiac involvement and shock. [90] The significant number of children experiencing shock and serious cardiac involvement is being echoed in other cohorts. [91, 92]

Dolhnikoff, et al identified SARS-CoV-2 in cardiac tissue in a child who presented with myocarditis and died of heart failure. This is the first documented case of viral particles in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells. [93]  

COVID-19 in pregnant women and neonates

The U.S. COVID-19 PRIORITY study (Pregnancy coRonavIrus Outcomes RegIsTrY) pregnancy registry is open. Additionally, the study has a dashboard for real time data. 

The CDC COVID-NET data published in September 2020 reported that among 598 hospitalized pregnant women with COVID-19, 55% were asymptomatic at admission. Severe illness occurred among symptomatic pregnant women, including intensive care unit admissions (16%), mechanical ventilation (8%), and death (1%). Pregnancy losses occurred for 2% of pregnancies completed during COVID-19-associated hospitalizations, and were experienced by both symptomatic and asymptomatic women. [94]

A multicenter study involving 16 Spanish hospitals reported outcomes of 242 pregnant women diagnosed with COVID-19 during their third trimester from March 13 to May 31, 2020. The women and their 248 newborns were monitored until the infant was 1 month old. COVID-19 positive who were hospitalized had a higher risk of ending their pregnancy via C-section (P = 0.027). Newborns whose mothers had been admitted owing to their COVID-19 infection had a higher risk of premature delivery (P = 0.006). No infants died and no vertical or horizontal transmission was detected. Infants exclusively breastfed at discharge was 41.7% and was 40.4% at 1 month. [95]

A cohort study of pregnant women (n = 64) with severe or critical COVID-19 disease hospitalized at 12 US institutions between March 5, 2020, and April 20, 2020 has been published. At the time of the study, most women (81%) received hydroxychloroquine; 7% of women with severe disease and 65% with critical disease received remdesivir. All women with critical disease received either prophylactic or therapeutic anticoagulation.  One 1 case of maternal cardiac arrest occurred, but there were no cases of cardiomyopathy or maternal death. Half of the women (n=32) delivered during their hospitalization (34% severe group; 85% critical group). Additionally, 88% with critical disease delivered preterm during their disease course, with 16 of 17 (94%) pregnant women giving birth through cesarean delivery. Overall, 15 of 20 (75%) women with critical disease delivered preterm. There were no stillbirths or neonatal deaths or cases of vertical transmission. [96]  

A case series of 6 pregnant patients hospitalized with severe or critical COVID-19 received inhaled nitric oxide therapy (160-200 ppm by mask twice daily). Cardiopulmonary function improved after initiating nitric oxide, as observed by increased systemic oxygenation in each administration session among those with evidence of baseline hypoxemia and reduced tachypnea in all patients in each session. [97]

Zhu et al analyzed the outcomes of 10 neonates born to mothers with confirmed COVID-19. [98] Of the 9 mothers (one gave birth to twins), 4 were symptomatic prior to delivery, 2 became symptomatic at delivery, and 3 developed symptoms in the postpartum period. Nine of the 10 neonates tested negative for COVID-19 from 1-9 days following delivery. One mother died, 5 were discharged, and 4 were hospitalized. The infants most commonly experienced respiratory distress, but abnormal liver function and thrombocytopenia aware also observed. Premature birth was observed in 6 women, consistent with a case report by Wang et al. [99]

Zeng et al presented data on 33 neonates born to mothers with COVID-19. [100] They reported good outcomes overall but drew attention to three newborns with COVID-19, all of whom presented with early-onset pneumonia but eventually recovered. The authors note that each was delivered via cesarean delivery while infection-control precautions were observed to minimize the risk of transmission. Therefore, they raise the possibility of vertical infection. This is in contrast to data analyzed by Schwartz et al, finding no instances of vertical transmission in 38 pregnant women with COVID-19. [101]

Chen et al reported data on 9 pregnant women with COVID-19 with live births delivered via cesarean delivery in Wuhan, China. [102] Seven of the 9 women presented with a fever; other symptoms included cough (4 of 9 patients), myalgia (3), sore throat (2), and malaise (2). Five of nine patients had lymphopenia (< 1.0 × 109 cells/L). Three patients had increased aminotransferase concentrations. None of the patients developed severe COVID-19 pneumonia or died as of Feb 4, 2020. Among the 9 neonates, 2 were reported to have fetal distress. All fared well, with excellent Apgar scores. Amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples from 6 of the neonates were tested for SARS-CoV-2, all with negative results.

Yu and colleagues presented data on 7 pregnant patients with COVID-19. The mean age was 32 years (range, 29-34 years), and the mean gestational age was 39 weeks plus 1 day (range, 37 weeks to 41 weeks plus 2 days). They observed fever in 86% of the women, cough in 14%, shortness of breath in 14%, and diarrhea in 14%. All underwent cesarean delivery within 3 days of clinical presentation, with an average gestational age of 39 weeks plus 2 days, with good outcomes. Three neonates were tested for SARS-CoV-2, and one neonate was infected with SARS-CoV-2 36 hours after birth. [103]

Breastfeeding

A study by Chambers et al found human milk is unlikely to transmit SARS-CoV-2 from infected mothers to infants.  The study included 64 milk samples provided by 18 mothers infected with COVID-19. Samples were collected before and after COVID-19 diagnosis. No replication-competent virus was detectable in any of their milk samples compared with samples of human milk that were experimentally infected with SARS-CoV-2. [104]

COVID-19 in patients with HIV

Data for people with HIV and coronavirus are emerging. A multicenter registry has published outcomes for 286 patients with HIV who tested positive for COVID-19 between April 1 and July 1, 2020. Patient characteristics included mean age of 51.4 years [SD, 14.4]), 25.9% were female, and 75.4% were African-American or Hispanic. Most patients (94.3%) were on antiretroviral therapy, 88.7% had HIV virologic suppression, and 80.8% had comorbidities. Within 30 days of positive SARS-CoV-2 testing, 164 (57.3%) patients were hospitalized, and 47 (16.5%) required ICU admission. Mortality rates were 9.4% (27/286) overall, 16.5% (27/164) among those hospitalized, and 51.5% (24/47) among those admitted to an ICU. [105]

COVID-19 in clinicians

Among a sample of health care providers who routinely cared for COVID-19 patients in 13 US academic medical centers from February 1, 2020, 6% had evidence of previous SARS-CoV-2 infection, with considerable variation by location that generally correlated with community cumulative incidence. Among participants who had positive test results for SARS-CoV-2 antibodies, approximately one-third did not recall any symptoms consistent with an acute viral illness in the preceding months, nearly one half did not suspect that they previously had COVID-19, and approximately two-thirds did not have a previous positive test result demonstrating an acute SARS-CoV-2 infection. [106]

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Prognosis

Early data

Early reports described COVID-19 as clinically milder than MERS or SARS in terms of severity and case fatality rate. [32] The reported mortality rate has fluctuated; the latest rate estimated by the CDC has been around 0.4% for symptomatic cases. [65]

Early in the outbreak, the WHO reported that severe cases in China had mostly been reported in adults older than 40 years with significant comorbidities and skewed toward men, although this pattern may be changing. [62]

COVID-19–related deaths in China have mostly involved older individuals (≥60 years) and persons with serious underlying health conditions. In the United States, attributable deaths have been most common in adults aged 85 years or older (10%-27%), followed by adults aged 65-84 years (3%-11%), adults aged 55-64 years (1%-3%), and adults aged 20-54 years (< 1%). As of March 16, 2020 no fatalities or ICU admissions had been reported in persons aged 19 years or younger. [71]

In China, the case-fatality rate was found to range from 5.8% in Wuhan to 0.7% in the rest of China. [107] In most cases, fatality occurs in patients who are older or who have underlying health conditions (eg, diabetes, cardiovascular disease, chronic pulmonary disease, cancer, hypertension). [108]

Mortality and diabetes

Type 1 and type 2 diabetes are both independently associated with a significant increased odds of in-hospital death with COVID-19. A nationwide analysis in England of 61,414,470 individuals in the registry alive as of February 19, 2020, 0.4% had a recorded diagnosis of type 1 diabetes and 4.7% of type 2 diabetes. A total of 23,804 COVID-19 deaths in England were reported as of May 11, 2020, one-third were in people with diabetes, including 31.4% with type 2 diabetes and 1.5% with type 1 diabetes. Upon multivariate adjustment, the odds of in-hospital COVID-19 death were 3.5 for those with type 1 diabetes and 2.03 for those with type 2 diabetes, compared with deaths without known diabetes. Further adjustment for cardiovascular comorbidities found the odds ratios were still significantly elevated in both type 1 (2.86) and type 2 (1.81) diabetes. [109]

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Virology

The full genome of SARS-CoV-2 was first posted by Chinese health authorities soon after the initial detection, facilitating viral characterization and diagnosis. [10] The CDC analyzed the genome from the first US patient who developed the infection on January 24, 2020, concluding that the sequence is nearly identical to the sequences reported by China. [10] SARS-CoV-2 is a group 2b beta-coronavirus that has at least 70% similarity in genetic sequence to SARS-CoV. [32] Like MERS-CoV and SARS-CoV, SARS-CoV-2 originated in bats. [10]

Mutation

In early May 2020, a study by Korber et al reported the emergence of a SARS-CoV-2 mutation (Spike D614G), one of several Spike (S) mutations that have been discovered. SARS-CoV-2 infections with this mutation have become the dominant viral lineage in North America, Europe, and Australia. The significance of the D614G mutation in terms of factors such as transmissibility, virulence, antigenicity, and potential treatment resistance is poorly understood. [110, 111]

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