Coronavirus Disease 2019 (COVID-19) 

Updated: Aug 03, 2020
Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD 

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 more than 130,000 deaths reported.

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

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]

Symptoms in children with infection appear to be uncommon, although some children with severe COVID-19 have been reported.[17, 21, 22]

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.[23]

See Workup.

Management

The antiviral drug remdesivir gained emergency use authorization (EUA) from the FDA on May 1, 2020, based on preliminary data showing a faster time to recovery of hospitalized patients with severe disease.[24, 25, 26] Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. Further data on remdesivir suggest that it shortens the time to recovery in hospitalized adults.[27]

In addition, infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases.[28]

No vaccine is currently available for SARS-CoV-2. 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.[29, 30, 31, 32]

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.

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.[33] 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%).[34]

Route of Transmission

SARS-CoV-2 is believed to spread primarily via respiratory droplets that are transmitted from person to person who are in close contact (usually within about 6 feet).[35, 36, 37] 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.[37]

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.[35] 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.[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.[35]

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.[51]

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.[52]

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.[53]

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.[54]

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.[55] 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.[56] In Boston, Massachusetts, 408 homeless individuals were tested for SARS-CoV-2 infection, and 147 tested positive, most (87.8%) of whom were asymptomatic.[57, 58]

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.[59]

A population survey conducted in Iceland found that 57% of persons who tested positive for SARS-CoV-2 infection reported symptoms.[60]

Epidemiology

Coronavirus outbreak and pandemic

As of August 3, 2020, COVID-19 has been confirmed in over 18.1 million individuals worldwide and has resulted in more than 690,000 deaths. More than 180 countries have reported laboratory-confirmed cases of COVID-19 on all continents except Antarctica.[61]

In the United States, more than 4.6 million cases of COVID-19 have been confirmed as of August 3, 2020, resulting in over 154,000 deaths.[62, 63] As of March 26, 2020, the United States has more confirmed infections than any other country in the world.[64]

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
  • Overall symptomatic case fatality rate: 0.4%
  • Overall symptomatic case hospitalization rate: 3.4%
  • Asymptomatic SARS-CoV-2 infection rate: 35%
  • Infectiousness of asymptomatic individuals relative to symptomatic individuals: 100%
  • Percentage of transmission occurring prior to symptom onset: 40%
  • Time from exposure to symptom onset: Mean of 6 days

United States incidence

A total of 1,761,503 cases of COVID-19 were reported in the United States from January 22 to May 30, 2020, resulting in 103,700 deaths. The cumulative incidence was 403.6 cases per 100,000 persons. The following data were derived from analysis of these cases.[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%)

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]

Incidence in China

COVID-19–related deaths in China have mostly involved older individuals (≥60 years) and persons with serious underlying health conditions.[70]

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).[71] 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.[72]

COVID-19 in children

To date, multiple outbreak reports have noted the relative sparing of the pediatric population, especially from severe disease. More recently, a severe multisystem inflammatory syndrome apparently linked to COVID-19 infection has been noted in children.

Of the 149,082 laboratory-confirmed COVID-19 cases in which patient age was known reported between February 12 and April 2, 2020, in the United States, 2,572 cases (1.7%) involved children (< 18 years). Among the small proportion of cases in which the patient’s symptoms, underlying conditions, and hospitalization status were known, 73% of children with COVID-19 had fever, cough, or shortness of breath (versus 93% in adults aged 18-65 years) and 20% were hospitalized (versus 33% in adults). Older children accounted for a greater number of hospitalizations than younger children (owing to more infections overall), but the greatest proportion of hospitalizations among children involved children younger than 1 year. Three children died of COVID-19 complications. The findings of this study continue to affirm the observations that children tend to be less symptomatic and could have missed infections.[73]

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.[21]

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.[22]

Similar outcomes were noted by Jiehao et al.[74]

Neonatal fever[75] and late-onset neonatal sepsis[76] 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

Recent media reports and a health alert from the New York State Department of Health have drawn attention to a newly recognized multisystem inflammatory syndrome in children (MIS-C) that may be related to COVID-19. To date, more than 26 states are investigating potential cases of MIS-C in children with a wide range of ages.[77, 78]

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.[79] 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.[80] The significant number of children experiencing shock and serious cardiac involvement is being echoed in other cohorts.[81, 82]

COVID-19 in pregnant women and neonates

Zhu et al analyzed the outcomes of 10 neonates born to mothers with confirmed COVID-19.[83] 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.[84]

Zeng et al presented data on 33 neonates born to mothers with COVID-19.[85] 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.[86]

Chen et al reported data on 9 pregnant women with COVID-19 with live births delivered via cesarean delivery in Wuhan, China.[87] 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.[88]

Prognosis

Early reports described COVID-19 as clinically milder than MERS or SARS in terms of severity and case fatality rate.[34] 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.[63]

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.[70]

In China, the case-fatality rate was found to range from 5.8% in Wuhan to 0.7% in the rest of China.[89] 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).[90]

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.[34] 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.[91, 92]

 

Presentation

History

Presentations of COVID-19 have ranged from asymptomatic/mild symptoms to severe illness and mortality. Common symptoms have included fever, cough, and shortness of breath.[15] Other symptoms, such as malaise and respiratory distress, have also been described.[34]

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]

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

Cheung et al conducted a systematic review and meta-analysis to evaluate the occurrence of gastrointestinal (GI) symptoms (anorexia, nausea, vomiting, diarrhea, abdominal pain or discomfort) in patients with COVID-19. They found that 17.6% of patients with COVID-19 had GI symptoms. Stool tested positive for SARS-CoV-2 RNA in 48.1%, including stool collected after respiratory samples tested negative for viral RNA.[93]

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]

In an initial report of 41 patients infected in Wuhan, China, Huang et al reported that most common clinic finding was fever (98%), followed by cough (76%) and myalgia/fatigue (44%). Headache, sputum production, and diarrhea were less common. The clinical course was characterized by the development of dyspnea in 55% of patients and lymphopenia in 66%. All patients with pneumonia had abnormal lung imaging findings. Acute respiratory distress syndrome (ARDS) developed in 29% of patients,[94] and ground-glass opacities are common on CT scans.[72]

Symptoms in children with infection appear to be uncommon, although some children with severe COVID-19 have been reported.[17, 21, 22]

Asymptomatic infections have been reported, but the incidence is unknown.[72]

Clinicians evaluating patients with fever and acute respiratory illness should obtain information regarding travel history or exposure to an individual who recently returned from a country or US state experiencing active local transmission.[95]

Risk factors for severe COVID-19, regardless of age, include the following:[41, 17, 96, 97]

  • Chronic kidney disease
  • COPD
  • Immunocompromised state due to solid organ transplant
  • Obesity (BMI ≥30)
  • Serious heart conditions (eg, heart failure, coronary artery disease, cardiomyopathies)
  • Sickle cell disease
  • Type 2 diabetes mellitus

The following are underlying conditions that may represent an increased risk of severe COVID-19:

  • Asthma (moderate to severe)
  • Cerebrovascular disease
  • Cystic fibrosis
  • Immunocompromised state due to blood or bone marrow transplant, immunodeficiencies, HIV infection, corticosteroid use (or other medications that weaken the immune system)
  • Neurologic conditions (eg, dementia)
  • Liver disease
  • Pregnancy
  • Pulmonary fibrosis
  • Smoking
  • Thalassemia
  • Type 1 diabetes mellitus

Williamson et al, in an analysis of 17 million patients, reaffirmed that severe COVID-19 and mortality was more common in males, older individuals, individuals in poverty, Black persons, and patients with medical conditions such as diabetes and severe asthma, among others.[98]

A multicenter observational cohort study conducted in Europe found frailty to be a greater predictor of mortality than age or comorbidities.[99]

Type A blood has been suggested as a potential factor that predisposes to severe COVID-19, specifically in terms of increasing the risk of respiratory failure. Blood type O appears to confer a protective effect.[100, 101]

Patients with suspected COVID-19 should be reported immediately to infection-control personnel at their healthcare facility and the local or state health department. Current CDC guidance calls for the patient to be cared for with airborne and contact precautions (including eye shield) in place.[23] Patient candidates for such reporting include those with fever and symptoms of lower respiratory illness who have travelled from Wuhan City, China, within the preceding 14 days or who have been in contact with an individual under investigation for COVID-19 or a patient with laboratory-confirmed COVID-19 in the preceding 14 days.[95]

Early in the outbreak, one patient with COVID-19 (a 61-year-old man with an underlying abdominal tumor and cirrhosis) was admitted with severe pneumonia and respiratory failure. Complications of infection included severe pneumonia, septic shock, acute respiratory distress syndrome (ARDS), and multiorgan failure, resulting in death.[34]

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] In a European study of 72 patients with PCR results positive for COVID-19, 53 patients (74%) reported reduced olfaction, while 50 patients (69%) reported a reduced sense of taste. Forty-nine patients (68%) reported both symptoms.[102]

Physical Examination

Patients who are under investigation for COVID-19 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.[23]

The most common serious manifestation of COVID-19 upon initial presentation is pneumonia. Fever, cough, dyspnea, and abnormalities on chest imaging are common in these cases.[103, 94, 104, 105]

Huang et al found that, among patients with pneumonia, 99% had fever, 70% reported fatigue, 59% had dry cough, 40% had anorexia, 35% experienced myalgias, 31% had dyspnea, and 27% had sputum production.[94]

Complications

Reported complications of COVID-19 have included pneumonia, acute respiratory distress syndrome, cardiac injury, arrhythmia, septic shock, liver dysfunction, acute kidney injury, and multi-organ failure, among others.

Acute respiratory distress syndrome

ARDS is a major complication in severe cases of COVID-19, affecting 20%-41% of hospitalized patients.[105, 106] Wu et al reported that, among 200 patients with COVID-19 who were hospitalized, older age, neutrophilia, and elevated lactate dehydrogenase and D-dimer levels increased the risks of ARDS and death.[106]

Cardiac concerns

Increasing data have shown a significant burden of cardiac injury in COVID-19. Up to 20% of patients in a cohort in China demonstrated cardiac injury, often associated with more severe disease. They were more likely to be older, to have ARDS, and to experience higher mortality rates.[107]

Clerkin et al[108] and Driggin et al[109] published excellent reviews delineating the current understanding and future investigation needs. Multiple case series have noted an increased burden of cardiovascular disease (4%-14%) and cardiovascular comorbidities in patients with COVID-19, often associated with increased morbidity and mortality. The risk of cardiac injury, evidenced by increased troponin levels, was up to 22% in ICU patients. Interestingly, up to 12% of patients without known cardiovascular disease had elevated troponin levels or experienced cardiac arrest during hospitalization for COVID-19. The pathophysiology of injury is under investigation, but some presentations seem related to cytokine storm.

Arentz et al, in a study of 21 patients with severe COVID-19 admitted to the ICU in Washington State, reported that 33% had cardiomyopathy.[110]

A study of 100 randomly selected patients in Germany showed 78% had abnormal MRI findings a median of 71 days after testing positive for SARS-CoV-2. Of these, 60% showed cardiac inflammation that was independent of preexisting conditions, severity and overall course of the acute illness. Approximately 20% reported atypical chest pain or palpitations at the time of MRI. Over one-third complained of ongoing shortness of breath.[111] Data continue to emerge regarding cardiovascular complications and ongoing research is warranted.

Acute kidney injury

In a study of 5,449 patients hospitalized with severe COVID-19 in New York, 1,993 (36.6%) developed acute kidney injury, 14.3% of whom required dialysis. The need for dialysis was associated with severe disease and respiratory failure.[112]

Clinical Progression

A retrospective, single-center study from Shanghai evaluated clinical progression of COVID-19 in 249 patients. The interval from symptom onset to hospitalization averaged 4 days (range, 2-7 days) among symptomatic patients. The vast majority (94.3%) of patients developed fever. Hospitalization lasted an average of 16 days (range, 12-20 days) before discharge.

The estimated median duration of fever in all febrile patients was 10 days after symptom onset.

In 163 patients (65.7%), radiological abnormalities (compared with baseline) occurred on day 7 following symptom onset, 154 (94.5%) of whom improved radiologically by day 14.

The median duration to negative results on RT-PCT using upper respiratory tract samples was 11 days. Viral clearance was more likely to be delayed in ICU patients.

The authors concluded that most cases of COVID-19 are mild. Early viral replication control and host-directed therapy applied at later stages were essential to improving outcomes.[113]

In collaboration with the National Health Commission of China, Liang et al developed clinical scoring at hospital admission to predict progression to critical illness (online risk calculator free for public use). The clinical scoring system was validated with data from a nationwide cohort (n = 1590) in China.[114]

In Germany, postmortem examination of ten patients with COVID-19 revealed extensive lung pathology over time with both acute and organizing components. Nonspecific and seemingly mild liver and cardiac inflammation was also found, but no CNS involvement.[115] A separate autopsy study of 7 lungs described widespread thrombosis and microangiopathy with evidence of severe endothelial injury. Compared with findings in patients who died of ARDS due to influenza A (H1N1), the lungs from patients with COVID-19 had significantly more microthrombi.[116]

 

Workup

Approach Considerations

Currently, diagnostic testing for SARS-CoV-2 infection can be conducted by the CDC, state public health laboratories, hospitals using their own developed and validated tests, and some commercial reference laboratories.[117]

State health departments with a patient under investigation (PUI) should contact CDC’s Emergency Operations Center (EOC) at 770-488-7100 for assistance with collection, storage, and shipment of clinical specimens for diagnostic testing. Specimens from the upper respiratory tract, lower respiratory tract, and serum should be collected to optimize the likelihood of detection.[95]

The FDA now recommends that nasal swabs that access just the front of the nose be used in symptomatic patients, allowing for (1) a more comfortable and simplified collection method and (2) self-collection at collection sites.[118]

Please see CDC Interim Guidance on Coronavirus Disease 2019 (COVID-19) for testing recommendations by the CDC.

The Infectious Diseases Society of America (IDSA) has also issued testing recommendations in terms of tier-based priority groups.[119]

According to the IDSA, the following patients should be considered highest priority for testing:

  • Patients who are critically ill or who have unexplained viral pneumonia or respiratory failure
  • Individuals with fever or signs/symptoms of lower respiratory tract illness who have had close contact with an individual with laboratory-confirmed COVID-19 within 14 days of symptom onset
  • Individuals with fever or signs/symptoms of lower respiratory tract illness who have traveled within 14 days of symptom onset to areas where sustained community transmission has been reported
  • Persons with fever or signs/symptoms of lower respiratory tract illness who are immunosuppressed, are older, or have underlying chronic health issues
  • Persons with fever or signs/symptoms of lower respiratory tract illness who are critical for the pandemic response, including healthcare workers, public health officials, and other essential leaders

Patients considered for second-priority testing include symptomatic residents of long-term care and hospitalized patients not in the ICU.

Patients considered for third-priority testing include those being treated in outpatient settings who meet criteria for influenza testing, including persons with certain comorbidities (eg, diabetes, COPD, CHF); pregnant women; and symptomatic pediatric patients with additional risk factors.

Finally, individuals considered for fourth-priority testing include persons who are undergoing monitoring for data collection and epidemiologic studies by health authorities.

Laboratory Studies

Diagnostic Laboratory Studies

Polymerase chain reaction

The CDC has developed a diagnostic test for detection of the virus and received special Emergency Use Authorization (EUA) from the FDA on February 4, 2020, for its use.[120] The test is a real-time reverse transcription–polymerase chain reaction (rRT-PCR) assay that can be used to diagnose the virus in respiratory and serum samples from clinical specimens.[10]

Although the CDC rRT-PCR test was found to have performance issues related to manufacture of one of the reagents, the CDC has since developed an updated protocol that excludes the need for the third (problematic) component of the test without affecting accuracy. The test kits are now being shipped to US state and local public health laboratories that the CDC has determined to be qualified.[10]

On April 13, 2020, the FDA granted EUA for a saliva-based COVID-19 test, which can be used to test patients’ self-collected saliva rather than swabs collected by healthcare personnel, potentially limiting exposure and increasing the capacity for testing.[121]

Of note, commercially available molecular tests for other respiratory viruses (even those detecting endemic coronaviruses) have not demonstrated the ability to detect SARS-CoV-2. Australian scientists have successfully grown the virus in cultures.[122]

A Chinese study reported that positive rates varied by sample type tested. In 205 patients with confirmed COVID-19 among 3 hospitals, pharyngeal swabs were collected 1-3 days after admission. Other types of samples were also collected throughout illness—sputum, blood, urine, feces, nasal swabs, and bronchial brush or bronchoalveolar lavage (BAL) fluid. Samples were tested with RT-PCR. Of 1070 total samples tested, types with the highest rates of positive results included BAL fluid (14/15; 93%), sputum (75/104; 72%), nasal swabs (5/8; 63%), brush biopsy (6/13; 46%), pharyngeal swabs (126/398; 32%), feces (44/153; 29%), blood (3/307; 1%), and urine (0/72; 0%). Nasal swabs were found to contain the most virus.[123]

Upper respiratory tract specimens have been reported to contain a smaller viral load than lower respiratory tract specimens do. If PCR tests are negative for SARS-CoV-2 using upper respiratory tract specimens despite persistent clinical suspicion, the WHO recommends retesting using lower respiratory tract specimens.[124, 123]

Viral dynamics

Xiao et al studied the prolonged positivity of PCR results beyond the acute phase of infection in 56 patients with confirmed mild or moderate COVID-19 (none had been admitted to the ICU). SARS-CoV-2 RT-PCR testing was performed in each patient an average of 5 times (299 total tests administered). They found the highest rate of positivity at week one (100%), followed by 89.3% at week 2, 66.1% at week 3, 32.1% at week 4, 5.4% at week 5, and 0% at week 6. They also found that prolonged viral shedding occurred more often in older patients and in persons with comorbidities such as diabetes.[125] These findings may have implications in terms of “relapsed” infections and positive PCR results following negative ones.[126, 127]

The diagnostic value of repeated testing was illustrated in a study from Singapore in which 70 patients underwent SARS-CoV-2 PCR testing. Sixty-two patients tested positive for SARS-CoV-2 using the first clinical specimen collected (nasopharyngeal swab in all cases). A second test was administered 24 hours after the first test, yielding positive results in 5 patients whose initial results were negative. The three remaining patients tested positive after more than two tests.[128]

RT-PCR tests positive for SARS-CoV-2 after apparently resolved COVID-19 (two negative PCR results consecutively, along with clinical improvement) have been reported. Various theories for these “re-positive” results have been posited, including inactivated viral RNA being detected or viral reactivation. Nonetheless, positive results following consecutive negative ones occurred after a relatively short interval, probably do not indicate reinfection, may not reflect infectious SARS-CoV-2, and were not accompanied by worsening symptoms. In a Korean study, all confirmatory viral cultures performed (108) were negative for SARS-CoV-2 in patients in whom PCR results were “re-positive,” and contact tracing revealed no new COVID-19 cases linked to these patients after initial resolution.[129, 130, 131]

Please see CDC Interim Guidance on Coronavirus Disease 2019 (COVID-19) for additional testing recommendations by the CDC.

Antibody testing

Cheng et al reviewed data on serodiagnostics and advised that, as of June 2020, molecular testing is hampered by limited testing capacity and imperfect sensitivity and that antibody testing may be able to aid specific diagnostic scenarios but should not be used for diagnosing acute COVID-19.[132]

The FDA has issued emergency use authorization for a qualitative immunoglobulin M (IgM)/immunoglobulin G (IgG) antibody tests for SARS-CoV-2 using serum, plasma (EDTA or citrate), or venipuncture whole blood. IgM antibodies generally become detectable several days after initial infection, while IgG antibodies can be detected later.[133]

Recently, the FDA tightened requirements for companies that develop COVID-19 antibody tests in an effort to combat fraud and to better regulate the spate of tests that have come to market. The new approach requires all commercial manufacturers to submit EUA requests with validation data within 10 business days from the date they notified the FDA of their validation testing or from the date of the May 4 policy, whichever is later. A list of serology tests granted EUA from the FDA, along with their reported sensitivity and specificity rates, can be found at the FDA’s EUA Authorized Serology Test Performance page.[134, 135]

In a preprint study, Wu F et al analyzed plasma from 175 patients with COVID-19 in recovery who had experienced mild symptoms. They found that titers of neutralizing antibodies varied. Titers in 10 patients were below the level of detection. Higher levels of antibody correlated with older and middle age and higher CRP levels at admission but negatively correlated with lymphocyte count at admission. The authors raised concerns about the development of lasting immunity after infection.[136]

In a Chinese study of 66 patients with PCR-confirmed COVID-19 and another 24 patients with suspected but unconfirmed COVID-19, the seroconversion of specific IgM and IgG antibodies were observed as early as 4 days following symptom onset.

In the 66 patients with confirmed COVID-19, the sensitivity of IgM was found to be 77.3%; specificity, 100%; positive predictive value (PPV), 100%; negative predictive value (NPV), 80%; and consistency rate, 88.1%. For IgG, the sensitivity was found to be 83.3%; specificity, 95%; PPV, 94.8%; NPV, 83.8%; and consistency rate, 88.1%.

In the 24 patients with suspected but unconfirmed COVID-19, the sensitivity of IgM was 87.5%, specificity, 100%; PPV, 100%; NPV, 95.2%; and consistency rate, 96.4%. For IgG, the sensitivity was 70.8%; specificity, 96.6%; PPV, 85%; NPV, 89.1%; and consistency rate, 88.1%.[137]

Guo et al reported that IgM enzyme-linked immunoassay (ELISA) results were positive in 93% of patients with suspected COVID-19 (characteristic radiographic, clinical, and epidemiologic features) despite negative PCR results and despite negative results on plasma specimens tested before the COVID-19 outbreak.[138]

Viral culture

In patients with suspected COVID-19, virus isolation in cell culture or initial characterization of viral agents recovered in cultures of specimens is not recommended for biosafety reasons.[95]

Laboratory findings in patients with COVID-19

Leukopenia, leukocytosis, and lymphopenia were common among early cases.[34, 94]

Lactate dehydrogenase and ferritin levels are commonly elevated.[94]

Wu et al reported that, among 200 patients with COVID-19 who were hospitalized, older age, neutrophilia, and elevated lactate dehydrogenase and D-dimer levels increased the risks of ARDS and death.[106]

CT Scanning

Chest CT scanning in patients with COVID-19–associated pneumonia usually shows ground-glass opacification, possibly with consolidation. Some studies have reported that abnormalities on chest CT scans are usually bilateral, involve the lower lobes, and have a peripheral distribution. Pleural effusion, pleural thickening, and lymphadenopathy have also been reported, although with less frequency.[94, 139, 140]

Bai et al reported the following common chest CT scanning features among 201 patients with CT abnormalities and positive RT-PCR results for COVID-19:[141]

  • Peripheral distribution (80%)
  • Ground-glass opacity (91%)
  • Fine reticular opacity (56%)
  • Vascular thickening (59%)

Less-common features on chest CT scanning included the following:[141]

  • Central and peripheral distribution (14%)
  • Pleural effusion (4.1%)
  • Lymphadenopathy (2.7%)

The American College of Radiology (ACR) recommends against using CT scanning for screening or diagnosis but instead reserving it for management in hospitalized patients.[142]

At least two studies have reported on manifestations of infection in apparently asymptomatic individuals. Hu et al reported on 24 asymptomatic infected persons in whom chest CT scanning revealed ground-glass opacities/patchy shadowing in 50% of cases.[143] Wang et al reported on 55 patients with asymptomatic infection, two-thirds of whom had evidence of pneumonia as revealed by CT scanning.[144]

Progression of CT abnormalities

Mingzhi et al recommend high-resolution CT scanning and reported the following CT changes over time in patients with COVID-19 among 3 Chinese hospitals:[145]

  • Early phase: Multiple small patchy shadows and interstitial changes begin to emerge in a distribution beginning near the pleura or bronchi rather than the pulmonary parenchyma.
  • Progressive phase: The lesions enlarge and increase, evolving to multiple ground-glass opacities and infiltrating consolidation in both lungs.
  • Severe phase: Massive pulmonary consolidations occur, while pleural effusion is rare.
  • Dissipative phase: Ground-glass opacities and pulmonary consolidations are absorbed completely. The lesions begin evolving into fibrosis. [145]
Axial chest CT demonstrates patchy ground-glass op Axial chest CT demonstrates patchy ground-glass opacities with peripheral distribution.
Coronal reconstruction chest CT of the same patien Coronal reconstruction chest CT of the same patient above, showing patchy ground-glass opacities.
Axial chest CT shows bilateral patchy consolidatio Axial chest CT shows bilateral patchy consolidations (arrows), some with peripheral ground-glass opacity. Findings are in peripheral and subpleural distribution.

Chest Radiography

In a retrospective study of patients in Hong Kong with COVID-19, common abnormalities on chest radiography, when present, included consolidation (30 of 64 patients; 47%) and ground-glass opacities (33%). Consolidation was commonly bilateral and of lower zone distribution. Pleural effusion was an uncommon finding. Severity on chest radiography peaked 10-12 days following system onset.[146]

Chest radiography may reveal pulmonary infiltrates.[147]

The heart is normal in size. There are diffuse, pa The heart is normal in size. There are diffuse, patchy opacities throughout both lungs, which may represent multifocal viral/bacterial pneumonia versus pulmonary edema. These opacities are particularly confluent along the periphery of the right lung. There is left midlung platelike atelectasis. Obscuration of the left costophrenic angle may represent consolidation versus a pleural effusion with atelectasis. There is no pneumothorax.
The heart is normal in size. There are bilateral h The heart is normal in size. There are bilateral hazy opacities, with lower lobe predominance. These findings are consistent with multifocal/viral pneumonia. No pleural effusion or pneumothorax are seen.
The heart is normal in size. Patchy opacities are The heart is normal in size. Patchy opacities are seen throughout the lung fields. Patchy areas of consolidation at the right lung base partially silhouettes the right diaphragm. There is no effusion or pneumothorax. Degenerative changes of the thoracic spine are noted.
The same patient as above 10 days later. The same patient as above 10 days later.
The trachea is in midline. The cardiomediastinal s The trachea is in midline. The cardiomediastinal silhouette is normal in size. There are diffuse hazy reticulonodular opacities in both lungs. Differential diagnoses include viral pneumonia, multifocal bacterial pneumonia or ARDS. There is no pleural effusion or pneumothorax.
 

Treatment

Approach Considerations

The antiviral drug remdesivir gained emergency use authorization (EUA) from the FDA on May 1, 2020, based on preliminary data showing a faster time to recovery of hospitalized patients with severe disease.[24, 25, 26] Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies.

All infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases.[28]

Early in the outbreak, concerns emerged about nonsteroidal anti-inflammatory drugs (NSAIDs) potentially increasing the risk of adverse effects in individuals with COVID-19. However, in late April, the WHO took the position that NSAIDS do not increase the risk of adverse events or affect acute healthcare utilization, long-term survival, or quality of life.[148]

No vaccine is currently available for SARS-CoV-2. 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.[29, 30, 31, 32]

Searching for effective therapies for COVID-19 infection is a complex process. Gordon et al identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays.[149]

How these potential COVID-19 treatments will translate to human use and efficacy is not easily or quickly understood. The question of whether some existing drugs that have shown in vitro antiviral activity might achieve adequate plasma pharmacokinetics with current approved doses was examined by Arshad et al. The researchers identified in vitro anti–SARS-CoV-2 activity data from all available publications up to April 13, 2020, and recalculated an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). The researchers also calculated the unbound drug to tissue partition coefficient to predict lung concentrations that would exceed their reported EC50 levels.[150]

The WHO has embarked on an ambitious global "megatrial" called SOLIDARITY in which confirmed cases of COVD-19 are randomized to standard care or one of four active treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). As of July 4, 2020, the treatment arms in hospitalized patients that include hydroxychloroquine, chloroquine, or lopinavir/ritonavir have been discontinued owing to the drugs showing little or no reduction in mortality compared with standard of care.[151]

The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data are not carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group intervention without a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety.[152]

Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy is unknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to base judgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks without proof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. In addition, demand for unproven therapies can cause shortages of medications that are approved and indicated for other diseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies.[153]

Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that are necessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand.[154, 155]

It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within a few months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has been presented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plus azithromycin, he provides clinicians with a quick review of critical analyses.[156]

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.

Additional information for investigational drugs and biologics can be obtained from the following resources:

Related articles

See the article Coronavirus Disease 2019 (COVID-19) in Emergency Medicine.

The Medscape article Acute Respiratory Distress Syndrome (ARDS) includes discussions of fluid management, noninvasive ventilation and high-flow nasal cannula, mechanical ventilation, and extracorporeal membrane oxygenation.

Some have raised concerns over whether patients with respiratory distress have presentations more like those of high-altitude pulmonary edema (HAPE) than ARDS.

See also the articles Viral Pneumonia, Respiratory Failure, Septic Shock, and Multiple Organ Dysfunction Syndrome in Sepsis.

Medscape resources describing relevant procedures are as follows:

Ventilator application techniques

Ventilator management and monitoring

Respiratory conditions assessment and management

Medical Care

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.

Prevention

No vaccine is currently available for SARS-CoV-2. Avoidance is the principal method of deterrence.

General measures for prevention of viral respiratory infections include the following:[28]

  • Handwashing with soap and water for at least 20 seconds. An alcohol-based hand sanitizer may be used if soap and water are unavailable.
  • Individuals should avoid touching their eyes, nose, and mouth with unwashed hands.
  • Individuals should avoid close contact with sick people.
  • Sick people should stay at home (eg, from work, school).
  • Coughs and sneezes should be covered with a tissue, followed by disposal of the tissue in the trash.

Frequently touched objects and surfaces should be cleaned and disinfected regularly.

Preventing/minimizing community spread of COVID-19

The CDC has recommended the below measures to mitigate community spread.[157, 158, 9]

All individuals in areas with prevalent COVID-19 should be vigilant for potential symptoms of infection and should stay home as much as possible, practicing social distancing (maintaining a distance of 6 feet from other persons) when leaving home is necessary.

Persons with an increased risk for infection—(1) individuals who have had close contact with a person with known or suspected COVID-19 or (2) international travelers (including travel on a cruise ship)—should observe increased precautions. These include (1) self-quarantine for at least 2 weeks (14 days) from the time of the last exposure and distancing (6 feet) from other persons at all times and (2) self-monitoring for cough, fever, or dyspnea with temperature checks twice a day.

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]

Facemasks

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.[47] 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]

Investigational agents for postexposure prophylaxis

PUL-042

PUL-042 (Pulmotech, MD Anderson Cancer Center, and Texas A&M) is a solution for nebulization with potential immunostimulating activity. It consists of two toll-like receptor (TLR) ligands: Pam2CSK4 acetate (Pam2), a TLR2/6 agonist, and the TLR9 agonist oligodeoxynucleotide M362.

PUL-042 binds to and activates TLRs on lung epithelial cells. This induces the epithelial cells to produce peptides and reactive oxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpG motifs to TLR9 and subsequent TLR9-mediated signaling, initiates the innate immune system and activates macrophages, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-alpha production; and induces a T-helper 1 cells–mediated immune response. Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to the production of specific cytokines.[159]

In May 2020, the FDA approved initiation of two COVID-19 phase 2 clinical trials of PUL-042 at up to 20 US sites. The trials are for the prevention of infection with SARS-CoV-2 and the prevention of disease progression in patients with early COVID-19. In the first study, up to 4 doses of PUL-042 or placebo will be administered to 200 participants via inhalation over a 10-day period to evaluate the prevention of infection and reduction in severity of COVID-19. In the second study, 100 patients with early symptoms of COVID-19 will receive PUL-042 up to 3 times over 6 days. Each trial will monitor participants for 28 days to assess effectiveness and tolerability.[160, 161]

Investigational Antiviral Agents

Remdesivir

The broad-spectrum antiviral agent remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. On May 1, 2020, The US FDA issued EUA of remdesivir to allow emergency use of the agent for severe COVID-19 (confirmed or suspected) in hospitalized adults and children.[24, 25] A phase 1b trial of an inhaled nebulized version was initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease.[162]

Remdesivir was studied in clinical trials for Ebola virus infections but showed limited benefit.[163] Remdesivir has been shown to inhibit replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV.[164]

Several phase 3 clinical trials are testing remdesivir for treatment of COVID-19 in the United States, South Korea, and China. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020.[165] The drug was prescribed under an open-label compassionate use protocol, but the US FDA has since moved to allow expanded access to remdesivir, permitting approved sites to prescribe the investigational product for multiple patients under protocol without requesting permission for each.[166] An adaptive randomized trial of remdesivir coordinated by the National Institute of Health (NCT04280705) was started first against placebo, but additional therapies can be added to the protocol as evidence emerges. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19.[167] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

EUA of remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) was announced April 29, 2020. The analysis included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients who received remdesivir recovered faster than similar patients who received placebo. Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days in patients treated with remdesivir compared with 15 days in those who received placebo. Results also suggested a survival benefit by day 14, with a mortality rate of 7.1% in the remdesivir group, compared with 11.9% in the placebo group, but this was not statistically significant.[26]

The ACTT results differ from a smaller randomized trial conducted in China and published hours before the press release by the NIH. Results from this randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158 to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinical benefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.[168]

A phase 3, randomized, open-label trial showed that remdesivir was associated with significantly greater recovery and reduced odds of death compared with standard of care in patients with severe COVID-19. The recovery rate at day 14 was higher in patients who received remdesivir (n = 312) compared with those who received standard of care (n = 818) (74.4% vs 59%; P< 0.001). The mortality rate at day 14 was also lower in the remdesivir group (7.6% vs 12.5%; P = 0.001).[169]

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (OR: 0.75 [95% CI 0.51-1.12]). In this study, 65% of patients who received a 5-day course of remdesivir showed a clinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a 10-day course. After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients.[168]

Data presented at the virtual COVID-19 Conference in July 2020 included a comparative analysis of clinical recovery and mortality outcomes from the phase 3 SIMPLE trials versus a real-world cohort of patients with severe COVID-19 receiving standard of care. The analysis showed remdesivir was associated with a 62% reduction in the risk of mortality compared with standard of care. Subgroup analyses found these results were similar across different racial and ethnic groups. While these data are important, they require confirmation in prospective clinical trials.[170]

Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease showed that 5 days of remdesivir treatment was 65% more likely to yield clinical improvement at day 11 than standard of care (P = 0.18). These data show that early intervention with a 5-day treatment course can significantly improve outcomes.[171]

The first published report concerning remdesivir compassionate use described clinical improvement in 36 of 53 hospitalized patients (68%) with severe COVID-19. At baseline, 30 patients (57%) were receiving ventilation and 4 (8%) extracorporeal membrane oxygenation (ECMO). Measurement of efficacy requires randomized, placebo-controlled trials.[172]

Observations during compassionate use follow-up (median of 18 days) included the following:

  • Oxygen-support class improved in 36 patients (68%), including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated.
  • Twenty-five patients (47%) were discharged.
  • Seven patients (13%) died.
  • The mortality rate was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

Additional data for compassionate use of remdesivir was released on July 10, 2020, and demonstrated that remdesivir treatment was associated with significantly improved clinical recovery and a 62% reduction in the risk of mortality compared with standard of care. Findings from the comparative analysis showed that 74.4% of remdesivir-treated patients recovered by day 14 versus 59% of patients receiving standard of care. The mortality rate in patients treated with remdesivir in the analysis was 7.6% at day 14 compared with 12.5% among patients not taking remdesivir (adjusted OR, 0.38; 95% CI, 0.22-0.68, P = 0.001). The analyses also found that 83% of pediatric patients (n = 77) and 92% of pregnant and postpartum women (n = 86) with a broad spectrum of COVID-19 severity recovered by day 28.[170]

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) was superior to that of lopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology.[173]

Remdesivir use in children

Remdesivir emergency use authorization includes pediatric dosing that was derived from pharmacokinetic data in healthy adults. Remdesivir has been available through compassionate use to children with severe COVID-19 since February 2020. A phase 2/3 trial (CARAVAN) of remdesivir was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacy in children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birth to age 18 years.[174]

Data were presented on compassionate use of remdesivir in children at the virtual COVID-19 Conference held July 10-11, 2020. Results showed most of the 77 children with severe COVID-19 improved with remdesivir. Clinical recovery was observed in 80% of children on ventilators or ECMO and in 87% of those not on invasive oxygen support.[175]

For additional information, see Coronavirus Disease 2019 (COVID-19) in Children.

Remdesivir use in pregnant women

Data were presented at the virtual COVID-19 Conference held July 10-11, 2020, on compassionate use of remdesivir in 86 pregnant women (67 while pregnant and 19 on postpartum days 0-3). No new safety signals were observed. Results showed pregnant women had higher rates of recovery than nonpregnant adults treated with compassionate use remdesivir (92% vs 62%), likely owing to the younger age of pregnant women (median age, 33 years vs 64 years).[176]

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir.[25]

Other Early-Stage Investigational Antivirals

Nitazoxanide

Nitazoxanide extended-release tablets (NT-300; Romark Laboratories) inhibit replication of a broad range of respiratory viruses in cell cultures, including SARS-CoV-2. Two phase 3 trials for prevention of COVID-19 are being initiated in high-risk populations, including elderly residents of long-term care facilities and healthcare workers. In addition to the prevention studies, a third trial for early treatment of COVID-19 is planned.[177, 178]

Ivermectin

Ivermectin, an antiparasitic drug, showed in vitro reduction of viral RNA in Vero-hSLAM cells 2 hours postinfection with SARS-CoV-2 clinical isolate Australia/VIC01/2020.[179] The authors note that this preliminary study does not translate to human use and the effective dose is not established at this early stage of discovery. More research is needed to determine if an antiviral effect would be elicited in humans, as the concentrations tested were much higher than what is achieved from the normal oral dose.

Available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans.[180]

Chaccour et al believe the recent findings regarding ivermectin warrant rapid implementation of controlled clinical trials to assess efficacy against COVID-19. They also raise concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19. In addition, drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs. Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans.[181]

A retrospective cohort study (n = 280) in hospitalized patients with confirmed SARS-CoV-2 infection at four Florida hospitals showed significantly lower mortality rates in those who received ivermectin compared with usual care (15% vs 25.2%; P = 0.03). The mortality rate was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%; P = 0.001), although the rate of successful extubation did not differ significantly.[182]

Table 1. Other Investigational Antivirals for COVID-19 (Open Table in a new window)

Antiviral Agent Description
Favipiravir (Avigan, Avifavir, Coronavir; Fujifilm Pharmaceuticals) [183, 184, 185] Oral antiviral approved for the treatment of influenza in Japan. It is approved in Russia for treatment of COVID-19. It selectively inhibits RNA polymerase, which is necessary for viral replication. In the United States, a phase 2 trial will enroll approximately 50 patients with COVID-19, in collaboration with Brigham and Women's Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School.
Merimepodib (VicromaxTM; ViralClear Pharmaceuticals, BioSig Technologies) [186, 187] Oral antiviral in phase 2 trial in combination with remdesivir initiated in June 2020. The mechanism of merimepodib is believed to be inhibition of inosine-5’-monophosphate dehydrogenase (IMPDH), leading to a depletion of guanosine for use by the viral polymerase during replication.
Niclosamide (FW-1002; FirstWave Bio) [188] Anthelmintic agent that has potential use as an antiviral agent. A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has been developed. Initiation of a phase 2a/2b study is planned for mid-2020.
Rintatolimod (Poly I:Poly C12U; Ampligen; AIM ImmunoTech) [189, 190] Toll-like receptor 3 (TLR-3) agonist that is being tested as a potential treatment for COVID-19 by the National Institute of Infectious Diseases (NIID) in Japan and the University of Tokyo. It is a broad-spectrum antiviral agent.
Beta-D-N4-hydroxycytidine (NHC, EIDD-2801) [191, 192] Orally bioavailable broad-spectrum antiviral. When administered both prophylactically and therapeutically to mice infected with SARS-CoV, NHC improved pulmonary function and reduced virus titer and body weight loss. It was announced that clinical trials will soon move to humans.
Bemcentinib (BerGenBio ASA) [193] Selective oral AXL kinase inhibitor, has previously been reported to exhibit potent antiviral activity in preclinical models against several enveloped viruses, including Ebola and Zika virus. Recent data have expanded this to SARS-CoV-2. A phase 2 study of bemcentinib in hospitalized patients with COVID-19 is planned as part of the UK’s Accelerating COVID-19 Research and Development (ACCORD) initiative.
Umifenovir (Arbidol)

Antiviral drug that binds to hemagglutinin protein; it is used in China and Russia to treat influenza. In a structural and molecular dynamics study, Vankadari corroborated that the drug target for umifenovir is the spike glycoproteins of SARS-CoV-2, similar to that of H3N2.[194] A retrospective study of non-ICU hospitalized patients (n = 81) with COVID-19 conducted in China did not show an improved prognosis or accelerated viral clearance.[195] Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group.[196] In India, a phase 3 trial combining 2 antiviral agents, favipiravir and umifenovir, started in May 2020.[184]

Plitidepsin (Aplidin; PharmaMar) Member of the compound class known as didemnins. In vitro studies from Spain report plitidepsin potentially targets EF1A, which is key to multiplication and spread of the virus. [197]
VIR-2703 (ALN-COV; Vir Biotechnology Inc and Alnylam Pharmaceuticals, Inc) [198] In vitro data shows the drug targets small interfering RNA (siRNA). RNA interference (RNAi) is a natural cellular process of gene silencing. The siRNA molecules mediate RNAi function by silencing messenger RNA (mRNA). mRNA is the genetic precursor that encodes for disease-causing proteins. The companies plan to advance development of the drug candidate as an inhalational formulation.
EIDD-2801 (Merck, Ridgeback Bio) [199, 200] Oral nucleoside analogue. Phase 1 trials have been completed. Two phase 2 clinical trials were initiated in June 2020 in both inpatient and outpatient settings.
Emetine hydrochloride (Acer Therapeutics) [201] Active ingredient of syrup of ipecac (given orally to induce emesis), has been formulated as an injection to treat amebiasis. Clinical trials have been conducted for viral hepatitis and varicella-zoster virus infection. Several in vitro studies have demonstrated potency against DNA and RNA-replicating viruses, including Zika, Ebola, Rabies Lyssavirus, CMV, HIV, influenza A, echovirus, metapneumovirus, and HSV2. It is also a potent inhibitor of multiple genetically distinct coronaviruses. Plans are underway to evaluate the safety and antiviral activity of emetine with an adaptive design phase 2/3 randomized, blinded, placebo-controlled multicenter trial in high-risk symptomatic adults with confirmed COVID-19 not requiring hospitalization.
AT-527 (Atea Pharmaceuticals) [202] Oral purine nucleotide prodrug designed to inhibit RNA polymerase enzyme. It has demonstrated in vitro and in vivo antiviral activity against several enveloped single-stranded RNA viruses, including human flaviviruses and coronaviruses. IND for phase 2 study accepted by FDA for patients hospitalized with moderate COVID-19.
Trabedersen (OT-101; Mateon Therapeutics, Oncotelic) [203] Antisense oligonucleotide that inhibits transforming growth factor (TGF)-beta2 expression. Viral replication requires cell cycle arrest that is mediated by viral induction of TBF-beta. IND for phase 2 randomized, controlled, multicenter trial submitted to FDA.
Stannous protoporphyrin (SnPP; RBT-9; Renibus Therapeutics) [204] Antiviral agent in phase 2 trial for treatment of COVID-19 in patients who are at high risk of deteriorating health owing to age or comorbid conditions (eg, kidney or cardiovascular disease).
Antroquinonol (Hocena; Golden Biotechnology Corp) [205] Antiviral/anti-inflammatory agent. Reduces viral nucleic acid replication and viral protein synthesis in both cell and animal experiments. Prevention of organ and tissue damage was also observed with antroquinonol when treating mice with excessive inflammation. The FDA has accepted the IND for a phase 2 clinical trial in patients with mild-to-moderate COVID-19 pneumonia.
Apilimod dimesylate (LAM-002A; AI Therapeutics) [206] Inhibits the lipid kinase enzyme PIKfyve. It disrupts lysosome dysfunction and interferes with the entry and trafficking of the SARS-CoV-2 virus in cells. Phase 2 trial is starting at Yale University in late July 2020.

Immunomodulators and Other Investigational Therapies

Various methods of immunomodulation are being quickly examined, mostly by repurposing existing drugs, in order blunt the hyperinflammation caused by cytokine release. Interleukin (IL) inhibitors, Janus kinase inhibitors, and interferons are just a few of the drugs that are in clinical trials. Ingraham et al provide a thorough explanation and diagram of the SARS-CoV-2 inflammatory pathway and potential therapeutic targets.[207]

Interleukin Inhibitors

Interleukin (IL) inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious COVID-19 infections. Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. The increased pulmonary inflammatory response may result in increased alveolar-capillary gas exchange, making oxygenation difficult in patients with severe illness.

Interleukin-6 inhibitors

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-6 inhibitors.[208]

On March 16, 2020, Sanofi and Regeneron announced initiation of a phase 2/3 trial of the IL-6 inhibitor sarilumab (Kevzara). The multicenter, double-blind, phase 2/3 trial has an adaptive design with two parts and is anticipated to enroll up to 400 patients. The first part will recruit patients with severe COVID-19 infection across approximately 16 US sites, and will evaluate the effect of sarilumab on fever and the need for supplemental oxygen. The second, larger, part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen, and/or hospitalization.[209]

Based on the phase 2 trial analysis, the ongoing phase 3 design was modified on April 27, 2020, to include only higher-dose sarilumab (400 mg) or placebo in critical patients (ie, requiring mechanical ventilation or high-flow oxygenation or ICU admission). Minor positive trends were observed in the primary prespecified analysis group (n = 194; critical patients on sarilumab 400 mg who were mechanically ventilated at baseline) that did not reach statistical significance, and these were countered by negative trends in a subgroup of critical patients who were not mechanically ventilated at baseline.[210] Based on the results, the US-based trial was stopped, including in a second cohort of patients who received a higher dose (800 mg).[211]

Another IL-6 inhibitor, tocilizumab (Actemra), is part of several randomized, double-blind, placebo-controlled phase 3 clinical trials (REMDACTA, COVACTA, EMPACTA) to evaluate the safety and efficacy of tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia compared to placebo plus standard of care. Results from the COVACTA trial were released in July 2020, announcing that the trial did not meet its primary endpoint of improved clinical status in patients with COVID-19–associated pneumonia or the secondary endpoint of reduced patient mortality. The trial did show a positive trend in time to hospital discharge among patients who received tocilizumab.[212]

An observational study of 239 consecutive patients with severe COVID-19 was conducted at Yale (New Haven, CT). Patients were treated with a standardized algorithm that included tocilizumab to treat cytokine release syndrome. These early observations showed that, despite a surge of hospitalizations, tocilizumab-treated patients (n = 153) comprised 90% of those with severe disease, but their survival rate was similar to that in patients with nonsevere disease (83% vs 91%; P = 0.11). In tocilizumab-treated patients requiring mechanical ventilation, the survival rate was 75%. Oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor levels increased significantly.[213] Similarly, a small compassionate use study (n = 27) found that a single 400-mg IV dose of tocilizumab reduced inflammation, oxygen requirements, vasopressor support, and mortality.[214]

A study compared outcomes of patients who received tocilizumab (n = 78) with tocilizumab-untreated controls in patients with COVID-19 requiring mechanical ventilation. Tocilizumab was associated with a 45% reduction in hazard of death (hazard ratio 0.55 [95% CI 0.33, 0.90]) and improved status on the ordinal outcome scale (odds ratio per one-level increase: 0.59 [0.36, 0.95]). Tocilizumab was associated with an increased incidence of superinfections (54% vs 26%; P< 0.001); however, there was no difference in 28-day case fatality rate among tocilizumab-treated patients with superinfection versus those without superinfection (22% vs 15%; P = 0.42).[215]

An observational study in New Jersey showed an improved survival rate among patients who received tocilizumab. Among 547 ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend toward an improved survival rate of 54% who received tocilizumab compared with 44% who did not receive the therapy and a propensity adjusted hazard ratio of 0.76.[216]

A retrospective, observational cohort study in tertiary care centers in Bologna, Reggio Emilia, and Modena, Italy, between February 21 and March 24, 2020, concluded that tocilizumab may reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia. Of 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. Fifty-seven (16%) of 365 patients in the standard care group needed mechanical ventilation compared with 33 (18%) of 179 patients treated with tocilizumab (P = 0.41; 16 [18%] of 88 patients treated IV and 17 [19%] of 91 patients treated SC). Seventy-three (20%) patients in the standard care group died, compared with 13 (7%; P< 0.0001) patients treated with tocilizumab (6 [7%] treated IV and 7 [8%] treated SC).[217]

However, another Italian study was halted after enrolling 126 patients with COVID-19 pneumonia, about one-third of the intended number, because the interim analysis showed it did not reduce severe respiratory symptoms, intensive care, or death compared with standard care.[218]

An open label, non-controlled, non–peer reviewed study was conducted in China in 21 patients with severe respiratory symptoms related to COVID-19. All had a confirmatory diagnosis of SARS-CoV-2 infection. The patients in the trial had a mean age of 56.8 years (18 of 21 were male). Although all patients met enrollment criteria of (1) respiratory rate of 30 breaths/min or more, (2) SpO2 of 93% or less, and (3) PaO2/FiO2 of 300 mm Hg or less, only two of the patients required invasive ventilation. The other 19 patients received various forms of oxygen delivery, including nasal cannula, mask, high-flow oxygen, and noninvasive ventilation. All patients received standard of care, including lopinavir and methylprednisolone. Patients received a single dose of 400 mg tocilizumab via intravenous infusion. In general, the patients improved with lower oxygen requirements, lymphocyte counts returned to normal, and 19 patients were discharged with a mean of 15.5 days after tocilizumab treatment. The authors concluded that tocilizumab was an effective treatment in patients with severe COVID-19.[219]

A retrospective review of 25 patients with confirmed severe COVID-19 who received tocilizumab plus investigational antivirals showed patients who received tocilizumab experienced a decline in inflammatory markers, radiological improvement, and reduced ventilatory support requirements. The authors acknowledged the study’s limitations and the need for adequately powered randomized controlled trials of tocilizumab.[220]

Nonetheless, these conclusions should be viewed with extreme caution. No controls were used in this study, and only one patient was receiving invasive mechanical ventilation. In addition, all patients were receiving standard therapy for at least a week before tocilizumab was started. AWP for 400 mg of tocilizumab is $2765.

Another anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and Novimmune) is currently under development.[221]

Interleukin-1 inhibitors

Endogenous IL-1 levels are elevated in individuals with COVID-19 and other conditions, such as severe CAR-T-cell–mediated cytokine-release syndrome. Anakinra has been used off-label for this indication. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-1 inhibitors.[222]

Several studies involving the IL-1 inhibitor anakinra (Kineret) have emerged. A retrospective study in Italy looked at patients with COVID-19 and moderate-to-severe ARDS who were managed with noninvasive ventilation outside of the ICU. The study compared outcomes of patients who received anakinra (5 mg/kg IV BID [high-dose] or 100 mg SC BID [low-dose]) plus standard treatment (ie, hydroxychloroquine 200 mg PO BID and lopinavir/ritonavir 400 mg/100 mg PO BID) with standard of care alone. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein levels and progressive improvements in respiratory function in 21 (72%) of 29 patients; 5 (17%) patients were on mechanical ventilation and 3 (10%) died. In the standard treatment group, 8 (50%) of 16 patients showed respiratory improvement at 21 days; 1 (6%) patient was on mechanical ventilation and 7 (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (P = 0.009).[223]

A study in Paris from March 24 to April 6, 2020, compared outcomes of 52 consecutive patients with COVID-19 who were given anakinra with 44 historical cohort patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0.22 [95% CI, 0.11-0.41; P< 0.0001). Similar results were observed for death alone (HR 0.30 [95% CI, 0.12-0.71]; P = 0.0063) and need for invasive mechanical ventilation alone (0.22 [0.09-0.56]; P = 0.0015).[224]

Corticosteroids

The UK RECOVERY trial assessed the mortality rate at day 28 in hospitalized patients with COVID-19 who received low-dose dexamethasone 6 mg PO or IV daily for 10 days added to usual care. Patients were assigned to receive dexamethasone (n = 2104) plus usual care or usual care alone (n = 4321). Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (P< 0.001). In the dexamethasone group, the incidence of death was lower than in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not among those who were receiving no respiratory support at randomization (17.8% vs 14%).[225]

Corticosteroids are not generally recommended for treatment of viral pneumonia.[226] The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS.[227]

Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and when to refrain from using corticosteroids. The recommendations depended on the precise clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular recommendations were based on evidence listed as weak.[228] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial.[225]

A study describing clinical outcomes of patients diagnosed with COVID-19 was conducted in Wuhan, China (N = 201). Eighty-four patients (41.8%) developed ARDS, and of those, 44 (52.4%) died. Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).[106]

Researchers at Henry Ford Hospital in Detroit implemented a protocol on March 20, 2020, using early, short-course, methylprednisolone 0.5-1 mg/kg/day divided in 2 IV doses for 3 days in patients with moderate-to-severe COVID-19. Outcomes of pre- and post-corticosteroid groups were evaluated. A composite endpoint of escalation of care from ward to ICU, new requirement for mechanical ventilation, or mortality was the primary outcome measure. All patients had at least 14 days of follow-up. They analyzed 213 eligible patients, 81 (38%) and 132 (62%) in pre-and post-corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the post-corticosteroid group than in the pre-corticosteroid group (34.9% vs 54.3%; P = 0.005). This treatment effect was observed within each individual component of the composite endpoint. A significant reduction in median hospital length of stay was observed in the post-corticosteroid group (8 vs 5 days; P< 0.001).[229]

A study in the Netherlands showed that a 5-day course of high-dose corticosteroids accelerated respiratory recovery, lowered hospital mortality rates, and reduced the likelihood of mechanical ventilation in patients with severe COVID-19–associated cytokine storm syndrome compared with historical controls. Forty-three percent of patients also received tocilizumab.[230]

A retrospective study at Montefiore Hospital in the Bronx borough of New York was conducted to evaluate if early glucocorticoid treatment (ie, within 48 hours of admission) reduced mortality rates or the need for mechanical ventilation in hospitalized patients with COVID-19. Of the 1,806 patients included in the study, 140 (7.7%) were treated with glucocorticoids, and 1,666 patients never received glucocorticoids. A key finding of this analysis is the need to verify which patients should receive glucocorticoid treatment. Glucocorticoid use in patients with initial C-reactive protein (CRP) levels of 20 mg/dL or greater was associated with significantly reduced risk of mortality or mechanical ventilation (OR, 0.23; 95% CI, 0.08-0.70), while use in patients with a CRP level of less than 10 mg/dL was associated with significantly increased risk of mortality or mechanical ventilation (OR, 2.64; 95% CI, 1.39-5.03).[231]

Convalescent Plasma

The FDA is facilitating access to convalescent plasma, antibody-rich products that are collected from eligible donors who have recovered from COVID-19. Convalescent plasma has not yet been shown to be effective in COVID-19. The FDA states that it is important to determine its safety and efficacy via clinical trials before routinely administering convalescent plasma to patients with COVID-19.

The FDA has posted information for investigators wishing to study convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 through the process of single-patient emergency Investigational New Drug (IND) applications for individual patients. The FDA is also actively engaging with researchers to discuss the possibility of collaboration on the development of a master protocol for use of convalescent plasma, with the goal of reducing duplicative efforts.[232]

The use of convalescent plasma has a long history in the treatment of infectious diseases. Writing in the Journal of Clinical Investigation Casadevall and Pirofski[233] proposed using it as a treatment for COVID-19, and Bloch et al[234] laid out a conceptual framework for implementation. To date, two small case series have been published.[235, 236] These series reported improvement in oxygenation, sequential organ failure assessment (SOFA) scores, and eventual ventilator weaning in some patients. The timelines of improvement varied from days to weeks. Caution is advised, as these were not controlled trials and other pharmacologic methods (antivirals) were used in some patients.[236]

A Cochrane review of convalescent plasma use in patients with COVID-19 is perpetually being updated as data emerge. As of July 10, 2020, the review included 20 studies with 5443 participants, of whom 5211 received convalescent plasma. Among these studies was one randomized controlled trial with 103 participants (52 received convalescent plasma). At the time of publication, the authors expressed uncertainty as to the benefits of convalescent plasma in terms of affecting mortality at hospital discharge, prolonging time to death, or improving clinical symptoms at 7 or 28 days.[237]

A meta-analysis of 15 controlled studies showed a significantly lower mortality rate in patients with COVID-19 who received convalescent plasma compared with control groups. However, the authors point out that the studies were mostly of low or very low quality with a moderate or high risk of bias.[238]

An open-label study (n = 103) of patients with laboratory-confirmed COVID-19 in Wuhan, China, given convalescent plasma did not result in a statistically significant improvement in time to clinical improvement within 28 days compared with standard of care alone.[239]

A nonrandomized study transfused patients based on supplemental oxygen needs with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of at least 1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls. Results showed convalescent plasma transfusion improved survival in nonintubated patients (P = 0.015), but not in intubated patients (P = 0.752).[240]

Nitric Oxide

Published findings from the 2004 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO; Mallinckrodt Pharmaceuticals, plc) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with iNO reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS.[241]

A phase 2 study of iNO is underway in patients with COVID-19 with the goal of preventing disease progression in those with severe ARDS.[242] A phase 3 study (PULSE-CVD19-001) for iNO (INOpulse; Bellerophon Therapeutics) was accepted by the FDA in mid-March 2020 to evaluate efficacy and safety in patients diagnosed with COVID-19 who require supplemental oxygen before the disease progresses to necessitate mechanical ventilation support.[243] The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies.[228] The cost of iNO is reported as exceeding $100/hour.

JAK and NAK Inhibitors

Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19 pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response. In particular, NAK inhibition has been shown to reduce viral infection in vitro. ACE2 receptors are a point of cellular entry by COVID-19, which is then expressed in lung AT2 alveolar epithelial cells. A known regulator of endocytosis is the AP2-associated protein kinase-1 (AAK1). The ability to disrupt AAK1 may interrupt intracellular entry of the virus. Baricitinib (Olumiant; Eli Lilly Co), a Janus kinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1.[244, 245, 246]

Mehta and colleagues describe the cytokine profile of COVID-19 as being similar to that of hemophagocytic lymphohistiocytosis (sHLH). sHLH is characterized by increased IL-2, IL-7, GCSF, INF-gamma, monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein-1 (MIP-1) alpha, and TNF-alpha. JAK inhibition may be a therapeutic option.[247]

Other selective JAK inhibitors (ie, fedratinib, ruxolitinib) may be effective against consequences of elevated cytokines, although baricitinib has the highest affinity for AAK1.[244]

Baricitinib is being studied as part of the NIAID Adaptive Covid-19 Treatment Trial, which evaluated the combination of baricitinib and remdesivir compared with remdesivir alone.[248] Another phase 3, placebo-controlled trial is studying baricitinib in hospitalized patients who have an elevated level of at least one inflammation marker but do not require invasive mechanical ventilation at study entry.[249]

A small open-labeled study (n = 12) conducted in Italy added baricitinib 4 mg/day to existing therapies (ie, lopinavir/ritonavir 250 mg BID and hydroxychloroquine 400 mg/day). All therapies were given for 2 weeks. Fever, SpO2, PaO2/FiO2, C-reactive protein, and modified early warning scores significantly improved in the baricitinib-treated group compared with controls (P: 0.000; 0.000; 0.017; 0.023; 0.016, respectively). ICU transfer occurred in 33% (4/12) of controls and in none of the baricitinib-treated patients (P = 0.093). Discharge at week 2 occurred in 58% (7/12) of the baricitinib-treated patients compared with 8% (1/12) of controls (P = 0.027).[250]

Ruxolitinib (Jakafi; Incyte) is part of the phase 3 RUXCOVID clinical trial.[251]

Pacritinib (CTI Biopharma) is a JAK2, interleukin-1 receptor-associated kinase-1 (IRAK-1), and colony stimulating factor-1 receptor (CSF-1R) inhibitor that is pending FDA approval for myelofibrosis. The phase 3 trial (PRE-VENT) has commenced to compare pacritinib with standard of care. Outcomes assessed include progression to mechanical ventilation, ECMO, or death in hospitalized patients with severe COVID-19, including those with cancer. As a JAK2/IRAK-1 inhibitor, pacritinib may ameliorate the effects of cytokine storm via inhibition of IL-6 and IL-1 signaling. Furthermore, as a CSF-1R inhibitor, pacritinib may mitigate effects of macrophage activation syndrome.[252]

Statins

In addition to the cholesterol-lowering abilities of HMG-CoA reductase inhibitors (statins), they also decrease the inflammatory processes of atherosclerosis.[253] Because of this, questions have arisen whether statins may be beneficial to reduce inflammation associated with COVID-19.

This question has been posed before with studies of patients taking statins who have acute viral infections. Virani[254] provides a brief summary of information regarding observational and randomized controlled trials (RCTs) of statins and viral infections. Some, but not all, observational studies suggest that cardiovascular outcomes were reduced in patients taking statins who were hospitalized with influenza and/or pneumonia. RCTs of statins as anti-inflammatory agents for viral infections are limited, and results have been mixed. An important factor that Virani points out regarding COVID-19 is that no harm was associated with statin therapy in previous trials of statins and viral infections, emphasizing that patients should adhere to their statin regimen.

Adjunctive Nutritional Therapies

Vitamin and mineral supplements have been promoted for the treatment and prevention of respiratory viral infections; however, there is insufficient evidence to suggest a therapeutic role in treating COVID-19.[255]

Zinc

A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19.[255]

Additional Investigational Drugs for ARDS/Cytokine Release

Table 2. Investigational Drugs for ARDS/Cytokine Release Associated With COVID-19 (Open Table in a new window)

Therapy Description
Ifenprodil (NP-120; Algernon Pharmaceuticals) [256] N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonist. NMDA is linked to inflammation and lung injury. An injectable and long-acting oral product are under production to begin clinical trials for COVID-19 and acute lung injury. Phase 2b/3 multinational study was initiated in May 2020. First US trial initiated in Florida in late July 2020.
Remestemcel-L (Ryoncil; Mesoblast Ltd) [257, 258, 259] Allogeneic mesenchymal stem cell (MSC) product currently pending FDA approval for graft versus host disease (GVHD). Phase 2/3 trial for COVID-19 ARDS started to enroll patients in May 2020. The trial will take place at up to 30 medical centers in North America over 3-4 months in collaboration with the Cardiothoracic Surgical Trials Network. Theorized mechanism is down-regulation of proinflammatory cytokines.
PLX-PAD (Pluristem Therapeutics) [260] Allogeneic mesenchymal-like cells with immunomodulatory properties that induce the immune system’s natural regulatory T cells and M2 macrophages. Initiating phase 2 study in mechanically ventilated patients with severe COVID-19.
BM-Allo.MSC (NantKwest, Inc) [261] Bone marrow-derived allogeneic mesenchymal stem cell product. IND for phase 1b trial initiating Q2 2020 in Los Angeles area hospitals.
Eculizumab (Soliris; Alexion) [262] Modulates activity of terminal complement to prevent the formation of the membrane attack complex; 10-patient proof of concept completed; if 100-patient single-arm trial in the United States and Europe for 2 weeks shows a positive risk/benefit ratio, a 300-patient randomized controlled trial will proceed.
Ravulizumab (Ultomiris; Alexion) [263] Phase 3 randomized controlled trial planned in hospitalized adults with severe pneumonia or acute ARDS to evaluate complement (C5) inhibition for treatment. Trial commencement based on preclinical data of animal models suggesting inhibition of terminal complement may lower cytokine levels and reduce lung inflammation, as well as preliminary evidence from eculizumab compassionate use program.
Aviptadil (RLF-100; NeuroRx and Relief Therapeutics) [264, 265] Synthetic vasoactive intestinal peptide that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. Phase 2b/3 clinical trial for treatment of ARDS in all patients with severe COVID-19 disease and respiratory failure was initiated June 2020. Expanded access for hospitals not participating in the ongoing phase 2/3 clinical trials was approved by the FDA in late July 2020.
Tradipitant (Vanda Pharmaceuticals) [266] Neurokinin-1 (NK-1) receptor antagonist. The NK-1 receptor is coded by the TACR1 gene and is the main receptor for substance P. The substance P NK-1 receptor system is involved in neuroinflammatory processes that lead to serious lung injury following numerous insults, including viral infections. ODYSSEY phase 3 trial initiated in New York area hospitals has enrolled over 50 of 300 patients as of mid-May 2020.
Gimsilumab (Riovant) [267, 268] Phase 2 BREATHE clinical trial at Mt Sinai and Temple University is analyzing monoclonal antibody that targets granulocyte macrophage-colony stimulating factor (GM-CSF) in patients with ARDS.
Mavrilimumab (Kiniksa Pharmaceuticals [269, 270] Open-label treatment protocol in Italy with mavrilimumab, an investigational fully human monoclonal antibody that targets granulocyte macrophage colony stimulating factor (GM-CSF) receptor alpha in patients with severe COVID-19 pneumonia and hyperinflammation. Over the course of the 14-day follow-up period, mavrilimumab-treated patients experienced greater and earlier clinical improvements than control-group patients, including earlier weaning from supplemental oxygen, shorter hospitalizations, and no deaths. Phase 2 trials are being conducted in the United States.
Otilimab (GlaxoSmithKline; NCT04376684) [271] Human monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis. Clinical trial initiating May 2020 for severe pulmonary COVID-19.
ATYR1923 (aTyr Pharma, Inc) [272] Phase 2 randomized, double-blind, placebo-controlled trial at up to 10 centers in the United States. In preclinical studies, ATYR1923 (a selective modulator of neuropilin-2) has been shown to down-regulate T-cell responses responsible for cytokine release.
BIO-11006 (Biomark Pharmaceuticals) [273] Results of a phase 2a study for 38 ventilated patients with ARDS showed 43% reduction at day 28 in the all-cause mortality rate. This study was initiated in 2017. The company is in discussion with the FDA to proceed with a phase 3 trial.
Ibudilast (MN-166; MediciNova) [274] First-in-class, orally bioavailable, small molecule phosphodiesterases (PDE) 4 and 10 inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that suppresses proinflammatory cytokines and promotes neurotrophic factors. The drug has been approved in Japan and South Korea since 1989 to treat post-stroke complications and bronchial asthma. An IND for a phase 2 trial in the United States to prevent ARDS has been accepted by the FDA.
Dociparstat sodium (DSTAT; Chimerix) [275] Glycosaminoglycan derivative of heparin with anti-inflammatory properties, including the potential to address underlying causes of coagulation disorders. Phase 2/3 trial starting May 2020.
Opaganib (Yeliva; RedHill Biopharma Ltd) [276, 277] Sphingosine kinase-2 (SK2) inhibitor that may inhibit viral replication and reduce levels of IL-6 and TNF-alpha. Nonclinical data indicate both antiviral and anti-inflammatory effects. Phase 2/3 trial has been initiated for hospitalized patients with severe COVID-19 who have developed pneumonia and require supplemental oxygen.
Tranexamic acid (LB1148; Leading BioSciences, Inc) [278] Oral/enteral protease inhibitor designed to preserve GI tract integrity and protect organs from proteases leaking from compromised mucosal barrier that can lead to ARDS. Phase 2 study announced May 15, 2020.
DAS181 (Ansun Biopharma) [279] Recombinant sialidase drug is a fusion protein that cleaves sialic receptors. Phase 3 substudy for COVID-19 added to existing study for parainfluenza infection.
TJM2 (I-MAB Biopharma) [280] TJM2 is a neutralizing antibody against human granulocyte-macrophage colony stimulating factor (GM-CSF), an important cytokine that plays a critical role in acute and chronic inflammation.
AT-001 (Applied Therapeutics) [281] Aldose reductase inhibitor shown to prevent oxidative damage to cardiomyocytes and to decrease oxidative-induced damage.
CM4620-IE (Auxora; CalciMedica, Inc) [282] Calcium release-activated calcium (CRAC) channel inhibitor that prevents CRAC channel overactivation, which can cause pulmonary endothelial damage and cytokine storm. Results in mid-July 2020 from a small randomized, controlled, open-label study showed CM4620-IE (n = 20) combined with standard of care therapy (n = 10) improved outcomes in patients with severe COVID-19 pneumonia, showing faster recovery (5 days vs 12 days), reduced use of invasive mechanical ventilation (18% vs 50%), and improved mortality rate (10% vs 20%) compared with standard of care alone. Part 2 of this trial will start late summer and will be a placebo-controlled trial, possibly including both remdesivir and dexamethasone.
Intranasal vazegepant (Biohaven Pharmaceuticals) [283] Calcitonin gene-related peptide (CGRP) receptor antagonist. Received FDA may proceed letter to initiate phase 2 study. Acute lung injury induces up-regulation of transient receptor potential (TRP) channels, activating CGRP release. CGRP contributes to acute lung injury (pulmonary edema with acute-phase cytokine/mediator release, with immunologic milieu shift toward TH17 cytokines). A CGRP receptor antagonist may blunt the severe inflammatory response at the alveolar level, delaying or reversing the path toward oxygen desaturation, ARDS, requirement for supplemental oxygenation, artificial ventilation, or death.
Selinexor (Xpovio; Karyopharma Therapeutics) [284] Selective inhibitor of nuclear export (SINE) that blocks the cellular protein exportin 1 (XPO1), which is involved in both replication of SARS-CoV-2 and the inflammatory response to the virus.
EDP1815 (Evelo Biosciences; Rutgers University; Robert Wood Johnson University Hospital) [285] Phase 2/3 trials underway in the United States and United Kingdom to determine if early intervention with oral EDP1815 (under development for psoriasis) prevents progression of COVID-19 symptoms and complications in hospitalized patients ≥15 years with COVID-19 who presented at the ER within the preceding 36 hours. The drug showed marked activity on inflammatory markers (eg, IL-6, IL-8, TNF, IL-1b) in a phase 1b study.
Acalabrutinib (Calquence; AstraZeneca; NCT04380688) [286, 287] Findings from an exploratory research project of this Bruton tyrosine kinase inhibitor showed encouraging improvement of excessive inflammation associated with COVID-19. Two phase 2 trials compared with best supportive care in hospitalized patients are underway.
VERU-111 (Veru, Inc) [288] Microtubule depolymerization agent that has broad antiviral activity and has strong anti-inflammatory effects. Phase 2 clinical trial beginning June 2020 for hospitalized patients with COIVD-19 at high risk for ARDS.
Vascular leakage therapy (Q BioMed; Mannin Research) [289] Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction.
Trans sodium crocetinate (TSC; Diffusion Pharmaceuticals) [290, 291] TSC increases the diffusion rate of oxygen in aqueous solutions. Guidance has been received from the FDA for a phase 1b/2b clinical trial.
Rayaldee (calcifediol; OPKO Health) [292] Extended-release formulation of calcifediol (25-hydroxyvitamin D3), a prohormone of the active form of vitamin D3. Phase 2 trial (REsCue) objective is to raise and maintain serum total 25-hydroxyvitamin D levels to mitigate COVID-19 severity. Raising serum levels is believed to enable macrophages.
Deupirfenidone (LYT-100; PureTech Bio) [293] Deuterated form of pirfenidone, an approved anti-inflammatory and anti-fibrotic drug. Inhibits TGF-beta and TNF-alpha. Clinical trial starting in summer 2020 to evaluate use for serious respiratory complications, including inflammation and fibrosis, that persist following resolution of SARS-CoV-2 infection.
OP-101 (Ashvattha Therapeutics) [294] Selectively targets reactive macrophages to reduce inflammation and oxidative stress.
Vidofludimus calcium (IMU-838; Immunic Therapeutics) [295, 296] Oral dihydroorotate dehydrogenase (DHODH) inhibitor. DHODH is located on the outer surface of the inner mitochondrial membrane. Inhibitors of this enzyme are used to treat autoimmune diseases. Phase 2 CALVID-1 clinical trial for hospitalized patients with moderate COVID-19. Another phase 2 trial (IONIC) in the UK combines vidofludimus with oseltamivir for moderate-to-severe COVID-19.
Vafidemstat (ORY-2001; Oryzon) [297] Oral CNS lysine-specific histone demethylase 1 (LSD1) inhibitor. Phase 2 trial (ESCAPE) initiated in May 2020 to prevent progression to ARDS in severely ill patients with COVID-19.
Icosapent ethyl (Vascepa; Amarin Co) [298] Study focuses on reduction of circulating proinflammatory biomarkers (eg, C-reactive protein).
Prazosin (Johns Hopkins) [299, 300] Cytokine storm syndrome is accompanied by increased catecholamine release. This amplifies inflammation by enhancing IL-6 production through a signaling loop that requires the alpha1 adrenergic receptor. A clinical trial at Johns Hopkins University is using prazosin, an alpha1 receptor antagonist, to evaluate its effects to prevent cytokine storm.
Aspartyl-alanyl diketopiperazine (DA-DKP; AmpionTM; Ampio Pharmaceuticals) [301] Low-molecular weight fraction of human serum albumin (developed for inflammation associated with osteoarthritis). Theorized to reduce inflammation by suppressing pro-inflammatory cytokine production in T-cells. Phase 1 trial began in July 2020 at Penrose-St Francis Hospital in Colorado Springs.
Losmapimod (Fulcrum Therapeutics) [302] Selective inhibitor of p38alpha/beta mitogen activated protein kinase (MAPK), which is known to mediate acute response to stress, including acute inflammation. FDA authorized a phase 3 trial (LOSVID) for hospitalized patients with COVID-19 at high risk. Losmapimod has been evaluated in phase 2 clinical trials for facioscapulohumeral muscular dystrophy (FSHD).
DUR-928 (Durect Corp) [303] Endogenous epigenetic regulator. Preclinical trials have shown the drug regulates lipid metabolism, inflammation, and cell survival. The FDA accepted the IND application. A phase 2 study is planned for approximately 80 hospitalized patients with COVID-19 who have acute liver or kidney injury.
ATI-450 (Aclaris Therapeutics, Inc) [304] IND approved mid-June 2020 for use in hospitalized patients with COVID-19. ATI-450 is an oral mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, or MK2) inhibitor that targets inflammatory cytokine expression. In a phase 1 clinical trial in healthy volunteers at the University of Kansas Medical Center, researchers used a first-in-human study using an ex vivo lipopolysaccharide (LPS) stimulation model that demonstrated a dose-dependent reduction of TNF-alpha, IL-1-beta, IL-6, and IL-8.
Leronlimab (CytoDyn) [305, 306] CCR5 antagonist. A phase 2 trial for mild-to-moderate COVID-19 and a phase 2b/3 trial for severe COVID-19 are ongoing. Laboratory data following leronlimab administration in 15 patients showed increased CD8 T-lymphocyte percentages by day 3, normalization of CD4/CD8 ratios, and resolving cytokine production, including reduced IL-6 levels correlating with patient improvement.
Sarconeos (BIO101; Biophytis SA) [307] Activates MAS, a component of the protective arm of the renin angiotensin system. Phase 2/3 trial (COVA) international trial assessing potential treatment for ARDS.
Abivertinib (Sorrento Therapeutics) [308] Tyrosine kinase inhibitor with dual selective targeting of mutant forms of EGFR and BTK. Phase 2 trial starting late July 2020 in hospitalized patients with moderate-to-severe COVID-19 who have developing cytokine storm in the lungs.
Nangibotide (LR12; Inotrem S.A.) [309] Immunotherapy that targets the triggering receptor expressed on myeloid cells-1 (TREM-1) protein pathway, a factor causing unbalanced inflammatory responses. Phase 2a clinical trial (ASTONISH) authorized in the United States, France, and Belgium for mechanically ventilated patients with COVID-19 who have systemic inflammation. Previous clinical studies demonstrated safety and tolerability in patients with septic shock.
Aprepitant (Cinvanti; Heron Therapeutics, Inc) [310] Substance P/neurokinin-1 (NK1) receptor antagonist. Substance P and its receptor, NK1, are distributed throughout the body in the cells of many tissues and organs, including the lungs. Phase 2 clinical study (GUARDS-1) initiated mid-July 2020 in early-hospitalized patients with COVID-19. Administration to these patients is expected to decrease production and release of inflammatory cytokines mediated by the binding of substance P to NK1 receptors, which could prevent the progression of lung injury to ARDS.
Piclidenoson (Can-Fite BioPharma) [311] A3 adenosine receptor (A3AR) agonist that elicits anti-inflammatory effects. Phase 2 trial planned in the United States to start late July 2020 involving hospitalized patients with moderate COVID-19.
LSALT peptide (MetaBlokTM; Arch Biopartners) [312] LSALT peptide that targets dipeptidase-1 (DPEP1), which is a vascular adhesion receptor for neutrophil recruitment in the lungs, liver, and kidney. The first US phase 2 trial will be at Broward Health Medical Center in Florida to treat complications in patients with COVID-19, including prevention of acute lung and/or kidney injury.
RLS-0071 (ReAlta Life Sciences) [313] Animal model shows that RLS-0071 decreases inflammatory cytokines IL-1b, IL-6, and TNF-alpha. A phase 1 randomized, double-blind, placebo-controlled trial is planned to begin Q3 2020 in adults with COVID-19 pneumonia and early respiratory failure.

Investigational Immunotherapies

Table 3. Investigational Immunotherapies for COVID-19 (Open Table in a new window)

Drug Description
CEL-SCI Corporation [314] Preferentially directed immunotherapy using ligand antigen epitope presentation system (LEAPS) peptide technology to reduce COVID-19 viral load and consequent lung damage.
Brilacidin (Innovation Pharmaceuticals) [315, 316] Defensin-mimetic that mimics the immune system and disrupts the pathogen membrane, leading to cell death. It is undergoing clinical-stage testing at a US regional biocontainment laboratory. Also see Table 5 for potential use as a vaccine adjuvant.
Allogeneic natural killer (NK) cells (CYNK-001; Celularity, Inc) [317] FDA-approved investigational new drug for phase 1/2 clinical trial; demonstrates a range of biological activities expected of NK cells, including expression of activating receptors such as NKG2D, DNAM-1, and the natural cytotoxicity receptors NKp30, NKp44, and NKp46, which bind to stress ligands and viral antigens on infected cells.
Autologous, adipose-derived mesenchymal stem cells (HB-adMSCs; Hope Biosciences) [318, 319, 320] Shown to attenuate systemic inflammation in phase 1/2 clinical trial for rheumatoid arthritis. FDA approves phase 2 single-arm, nonrandomized study for COVID-19 in patients ≥50 years with preexisting health conditions or at high exposure risk. Another phase II trial will enroll 100 frontline healthcare workers and first responders. A third clinical trial placebo-controlled study is planned in collaboration with advanced diagnostics healthcare.
MultiStem cell therapy (Athersys) [321] Potential to produce therapeutic factors in response to signals of inflammation and tissue damage. A previous phase 1-2 study assessed therapy in ARDS. The first patient has been enrolled in the phase 2/3 trial—MultiStem Administration for COVID-19 Induced Acute Respiratory Distress Syndrome (MACOVIA) at University Hospital’s Cleveland Medical Center.
CD24Fc (OncoImmune) [322] Biologic that fortifies an innate immune checkpoint against excessive inflammation caused by tissue injuries. Phase 3 testing was initiated April 20, 2020, at the University of Maryland. As of mid-June 2020, 70 patients have been enrolled.
LY3127804 (Eli Lilly Co) [249] Selective monoclonal antibody against angiopoietin 2 (Ang2), which is known to be elevated in patients with ARDS. Trial initiated at several US medical centers to determine if it reduces progression to ARDS or mechanical ventilation.
Bucillamine (Revive Therapeutics) [323] Bucillamine has been shown to significantly attenuate clinical symptoms in respiratory viral infections in humans, primarily via donation of thiols to restore antioxidant and to reduce the activity of cellular glutathione. A phase 3 trial for treatment of mild-to-moderate COVID-19 was approved by the FDA in late April 2020.
Peginterferon lambda (Eiger Biopharmaceuticals; Stanford University) [324] Phase 2 trial initiated in outpatients with mild COVID-19 to evaluate efficacy of reducing viral shedding. Patients receive a single SC dose and are monitored for 28 days. Interferon lambda is thought to target innate immune response against viral pathogens.
Immune globulin IV (Octagam 10%; Octapharma) [325] IND for phase 3 randomized trial accepted by FDA to assess efficacy and safety in patients with severe COVID-19 disease.
Efineptakin alfa (NT-17; NeoImmuneTech, Inc) [326] A long-acting human interleukin-7 (IL-7), which plays a key role in T-cell development. IL-7 acts through IL-7 receptor (IL-7R), which is expressed on naïve and memory CD4+ and CD8+ T cells and promotes proliferation, maintenance, and functionality of these T-cell subsets that mediate immune responses. A phase 1 trial was announced inmid-July 2020 for adults with mild COVID-19 in conjunction with NIAID and the University of Nebraska Medical Center.
IFX-1 (InflaRx) [327] First-in-class monoclonal anti-human complement factor C5a antibody. IFX-1 blocks the biological activity of C5a and demonstrates high selectivity toward its target in human blood; therefore, it leaves the formation of the membrane attack complex (C5b-9) intact as an important defense mechanism, which is not the case for molecules blocking C5 cleavage. Plans for phase 3 trial in patients with severe COVID-19–induced pneumonia who are mechanically ventilated.

Investigational Antibody-Directed Therapies

Table 4. Investigational Antibody-Directed Therapy Examples for COVID-19 (Open Table in a new window)

Antibody Description
Anti-SARS-CoV-2 polyclonal hyperimmune globulin (Takeda) [328] Under development to treat high-risk patients.
REGN-COV2 Anti-Viral Antibody Cocktail (Regeneron) [329, 330] Clinical trials of dual mAb cocktail initiated in June 2020 for prevention and treatment of COVID-19. The 2 antibodies bind noncompetitively to the critical receptor binding domain (RBD) of the virus' spike protein, which diminishes the ability of mutant viruses to escape treatment. The clinical program consists of 4 separate study populations: hospitalized patients, nonhospitalized symptomatic patients, uninfected people in groups that are at high risk of exposure (eg, healthcare workers, first responders), and uninfected people with close exposure to an individual with COVID-19 (eg, patient's housemate). A manufacturing and supply agreement for BARDA and the US Department of Defense was announced in July 2020.
VIR-7831 & VIR-7832 (Vir Biotechnology collaborating with Biogen and Generation Bio) [331] VIR-7831 and VIR-7832 are mAbs that binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1, indicating the epitope is highly conserved and more difficult to mutate. Each are engineered to have an extended half-life.
Polyclonal hyperimmune immunoglobulin (TAK-888; Takeda) [332] Concentrated virus-specific antibodies from plasma collected from people who have already recovered from COVID-19.
LY-CoV555 (Eli Lilly and AbCellera) [333] Antibody treatment from more than 500 unique antibodies isolated from one of the first US patients to recover from COVID-19. Phase 1 initiated late May 2020.
JS-016 (Junshi Bioschiences and Eli Lilly) [334] Neutralizing antibody that binds a different epitope on the COVID spike protein than Lilly’s other antibody (LY-CoV555). Phase 1 trial to be initiated June 2020.
Amgen collaborating with Adaptive Biotechnologies [335] Discovery/development of fully human neutralizing antibodies targeting SARS-CoV-2.
COVI-SHIELD (Sorrento Therapeutics; NCT04376684) [336] mAb cocktail development in conjunction with Mt Sinai Health System in New York City.
Antibody combination (AstraZeneca; Vanderbilt University) [337] Phase 1 trial of a two-antibody combination product planned to start in August 2020. The two antibodies bind to distinct sites on the SARS-CoV-2 spike protein.

Investigational Vaccines

The genetic sequence of SARS-CoV-2 was published on January 11, 2020. The rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers that followed has produced nearly 80 confirmed active vaccine candidates as of April 8, 2020. Various methods are used for vaccine discovery and manufacturing.

In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally.

Thanh Le et al describe platforms based on DNA or mRNA that offer flexibility regarding antigen manipulation and speed of development. Recombinant protein-based development may be beneficial owing to existing large-scale production capabilities. Use of an adjuvant can be of particular importance in a pandemic situation. Adjuvants are compounds that potentiate that antigen in the vaccine, thereby reducing the amount of antigen protein required per dose. This method allows more people to be vaccinated and conserves antigen resources.[338]

Examples of vaccines under development in the United States are included in Table 5.

Table 5. Investigational Vaccines for COVID-19 (Open Table in a new window)

Vaccine Comments
mRNA-1273 (Moderna Inc) [339, 340] mRNA-1273 encodes the S-2P antigen. The phase 1 study, a dose-escalation trial, was initiated in 45 healthy volunteers aged 18-55 years on March 16, 2020 at Kaiser Permanente Washington Health Research Instituted in Seattle and at the Emory University School of Medicine in Atlanta. Three doses—25, 100, and 250 mcg—were administered on a 2-dose schedule given 28 days apart. After the second vaccination, serum-neutralizing activity was detected via 2 methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Phase 2 testing of placebo, 50-mcg, or 100-mcg given as 2 doses 28 days apart in adults aged 18-55 years (n=300) and in adults aged 55 years or older (n=50) was completed in June. US phase 3 trial (COVD) launched July 27, 2020, in cooperation with NIAID and will include about 30,000 participants who will receive two 100-mcg doses on days 1 and 29 or matched placebo.
ChAdOx1 nCoV-19 vaccine (Jenner Institute, Oxford University; AstraZeneca) [341] Phase 1/2 trial (n = 1077) completed. Spike-specific T-cell responses peaked on day 14. Anti-spike IgG responses rose by day 28 and were boosted following a second dose.
Two vaccine candidates (Merck in collaboration with nonprofit IAVI) [342] Developing 2 separate single-dose vaccines. After purchasing Themis Bioscience (Austrian vaccine maker), one vaccine will be based on a modified measles virus that delivers portions of SARS-CoV-2 virus. The second vaccine in collaboration with IAVI uses Merck’s Ebola vaccine technology. This vaccine is expected to start human trials in 2020.
mRNA vaccine BNT16b2b2 (BioNTech and Pfizer) [343, 344, 345] Nucleoside-modified messenger RNA (modRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. Human testing was initiated in early May 2020. Preliminary results from the phase 1/2 trial showed the vaccine (BNT162b1) could be administered in a 2-dose series that was well tolerated and that generated dose-dependent immunogenicity as measured by RBD-binding IgG concentrations and SARS-CoV-2 neutralizing antibody titers. All subjects in the prime-boost cohorts, except for 2 at the lowest dose level, had CD4+ T-cell responses. The phase 2b/3 trial is slated to begin in late July 2020 with BNT162b2 vaccine (one of four mRNA constructs being clinically evaluated). BNT162b2 emerged as the strongest candidate and it elicited T-cell responses against the RBD, which may generate more consistent responses across diverse populations, including older individuals.
Ad26.COV2.S vaccine (Johnson & Johnson [J&J]) [346, 347] Adenovirus serotype 26 (Ad26) vector-based vaccine. Preclinical trials showed a single dose elicited neutralizing antibodies and successfully prevented subsequent infection in nonhuman primates. Phase 1/2a testing in healthy volunteers initiating in late July 2020 in Belgium, the United States, Netherlands, Spain, Germany, and Japan. Phase 3 trial expected to commence in September 2020.
Saponin-based Matrix-M adjuvant vaccine (NVX-CoV2373; Novavax and Emergent BioSolutions) [348] Stimulates the entry of antigen-presenting cell into the injection site and enhances antigen presentation in local lymph nodes to boost the immune response. Phase 1/2 trials were initiated in May 2020. Funding received by the Department of Defense (DoD). Plans are to deliver 10 million doses to the DoD for phase 2/3 clinical trial contingent on preliminary data from earlier trials.
INO-4800 (Inovio Pharmaceuticals) [349, 350] The phase 1 human clinical trial enrolled 40 healthy volunteers and was completed late April 2020. Favorable interim results of safety and immunogenicity were reported in June 2020. The phase 1 trial was expanded to include older participants, and phase 2/3 efficacy trials are planned to commence in summer 2020. Inovio has received a grant from the Bill and Melinda Gates Foundation to accelerate testing and scale up a smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery.
mRNA vaccine (CureVac) [351] Vaccine is in development and not yet ready for human testing as of March 16, 2020.
COVID-19 S-Trimer (GlaxoSmithKline [GSK] and Clover Biopharmaceuticals) [352] Preclinical development is underway using GSK’s adjuvants (compounds that enhance vaccine efficacy) and Clover’s proprietary proteins, which stimulate an immune response.
XWG-03 (GlaxoSmithKline and Xiamen Innovax collaboration) [353] GSK will provide Innovax with its adjuvant system for preclinical vaccine evaluation.
CpG 1018 adjuvant (Dynavax) and Sinovac’s inactivated coronavirus vaccine candidate [354] Collaboration for adjuvanted vaccine development.
Vaccine with CpG 1018 adjuvant (Dynavax and Clover Biopharmaceuticals) [355] Dynavax is providing Clover with adjuvant for its protein-based coronavirus vaccine candidate.
CpG 1018 adjuvant (Dynavax and Valneva) [356] Dynavax is providing technical expertise and the toll-like receptor 9 (TLR9) agonist adjuvant CpG 1018. Valneva is leveraging their platform for Japanese encephalitis vaccine, which operates on a highly purified Vero-cell–based, inactivated, whole-virus strategy for vaccine development.
rDNA vaccine (Sanofi) [357] Collaborating with BARDA to develop a vaccine using their recombinant DNA platform.
Adjuvanted vaccine (GlaxoSmithKline and Sanofi) [358] Adjuvanted vaccine will be developed by combining Sanofi’s S-protein COVID-19 antigen and GSK’s pandemic adjuvant technology.
Live-attenuated vaccine (Codagenix) [359] Codagenix, a clinical-stage biotechnology company, is collaborating with the Serum Institute of India to co-develop a live-attenuated vaccine.
PCR-based DNA vaccine (Applied DNA Sciences and Takis Biotech) [360] The collaboration has designed four COVID-19 vaccine candidates utilizing PCR-based DNA manufacturing systems for preclinical testing in animals.
Intranasal COVID-19 vaccine (Altimmune, Inc) [361] Design and synthesis has been completed and is advancing toward animal testing.
Brilacidin adjuvant vaccine (Innovation Pharmaceuticals) [362] Material Transfer Agreement (MTA) signed with a leading public health-focused US university and top coronavirus expert to evaluate the potential antiviral properties as a defensing adjuvant. Also see Table 1.
HaloVax (Hoth Therapeutics; Voltron Therapeutics) [363] Collaboration with the Vaccine and Immunotherapy Center of the Massachusetts General Hospital. Use of VaxCelerate self-assembling vaccine platform offers one fixed immune adjuvant and one variable immune targeting to allow rapid development.
PittCoVax (U of Pittsburgh School of Medicine) [364] Vaccine candidate using microneedle transdermal for COVID-19. Testing in mice produced antibodies over a 2-week period. Microneedles are made of sugar, making it easy to mass-produce and store without refrigeration.
Nanoparticle SARS-CoV-2 vaccine (Ufovax) [365] Vaccine prototype development utilizing self-assembling protein nanoparticle (1c-SapNP) vaccine platform technology.
Vaccine candidate (PDS Biotechnology Corp) [366] Utilizes Versamune T-cell activating platform for vaccine development.
TNX-1800 (Tonix Pharmaceuticals and Fujifilm Diosynth Biotechnologies) [367] Modified horsepox virus that is designed to express a protein from the SARS-CoV-2 virus.
Virus-like protein (VLP) based vaccine (Catalent; Spicona) [368] Catalent will use its proprietary GPEx cell line development technology to develop a cell line expressing the recombinant VLP.
Recombinant coronavirus Virus-Like Particles (CoVLP; Medicago and GlaxoSmithKline) [369] Combines Medicago’s rCoVLP with GSK’s adjuvant system. Phase 1 trial initiation planned for mid-July 2020.
Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; CanSino Biologics Inc [China]) [370, 371] Phase 2 trial (n = 508) completed. The vaccine induced seroconversion of neutralizing antibodies in 59% and 47% of participants in the 1x 1011 and 5x 1010 viral particles dose groups, respectively, and seroconversion of binding antibody in 96% and 97% of participants, respectively. Positive specific T-cell responses were found in 90% and 88%, respectively.

Renin Angiotensin System Blockade and COVID-19

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells.[372] Data are limited concerning whether to continue or discontinue drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), namely angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).

Concern arose regarding appropriateness of continuation of ACEIs and ARBs in patients with COVID-19 after early reports noted an association between disease severity and comorbidities such as hypertension, cardiovascular disease, and diabetes, which are often treated with ACEIs and ARBs. The reason for this association remains unclear.[373, 108]

The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2. It was therefore hypothesized that any agent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellular entry;[373] however, physiologically, ACE2 also converts angiotensin 2 to angiotensin 1-7, which leads to vasodilation and may protect against lung injury by lowering angiotensin 2 receptor binding.[108, 374] It is therefore uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs.

Vaduganathan et al note that data in humans are limited, so it is difficult to support or negate the opposing theories regarding RAAS inhibitors. They offer an alternate hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. As mentioned, ACE2 acts as a counterregulatory enzyme that degrades angiotensin 2 to angiotensin 1-7. SARS-CoV-2 not only appears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatory effects of ACE2.[375]

There are also conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2,[376, 377, 378] while other studies have not shown this effect.[379, 380]

As controversy remains regarding whether ACEIs and/or ARBs increase ACE2 expression and how this effect may influence outcomes in patients with COVID-19, cardiology societies have largely recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection.[381, 382]

Two clinical trials are currently in development at the University of Minnesota evaluating the use of losartan in patients with COVID-19 in inpatient and outpatient settings.[383, 384] Results from these trials will provide insight into the potential role of ARBs in the treatment of COVID-19.

Diabetes and COVID-19

High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia.[385, 386] Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following:[387]

  • Higher-affinity cellular binding and efficient virus entry
  • Decreased viral clearance
  • Diminished T-cell function
  • Increased susceptibility to hyperinflammation and cytokine storm syndrome
  • Presence of cardiovascular disease

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2.[387] Dipeptidyl peptidase 4 (DPP-4) is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19.[388]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. Important clinical conclusions of the review include the following:[386]

  • Hospitalization is more common for acute COVID-19 among patients with diabetes and obesity.
  • Diabetic medications need to be reevaluated upon admission.
  • Insulin is the glucose-lowering therapy of choice, not DPP-4 inhibitors or GLP-1 receptor agonists, in patients with diabetes who are hospitalized with acute COVID-19.

Hydroxychloroquine, Chloroquine, and Lopinavir/Ritonavir

Hydroxychloroquine and chloroquine

On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated to the Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible.[389]

Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that hydroxychloroquine is unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other potential serious adverse effects, the known and potential benefits of hydroxychloroquine no longer outweigh the known and potential risks for the EUA.

While additional clinical trials may continue to evaluate potential benefit, the FDA determined the EUA was no longer appropriate.

Additionally, the NIH halted the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) study on June 20, 2020. After the fourth analysis that included more than 470 participants, the NIH data and safety monitoring board determined that, while there was no harm, the study drug was very unlikely to be beneficial to hospitalized patients with COVID-19.[390]

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro.[391] The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days.[392]

Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients. Owing to widely varying dosage regimens, disease severity, measured outcomes, and lack of control groups, efficacy data have been largely inconclusive.

The UK RECOVERY Trial randomized 1542 patients to hydroxychloroquine and 3132 patients to usual care alone. Preliminary results found no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs 23.5% usual care; hazard ratio 1.11 [95% CI, 0.98-1.26]; P = 0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes.[393]

A multicenter, randomized, open-label trial in Brazil found no improvement in 504 hospitalized patients with mild-to-moderate COVID-19. Use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days compared with standard care. Prolonged QTc interval and elevated liver-enzyme levels were more common in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.[394]

An observational study of 2512 hospitalized patients in New Jersey with confirmed COVID-19 was conducted between March 1, 2020 and April 22, 2020, with follow-up through May 5, 2020. Outcomes included 547 deaths (22%) and 1539 (61%) discharges; 426 (17%) remained hospitalized. Patients who received at least one dose of hydroxychloroquine totaled 1914 (76%), and those who received hydroxychloroquine plus azithromycin totaled 1473 (59%). No significant differences were observed in associated mortality among patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality rate in patients receiving hydroxychloroquine alone, azithromycin alone, the combination, or neither drug was 25%, 20%, 18%, and 20%, respectively.[216]

Because of these findings, the WHO paused the hydroxychloroquine arm of the Solidarity Trial and then removed its use entirely as of July 4, 2020.[151] The FDA issued a safety alert for hydroxychloroquine or chloroquine use in COVID-19 on April 24, 2020.[395]

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City area showed hydroxychloroquine was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death.[396]

A retrospective observational study of 2,541 consecutive patients hospitalized with COVID at Henry Ford Health System from March 10, 2020, to May 2, 2020, showed a decreased mortality rate in patients treated with hydroxychloroquine alone or in combination with azithromycin. Overall in-hospital mortality was 18.1%; by treatment: hydroxychloroquine plus azithromycin, 157/783 (20.1%), hydroxychloroquine alone, 162/1202 (13.5%), azithromycin alone, 33/147 (22.4%), and neither drug, 108/409 (26.4%). Therapy with corticosteroids (methylprednisolone and/or prednisone) was administered in 68% of all patients. Corticosteroids were administered to 78.9% of patients who received hydroxychloroquine alone. In addition to adjunctive use of corticosteroids, an accompanying editorial discusses time bias, missing prognostic indicators, and other confounding factors of this observational study.[397, 398]

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified. A total of 368 patients were evaluated (HC n=97; HC + AZ n=113; no HC n=158). Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective, randomized controlled trials before wide adoption of these drugs.[399]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia.[400] While no peer-reviewed treatment outcomes are available, Gao and colleagues report that 100 patients have demonstrated significant improvement with this regimen without documented toxicity.[401] It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19. It should also be noted that chloroquine was previously found to be active in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomes in human studies of Chikungunya virus infection (a virus unrelated to SARS-CoV-2).

A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients (average age, 44.7 years) with confirmed COVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO2/SPOs ratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids). Thirty-one patients were randomized to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressed to severe illness, all of whom were in the control group.[402]

The French have embraced hydroxychloroquine as a potentially more potent therapy with an improved safety profile to treat and prevent the spread of COVID-19.[403] If it is effective, the optimal regimen of hydroxychloroquine is unknown, although some experts have recommended higher doses, such as 600-800 mg per day. A study of hydroxychloroquine for postexposure prophylaxis in healthcare workers or household contacts is underway.[404]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days for seronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150 patients in China with mild-to-moderate disease.[405]

Hydroxychloroquine plus azithromycin

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published.[406, 407, 408]

A small prospective study found no evidence of a strong antiviral activity or clinical benefit conferred by hydroxychloroquine plus azithromycin. Molina et al assessed virologic and clinical outcomes of 11 consecutive hospitalized patients who received hydroxychloroquine (600 mg/day for 10 days) and azithromycin (500 mg on day 1, then 250 mg days 2-5). The study group included 7 men and 4 women with a mean age of 58.7 years (range, 20-77 years); 8 had significant comorbidities associated with poor outcomes (ie, obesity in 2, solid cancer in 3, hematological cancer in 2, and HIV infection in 1). Ten of the eleven patients had fever and received oxygen via nasal cannula. Within 5 days, one patient died and two were transferred to the ICU. Hydroxychloroquine and azithromycin were discontinued in one patient owing to prolonged QT interval. Nasopharyngeal swabs remained positive for SARS-CoV-2 RNA in 8 of 10 patients (80%; 95% confidence interval, 49-94) at days 5-6 after treatment initiation.[408]

In direct contrast to the aforementioned results, another study in France evaluated patients treated with hydroxychloroquine (n=26) against a control group (n=16) who received standard of care. After dropping 6 patients from the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6 (70% [14/20] vs 12.5% [2/16]).[406] This is an unusual approach to reporting results because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed status within a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also not explained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time but were not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the control arm, indicating unorthodox study enrollment.

This small open-label study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterial superinfection (500 mg once, then 250 mg PO daily for 4 days). These patients were reported to have 100% clearance of SARS-CoV-2. While intriguing, these results warrant further analysis. The patients receiving combination therapy had initially lower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results are fairly similar (6/6 vs 7/9).[406]

The French researchers continued their practice of using hydroxychloroquine plus azithromycin and accumulated data in 80 patients with at least 6 days of follow-up. They note that the 6 patients enrolled in their first analysis were also included in the present case series, with a longer follow-up. However, it was not clear from the description in their posted methods when patients were assessed. A favorable outcome was defined as not requiring aggressive oxygen therapy or transfer to the ICU after 3 days of treatment. Sixty-five of the 80 patients (81.3%) met this outcome. One patient aged 86 years died, and a 74-year-old patient remained in the ICU. Two others were transferred to the ICU and then back to the infection ward. Results showed a decrease in nasopharyngeal viral load tested via qPCR, with 83% negative at day 7 and 93% at day 8. Virus culture results from patient respiratory samples were negative in 97.5% patients at day 5.[407] This is described as a promising method of reducing spread of SARS-CoV-2, but, unfortunately, the study lacked a control group and did not compare treatment with hydroxychloroquine plus azithromycin to a similar group of patients receiving no drug therapy or hydroxychloroquine alone. Overall, the acuity of these patients was low, and 92% had a low score on the national Early Warning System used to assess risk of clinical deterioration. Only 15% were febrile, a common criterion for testing in the United States, and 4 individuals were considered asymptomatic carriers. In addition, the results did not delineate between asymptomatic carriers and those with high viral load or low viral load.

Nonhospitalized patients with early COVID-19

Hydroxychloroquine did not improve outcomes when administered to outpatient adults (n = 423) with early COVID-19. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine compared with 22% (46 of 211) receiving placebo (P< 0.001). Among patients receiving placebo, 10 were hospitalized (two cases unrelated to COVID-19), one of whom died. Among patients receiving hydroxychloroquine, four were hospitalized and one nonhospitalized patient died (P = 0.29).[409]

Clinical trials evaluating prevention

Various clinical trials in the United States were initiated to determine if hydroxychloroquine reduces the rate of infection when used by individuals at high risk for exposure, such as high-risk healthcare workers, first responders, and individuals who share a home with a COVID-19–positive individual.[404, 410, 411, 412, 413, 414, 415]

Results from a double-blind randomized trial (n = 821) from the University of Minnesota found no benefit of hydroxychloroquine (n = 414) in preventing illness due to COVID-19 compared with placebo (n = 407) when used as postexposure prophylaxis in asymptomatic participants within 4 days following high-risk or moderate-risk exposure. Overall, 87.6% of participants had high-risk exposures without eye shields and surgical masks or respirators. New COVID-19 (either PCR-confirmed or symptomatically compatible) developed in 107 participants (13%) during the 14-day follow-up. Incidence of new illness compatible with COVID-19 did not differ significantly between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]) (P = 0.35).[416]

QT prolongation with hydroxychloroquine and azithromycin

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population.[417] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion of the arrhythmogenicity of hydroxychloroquine and azithromycin that includes a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered.[418, 419]

A Brazilian study comparing chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days) observed QT prolongation in 25% of patients in the high-dose group. All patients received other drugs (ie, azithromycin, oseltamivir) that may contribute to prolonged QT.[420]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine from an analysis of pooled data from Japan, Europe, and the United States. The analysis compared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin or hydroxychloroquine plus azithromycin.[319]

For more information, see QT Prolongation with Potential COVID-19 Pharmacotherapies.

Lopinavir/ritonavir

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19.[421]

The Infectious Diseases Society of America (IDSA) guidelines recommend use of lopinavir/ritonavir only in the context of a randomized clinical trial. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition.[30]

On June 29, 2020, analysis of the RECOVERY trial concluded no beneficial effect in hospitalized patients with COVID-19 who were randomized to receive lopinavir/ritonavir (n = 1596) compared with those who received standard care (n = 3376). Of these patients, 4% required invasive mechanical ventilation when they entered the trial, 70% required oxygen alone, and 26% did not require any respiratory intervention. No significant difference was observed in the 28-day mortality rate (22.1% lopinavir/ritonavir vs 21.3% standard care; relative risk 1.04 [95% CI, 0.91-1.18]; P = 0.58), and the results were consistent in different patient subgroups. No evidence was found for beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay.[422]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020.[151]

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO2 of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance.[423] An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak.[424]

Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group.[196]

A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Results showed that triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19.[425]

Average wholesale price (AWP) for a course of lopinavir/ritonavir at this dose is $575.

QT Prolongation with Potential COVID-19 Pharmacotherapies

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population.[417] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on the arrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered.[418, 419]

Giudicessi et al have published guidance for evaluating the torsadogenic potential of chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin. Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2-encoded HERG/Kv11.1. Additional modifiable risk factors (eg, treatment duration, other QT-prolonging drugs, hypocalcemia, hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QT syndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness.[426]

A cohort study was performed from March 1 through April 7, 2020, at an academic tertiary care center in Boston to characterize the risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or without azithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefully monitor QTc and concomitant medication usage if considering using hydroxychloroquine.[427]

A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU Langone Medical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin. QTc increased by greater than 40 ms in 30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation.[428]

A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days). A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients. In addition, all patients received ceftriaxone and azithromycin. Oseltamivir was also prescribed in 89% of patients. Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose. The high incidence of QT prolongation prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval. The fatality rate was 13.5%. In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient.[420]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine. Pooled data from 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, United Kingdom, and the United states were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations of hydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis.[319]

Investigational Devices

Blood purification devices

Several extracorporeal blood purification filters (eg, CytoSorb, oXiris, Seraph 100 Microbind, Spectra Optia Apheresis) have received emergency use authorization from the FDA for the treatment of severe COVID-19 pneumonia in patients with respiratory failure. The devices have various purposes, including use in continuous renal replacement therapy or in reduction of proinflammatory cytokines levels.[429]

Nanosponges

Cellular nanosponges made from plasma membranes derived from human lung epithelial type II cells or human macrophages have been evaluated in vitro. The nanosponges display the same protein receptors required by SARS-CoV-2 for cellular entry and act as decoys to bind the virus. In addition, acute toxicity was evaluated in vivo in mice by intratracheal administration.[430]

 

Guidelines

Guidelines Summary

Numerous clinical guidelines have been issued for COVID-19. The following guidelines have been summarized at Medscape's COVID-19 Clinical Guidelines center:

Information regarding COVID-19 is rapidly emerging and evolving. For the latest information, see the following:

CDC Evaluating and Testing Persons Under Investigation (PUI) for COVID-19 Clinical Guidelines

The CDC has issued interim guidance for the COVID-19 outbreak, including evaluation and testing of persons under investigation (PUIs) for COVID-19.[431]

Criteria to guide evaluation and testing of patients under investigation for COVID-19

Clinicians should work with state and local health departments to coordinate testing. The FDA has authorized COVID-19 diagnostic testing to be made available in clinical laboratories, expanding the capacity for clinicians to consider testing symptomatic patients.

The decision to administer COVID-19 testing should be based on clinical judgment, along with the presence of compatible signs and symptoms. The CDC now recommends that COVID-19 be considered a possibility in patients with severe respiratory illness regardless of travel history or exposure to individuals with confirmed infection. The most common symptoms in patients with confirmed COVID-19 have included fever and/or symptoms of acute respiratory illness, including breathing difficulties and cough.

Patient groups in whom COVID-19 testing may be prioritized include the following:

  1. Hospitalized patients with compatible signs and symptoms in the interest of infection control
  2. High-risk symptomatic patients (eg, older patients and patients with underlying conditions that place them at higher likelihood of a poor outcome)
  3. Symptomatic patients who have had close contact with an individual with suspected or confirmed COVID-19 or who have traveled from affected geographic areas within 14 days of symptom onset

Clinicians should also consider epidemiologic factors when deciding whether to test for COVID-19. Other causes of respiratory illness (eg, influenza) should be ruled out.

Patients with mild illness who are otherwise healthy should stay home and coordinate clinical management with their healthcare provider over the phone. Patients with severe symptoms (eg, breathing difficulty) should seek immediate care. High-risk patients (older individuals and immunocompromised patients or those with underlying medical conditions) should be encouraged to contact their healthcare provider in the case of any illness, even if mild.[431]

Reporting, testing, and specimen collection

In the event that a patient is classified a PUI for COVID-19, infection-control personnel at the healthcare facility should immediately be notified. Upon identification of a PUI, state health departments should immediately complete a PUI and Case Report form and can contact CDC’s Emergency Operations Center (EOC) at 770-488-7100 for assistance.

Currently, diagnostic testing for COVID-19 is being performed at state public health laboratories and the CDC. Testing for other respiratory pathogens should not delay specimen testing for COVID-19.

The CDC recommends collecting and testing upper respiratory specimens (oropharyngeal and nasopharyngeal swabs) and lower respiratory specimens (sputum, if possible) in patients with a productive cough for initial diagnostic testing. Sputum induction is not indicated. If clinically indicated, a lower respiratory tract aspirate or bronchoalveolar lavage sample should be collected and tested. Once a PUI is identified, specimens should be collected as soon as possible.[431]

CDC Sample Collection and Testing Guidelines for COVID-19

In March 2020, the CDC published interim guidelines regarding the collection, handling, and testing of clinical specimens for the diagnosis of COVID-19.[432]

Collection and evaluation of an upper respiratory nasopharyngeal swab (NP) is recommended for initial COVID-19 testing.

If an oropharyngeal swab (OP) is collected, it should be combined in the same tube as the NP; however, OPs are a lower priority than NPs.

Only patients with a productive cough should undergo sputum collection. Sputum induction is not recommended.

If lower respiratory tract specimens are available, they should also be tested.

If clinically indicated (eg, if the patient is undergoing invasive mechanical ventilation), collection and testing of a lower respiratory tract aspirate or bronchoalveolar lavage sample should be performed.

Once a possible COVID-19 case has been identified, specimen collection should be performed as soon as possible, regardless of when the individual’s symptoms began.

Proper infection control must be maintained during specimen collection.

Lower respiratory tract specimens

Bronchoalveolar lavage, tracheal aspirate

Two to 3 mL should be collected in a sterile, leak-proof, screw-cap sputum collection cup or sterile, dry container.

Sputum

The patient should rinse his or her mouth with water and then expectorate deep cough sputum directly into a sterile, leak-proof, screw-cap sputum collection cup or sterile, dry container.

Upper respiratory tract specimens

Nasopharyngeal swab/oropharyngeal swab

Only synthetic fiber swabs with plastic shafts should be used. Calcium alginate swabs or swabs with wooden shafts—both of which may contain substances that inactivate some viruses and inhibit PCR testing—should not be used. Swabs should be placed immediately in sterile tubes containing 2-3 mL of viral transport media. In general, the CDC recommends that only an NP should be collected. If an OP is collected as well, it should be combined at collection with the NP in a single vial.

To collect an NP, the swab should be inserted into the nostril parallel to the palate, reaching a depth equal to the distance from the nostrils to the ear’s outer opening. To absorb secretions, the swab should be left in place for several seconds. It should then be slowly removed while the clinician rotates it.

In collecting an OP (eg, a throat swab), the posterior pharynx should be swabbed, with avoidance of the tongue.

Nasopharyngeal wash/aspirate or nasal aspirate

Two to 3 mL should be collected in a sterile, leak-proof, screw-cap sputum collection cup or sterile, dry container.

Storage

Specimens should be stored at 2-8°C for up to 72 hours after collection. If testing or shipping may be delayed, the specimens should be stored at -70°C or below.

Shipping

Packaging, shipping, and transportation of specimens must be performed as designated in the current edition of the International Air Transport Association (IATA) Dangerous Goods Regulations. Specimens should be stored at 2-8°C and shipped overnight to the CDC on ice pack. Specimens frozen at -70°C should be shipped overnight to the CDC on dry ice.

Guidance for Hospitals on Containing Spread of COVID-19

The guideline on coronavirus disease (COVID-19) infection control and prevention for hospitals was released on March 4, 2020 by the Centers for Medicare & Medicaid Services.[433]

Hospitals should monitor the CDC website (https://www.cdc.gov/coronavirus/2019-ncov/index.html) for up-to-date information and resources.

Hospitals should contact their local health department if they have questions or suspect a patient or healthcare provider (HCP) has COVID-19.

Hospitals should have plans for monitoring healthcare personnel with exposure to patients with known or suspected COVID-19. Additional information about monitoring healthcare personnel is available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesmenthcp.html.

Risk assessment and screening

Older adults and those with underlying chronic medical conditions or immunocompromised state may be at highest risk for severe outcomes. This should be considered in the decision to monitor the patient as an outpatient or inpatient.

Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility. They should ask patients about the following:

  • Fever or symptoms of a respiratory infection, such as a cough and sore throat
  • International travel within the last 14 days to restricted countries (For updated information on restricted countries, visit https://www.cdc.gov/coronavirus/2019-ncov/travelers/index.html.)
  • Contact with someone with known or suspected COVID-19

For patients identified as at-risk, implement respiratory hygiene and cough etiquette (ie, placing a face mask over the patient’s nose and mouth) and isolate the patient in an examination room with the door closed.

If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care. Identify a separate, well-ventilated space that allows waiting patients to be separated by 6 or more feet, with easy access to respiratory hygiene supplies. In some settings, medically stable patients might opt to wait in a personal vehicle or outside the healthcare facility where they can be contacted by mobile phone when they can be evaluated.

Inform infection prevention and control services, local and state public health authorities, and other healthcare facility staff as appropriate about the presence of a person under investigation for COVID-19.

Additional guidance for evaluating patients in the United States for COVID-19 can be found on the CDC COVID-19 Web site.

Provide supplies for respiratory hygiene and cough etiquette, including 60%-95% alcohol-based hand sanitizer (ABHS), tissues, no-touch receptacles for disposal, facemasks, and tissues at healthcare facility entrances, waiting rooms, patient check-ins, etc.

Monitoring or restriction of healthcare facility staff

The same screening performed for visitors should be performed for hospital staff.

HCP who have signs and symptoms of a respiratory infection should not report to work.

Any staff that develop signs and symptoms of a respiratory infection while on the job should do the following:

  • Immediately stop work, put on a facemask, and self-isolate at home.
  • Inform the hospital’s infection prevention specialist and include information on individuals, equipment, and locations with which the person came into contact.
  • Contact and follow the local health department recommendations for next steps (eg, testing, locations for treatment).

Refer to the CDC guidance for exposures that might warrant restricting asymptomatic health care personnel from reporting to work (https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html).

Hospitals should contact their local health department for questions and frequently review the CDC website dedicated to COVID-19 for health care professionals: https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html.

Patient placement and infection prevention and control for known or suspected COVID-19 cases

Patient placement and other detailed infection prevention and control recommendations regarding hand hygiene, transmission-based precautions, environmental cleaning and disinfection, managing visitors, and monitoring and managing health care personnel are available in the CDC Interim Infection Prevention and Control Recommendations for Patients with Confirmed Coronavirus Disease 2019 (COVID-19) or Persons under Investigation for COVID-19 in Healthcare Settings.

Patients may not require hospitalization and can be managed at home if they are able to comply with monitoring requests. More information is available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-home-care.html.

Patients with known or suspected COVID-19 should continue to receive the intervention appropriate for the severity of their illness and overall clinical condition. Because some procedures create high risks for transmission (eg, intubation), additional precautions include the following:

  • HCP should wear all recommended personal protective equipment (PPE).
  • The number of HCP present should be limited to essential personnel.
  • The room should be cleaned and disinfected in accordance with environmental infection control guidelines.

Additional information about performing aerosol-generating procedures is available at https://www.cdc.gov/coronavirus/2019-ncov/infection-control/controlrecommendations.html.

The decision to discontinue transmission-based precautions for hospitalized patients with COVID-19 should be made on a case-by-case basis in consultation with clinicians, infection prevention and control specialists, and public health officials. This decision should consider disease severity, illness signs and symptoms, and results of laboratory testing for COVID-19 in respiratory specimens.

More detailed information about criteria to discontinue transmission-based precautions are available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html.

Visitation rights

Medicare regulations require a hospital to have written policies and procedures regarding the visitation rights of patients, including those setting forth any clinically necessary or reasonable restriction or limitation that the hospital may need to place on such rights and the reasons for the clinical restriction or limitation, such as infection control concerns.

Patients must be informed of their visitation rights and the clinical restrictions or limitations on visitation.

The development of such policies and procedures require hospitals to focus efforts on preventing and controlling infections, not just between patients and personnel, but also between individuals across the entire hospital setting (for example, among patients, staff, and visitors), as well as between the hospital and other healthcare institutions and settings and between patients and the healthcare environment.

Hospitals should work with their local, state, and federal public health agencies to develop appropriate preparedness and response strategies for communicable threats.

Hospital discharge

The decision to discharge a patient from the hospital should be based on the clinical condition of the patient. If transmission-based precautions must be continued in the subsequent setting, the receiving facility must be able to implement all recommended infection prevention and control measures.

Although patients COVID-19 who have mild symptoms may be managed at home, the decision to discharge to home should take into account the patient’s ability to adhere to isolation recommendations, as well as the potential risk of secondary transmission to household members with immunocompromising conditions. More information is available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-home.

Medicare’s Discharge Planning Regulations (updated in November 2019) require that the hospital assess the patient’s needs for post-hospital services and the availability of such services. When a patient is discharged, all necessary medical information (including communicable diseases) must be provided to any post-acute service provider. For patients with COVID-19, this must be communicated to the receiving service provider prior to discharge/transfer and to the healthcare transport personnel.

American Academy of Pediatrics Guidance on Management of Infants Born to Mothers with COVID-19

The American Academy of Pediatrics Committee on Fetus and Newborn, Section on Neonatal Perinatal Medicine, and Committee on Infectious Diseases has issued guidance on the management of infants born to mothers with COVID-19.[434, 435]

Early evidence has shown low rates of peripartum SARS-CoV-2 transmission and uncertainty concerning in utero viral transmission.

Neonates can be infected by SARS-CoV-2 after birth. Because of their immature immune systems, they are vulnerable to serious respiratory viral infections. SARS-CoV-2 may be able to cause severe disease in neonates.

Precautions during delivery

A gown and gloves should be worn by birth attendants, along with an N95 respiratory mask plus goggles or an air-purifying respirator that protects the eyes.

Delayed cord clamping

Transplacental viral transmission from mother to newborn has not been clearly demonstrated, so delayed cord clamping can continue per normal center practices. The mother can briefly hold the newborn during delayed cord clamping if infection-control precautions are observed.

Room-in of mother and well newborn

This is a controversial. Some information has shown good outcomes among most newborns exposed to mothers with COVID-19, although some infants have developed severe illness. The safest approach is to minimize the infection risk via separation, at least temporarily, allowing time for the mother to become less infectious. If the mother chooses against separation or other factors preclude separation, infection risks should be minimized with distancing (at least 6 feet between mother and newborn) and provision of hands-on care to the infant by a noninfected caregiver. Mothers who provide hands-on care should wear a facemask and observe proper hand hygiene.

Breastfeeding

Breastfeeding is strongly supported as the best choice for infant feeding. Breastmilk is unlikely to transmit SARS-CoV-2. Mothers with COVID-19 may express breast milk after appropriate hand and breast hygiene to be fed to the newborn by caregivers without COVID-19. Mothers who opt for nursing should observe strict precautions, including use of a facemask and breast and hand hygiene.

Neonatal intensive care

If the newborn requires intensive care and respiratory support, admission to a single-patient room with negative room pressure is optimal. If multiple newborns with exposure to COVID-19 must be treated in the same room, they should be kept at least six feet apart and/or kept in temperature-controlled isolettes.

Care providers should wear gowns and gloves, along with an N95 respiratory mask plus goggles or an air-purifying respirator that protects the eyes to treat infants who require supplemental oxygen at more than 2 LPM, continuous positive airway pressure, or mechanical ventilation.

Neonatal testing for COVID-19

Following birth, newborns born to mothers with COVID-19 should be bathed to remove virus from the skin. Newborns should undergo testing for SARS-CoV-2 at 24 hours and 48 hours (if still at the birth facility) after birth. Centers with limited testing resources can make testing decisions on a case-by-case basis.

Newborn discharge

Newborns born to mothers with COVID-19 should be discharged per the hospital’s normal criteria. Early discharge is not necessary.

Newborns who test positive for SARS-CoV-2 but are asymptomatic should undergo frequent outpatient follow-up (via phone, telemedicine, or office visit) through 14 days after birth. Infection-control precautions should be observed at home and in the outpatient office.

Infants who test negative for SARS-CoV-2 are likely to be discharged to the care of individuals who have COVID-19 or who have been exposed to COVID-19. All potential caregivers should receive infection-prevention instructions. Following hospital discharge, mothers with COVID-19 should stay at least 6 feet away from their newborns. If a closer proximity is required, the mother should wear a mask and observe hand hygiene for newborn care until (1) her temperature has normalized for 72 hours without antipyretic therapy and (2) at least 10 days has passed since the onset of symptoms. If the mother has asymptomatic SARS-CoV-2 infection (identified with obstetric screening tests), she should wait at least 10 days from the positive test or until two consecutive tests administered more than 24 hours apart show negative results.

Newborns who cannot undergo SARS-CoV-2 testing should be treated as infected for an observation period of 14 days. The mother should still observe the precautions detailed above.

NICU visitation

Access to NICUs during the COVID-19 pandemic is limited. Mothers and partners with confirmed or suspected COVID-19 (PUIs) should not enter the NICU until their status is resolved and transmission is no longer a risk.

NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines

Antiviral therapy

Remdesivir

Remdesivir is recommended in the treatment of COVID-19 in hospitalized patients with SpO2 ≤94% on ambient air (at sea level) and in patients who require supplemental oxygen.

Remdesivir is also recommended in patients who are on mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

Five days of remdesivir treatment is recommended in hospitalized patients with severe COVID-19 who are not intubated. The optimal duration of remdesivir treatment is undetermined in mechanically ventilated patients, patients on ECMO, and patients in whom improvement is inadequate after 5 days of therapy.

The data are insufficient to recommend for or against remdesivir in patients with mild or moderate COVID-19.

Chloroquine or hydroxychloroquine

The Panel recommends against chloroquine or hydroxychloroquine in the treatment of COVID-19 outside the context of a clinical trial.

Other antivirals

The Panel recommends against (1) hydroxychloroquine plus azithromycin, (2) lopinavir/ritonavir, and (3) other HIV protease inhibitors except in a clinical trial.

Immunotherapy

The data are insufficient to recommend for or against COVID-19 convalescent plasma or SARS-CoV-2 immune globulins to treat COVID-19.

The Panel recommends against non–SARS-CoV-2–specific IVIG to treat COVID-19 except in the context of a clinical trial.

The data are insufficient to recommend for or against interleukin-1 inhibitors (eg, anakinra) or interleukin-6 inhibitors (eg, sarilumab, siltuximab, tocilizumab).

The Panel recommends against other immunomodulators (interferons, Janus kinase inhibitors [eg, baricitinib]), except in the context of a clinical trial

Corticosteroids

The Panel recommends dexamethasone (6 mg/day for up to 10 days) in patients with COVID-19 who are mechanically ventilated and in patients who require supplemental oxygen but are not mechanically ventilated.

The Panel recommends against dexamethasone in patients with COVID-19 who do not require supplemental oxygen.

NIH COVID-19 Treatment Guidelines[436]

Care of Critically Ill Patients with COVID-19

Potential Antiviral Drugs Under Evaluation for the Treatment of COVID-19

Immune-Based Therapy Under Evaluation for Treatment of COVID-19

Considerations for certain Concomitant Medications in Patients with COVID-19

Infectious Diseases Society of America (IDSA) Management Guidelines

The Infectious Diseases Society of America (IDSA) has formed a multidisciplinary guideline panel to provide treatment recommendations for coronavirus disease 2019 (COVID-19).[30]

The panel’s current recommendations (subject to change given the rapid evolution of the COVID-19 pandemic) are as follows:

  • Hydroxychloroquine/chloroquine: In patients with COVID-19, the panel recommends hydroxychloroquine/chloroquine only in the context of a clinical trial.
  • Hydroxychloroquine/chloroquine plus azithromycin: In patients with COVID-19, the panel suggests against hydroxychloroquine/chloroquine plus azithromycin outside the context of a clinical trial.
  • Combination of lopinavir/ritonavir: In hospitalized patients with severe COVID-19, the panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial.
  • Corticosteroids: In hospitalized patients with COVID-19 pneumonia, the panel suggests glucocorticoids over no glucocorticoids (dexamethasone 6 mg IV or PO for 10 days). In hospitalized patients with COVID-19 without hypoxemia who require supplemental oxygen, the panel suggests against glucocorticoids.
  • Corticosteroids: In hospitalized patients with acute respiratory distress syndrome (ARDS) due to COVID-19, the panel recommends the use of corticosteroids in the context of a clinical trial.
  • Tocilizumab: In hospitalized patients with COVID-19, the panel recommends tocilizumab only in the context of a clinical trial.
  • Convalescent plasma: In hospitalized patients with COVID-19, the panel recommends COVID-19 convalescent plasma only in the context of a clinical trial.
  • Remdesivir: In hospitalized patients with severe COVID-19, the panel suggests remdesivir over no antiviral treatment. In patients with severe COVID-19 who are receiving supplemental oxygen but not on mechanical ventilation or ECMO, the panel suggests 5 days of remdesivir therapy instead of 10 days.
  • Famotidine: In hospitalized patients with severe COVID-19, the panel suggests against famotidine for the sole intent of COVID-19 treatment outside the context of a clinical trial.

In addition to these recommendations, the IDSA panel emphasized the overarching goal that patients be recruited into clinical trials to evaluate the efficacy and safety of potential therapies. Such data will help clinicians obtain further benefit-risk information.

The IDSA plans to update these guidelines often; the most recent version is accessible at http://www.idsociety.org/covid19guidelines.

Thromboembolism Prevention and Treatment

American College of Chest Physicians

Guideline summary is as follows:[437]

  • In the absence of contraindications, all acutely hospitalized patients with COVID-19 should receive thromboprophylaxis therapy.
  • Low-molecular-weight heparin (LMWH) or fondaparinux should be used for thromboprophylaxis over unfractionated heparin and direct oral anticoagulants.
  • Data are insufficient to justify routine increased-intensity anticoagulant dosing in hospitalized or critically ill patients with COVID-19.
  • Recommend only inpatient thromboprophylaxis for patients with COVID-19.
  • In critically ill patients with COVID-19, suggest against routine ultrasonographic screening for asymptomatic deep vein thrombosis (DVT).
  • In critically ill patients with COVID-19 who have proximal DVT or pulmonary embolism, recommend parenteral anticoagulation therapy with therapeutic weight-adjusted LMWH or fondaparinux over unfractionated heparin.

International Society on Thrombosis and Haemostasis

Guideline summary is as follows:[438]

  • In hospitalized patients, measure D-dimers, prothrombin time, and platelet count (and possibly fibrinogen).
  • The guidelines include an algorithm for management of coagulopathy based on laboratory markers.
  • Monitoring for septic coagulopathy can be helpful in determining prognosis in patients with COVID‐19 requiring hospital admission.
  • Use of LMWH to protect critically ill patients against venous thromboembolism appears to improve prognosis.

National Institutes of Health Antithrombotic Therapy in Patients with COVID-19

Guideline summary is as follows:[439]

  • Measure hematologic and coagulation parameters (eg, D-dimers, PT, platelet count, fibrinogen) in hospitalized patients.
  • Patients on anticoagulant or antiplatelet therapies for underlying conditions should continue these medications if they receive a diagnosis of COVID-19.
  • Hospitalized adults with COVID-19 should receive VTE prophylaxis per the standard of care for other hospitalized adults.
  • Hospitalized patients with COVID-19 should not routinely be discharged on VTE prophylaxis.
  • In hospitalized patients, the possibility of thromboembolic disease should be evaluated in the event of rapid deterioration of pulmonary, cardiac, or neurological function or of sudden localized loss of peripheral perfusion.
 

Questions & Answers

Overview

What is coronavirus?

What is novel coronavirus?

What is COVID-19?

How did the coronavirus outbreak start?

Where did the coronavirus outbreak start?

Why is coronavirus infection called COVID-19?

What are the signs and symptoms of coronavirus disease 2019 (COVID-19)?

What is the CDC risk assessment for coronavirus disease 2019 (COVID-19) in the US?

Who is at highest risk of contracting coronavirus disease 2019 (COVID-19)?

Can coronavirus disease 2019 (COVID-19) spread from person to person?

Which precautions should high-risk persons take to prevent coronavirus disease 2019 (COVID-19)?

What is the process for diagnosing coronavirus disease 2019 (COVID-19)?

How is coronavirus disease 2019 (COVID-19) treated?

What are coronaviruses?

Are facemasks effective in preventing coronavirus disease 2019 (COVID-19)?

Are surgical facemasks more effective than N95 masks in preventing coronavirus disease 2019 (COVID-19)?

How does coronavirus disease 2019 (COVID-19) spread?

Can asymptomatic people spread coronavirus disease 2019 (COVID-19)?

What is the duration of viral shedding in persons with coronavirus disease 2019 (COVID-19)?

Which patient groups in the US have the highest risk of dying of coronavirus disease 2019 (COVID-19)?

What is the global and US prevalence of coronavirus disease 2019 (COVID-19)?

In which age groups is coronavirus disease 2019 (COVID-19) most common?

What are the epidemiology and outcomes of coronavirus disease 2019 (COVID-2019) in and around New York City?

What is the incidence of coronavirus disease 2019 (COVID-19) in the United States?

What are the US hospitalization, ICU admission, and mortality rates for coronavirus disease 2019 (COVID-19)?

Can children develop coronavirus disease 2019 (COVID-19)?

How does coronavirus disease 2019 (COVID-19) affect pregnant women and neonates?

What was the epidemiology of coronavirus disease 2019 (COVID-19) in Wuhan, China?

Can coronavirus disease 2019 (COVID-19) be transmitted vertically?

What were the epidemiologic and clinical features of the coronavirus disease 2019 (COVID-19) outbreak in China?

What are the CDC estimates of coronavirus disease 2019 (COVID-19) epidemiology parameters?

What are the characteristics of multisystem inflammatory syndrome in children (MIS-C) due to coronavirus disease 2019 (COVID-19)?

Which age groups are most likely to die of coronavirus disease 2019 (COVID-19)?

Is coronavirus disease 2019 (COVID-19) more severe than SARS and MERS?

Which patient groups were more likely to develop severe coronavirus disease 2019 (COVID-19) in China?

What were the mortality risk factors for coronavirus disease 2019 (COVID-19) in China?

Is the genome of SARS-CoV-2 (coronavirus) known?

Have any mutations been discovered for SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19)?

Presentation

Are gastrointestinal (GI) symptoms associated with coronavirus disease 2019 (COVID-19)?

What are the possible symptoms of coronavirus disease 2019 (COVID-19)?

How long do coronavirus disease 2019 (COVID-19) symptoms take to develop?

What is the incubation period for coronavirus disease 2019 (COVID-19)?

Are symptoms of coronavirus disease 2019 (COVID-19) in children common?

How common is asymptomatic coronavirus disease 2019 (COVID-19)?

What are important history details when evaluating a patient for coronavirus disease 2019 (COVID-19)?

What were the most common presentations of coronavirus disease 2019 (COVID-19) in China?

Does blood type affect coronavirus 2019 (COVID-19) severity?

What is the most common serious symptom of coronavirus disease 2019 (COVID-19)?

How should a patient under investigation for coronavirus disease 2019 (COVID-19) be evaluated in healthcare settings?

What are the potential complications of coronavirus disease 2019 (COVID-19)?

How common is acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19)?

Are cardiac complications common in coronavirus disease 2019 (COVID-19)?

Is acute kidney injury a common complication of coronavirus disease 2019 (COVID-19)?

What is the clinical progression of coronavirus disease 2019 (COVID-19)?

Workup

Where are diagnostic tests for coronavirus disease 2019 (COVID-19) processed?

What are the IDSA recommendations for prioritizing patients to be tested for coronavirus disease 2019 (COVID-19)?

Should coronavirus disease 2019 (COVID-2019) testing be repeated if PCR results are negative?

Is an antibody test available for coronavirus disease 2019 (COVID-19)?

Can viral culture be used to diagnose coronavirus disease 2019 (COVID-19)?

What are common lab features in patients with coronavirus disease 2019 (COVID-19)?

What type of test is used to evaluate for coronavirus disease 2019 (COVID-19)?

What is the significance of a positive SARS-CoV-2 test result after clinical resolution of coronavirus disease 2019 (COVID-19)?

Which clinical specimen samples are best for coronavirus disease 2019 (COVID-19) testing?

Are there any signs of coronavirus disease 2019 (COVID-19) in seemingly asymptomatic patients?

What is the role of CT scanning in the diagnosis of coronavirus disease 2019 (COVID-19)?

What is the role of chest radiography in the diagnosis of coronavirus disease 2019 (COVID-19)?

Treatment

Are nonsteroidal anti-inflammatory drugs (NSAIDS) safe in persons with coronavirus disease 2019 (COVID-19)?

How is coronavirus disease 2019 (COVID-19) treated?

Are any drugs available for coronavirus disease 2019 (COVID-19) postexposure prophylaxis?

Is a coronavirus disease 2019 (COVID-19) vaccine available?

How can community spread of coronavirus disease 2019 (COVID-19) be prevented/minimized?

What is the role of the antiparasitic drug ivermectin in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of the antiviral drug remdesivir in the treatment of coronavirus disease 2019 (COVID-19)?

What other antiviral agents are being investigated for the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of nitazoxanide in the treatment of coronavirus disease 2019 (COVID-2019)?

What is the role of convalescent plasma in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of interleukin (IL) inhibitors in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of the IL-6 inhibitor sarilumab (Kevzara) in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of the IL-6 inhibitor tocilizumab (Actemra) in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of corticosteroids (such as dexamethasone) in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of nitric oxide in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of the interleukin-1 inhibitor (IL-1) inhibitor anakinra (Kineret) in the treatment of coronavirus diseaes 2019 (COVID-19)?

What is the role of JAK and NAK inhibitors (baricitinib, fedratinib, ruxolitinib, pacritinib) in the treatment of coronavirus disease 2019 (COVID-2019)?

What is the role of statins in the treatment of coronavirus disease 2019 (COVID-2019)?

What other drugs are being investigated to treat ARDS/cytokine release associated with coronavirus disease 2019 (COVID-19)?

Which immunotherapies are being investigated for the treatment of coronavirus disease 2019 (COVID-19)?

Which antibody-directed therapies are being investigated for the treatment of coronavirus disease 2019 (COVID-19)?

Which vaccines are being investigated for coronavirus disease 2019 (COVID-19) prevention?

What is the role of losartan in the treatment of coronavirus disease 2019 (COVID-2019)?

What are considerations for using ACE inhibitors (ACEIs) and ARBs in patients with coronavirus disease 2019 (COVID-19)?

Why is diabetes a risk factor for coronavirus disease 2019 (COVID-19)?

What is the role of the antivirals lopinavir/ritonavir in the treatment of coronavirus disease 2019 (COVID-19)?

What are the roles of hydroxychloroquine and chloroquine in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of hydroxychloroquine plus azithromycin in the treatment of coronavirus disease 2019 (COVID-19)?

Which drugs being studied for the treatment of coronavirus disease 2019 (COVID-19) are associated with QT prolongation and an increased risk of cardiac death?

What is the role of blood purification devices in the treatment of coronavirus disease 2019 (COVID-19)?

What is the role of nanosponges in the treatment of coronavirus disease 2019 (COVID-19)?

Guidelines

What guidelines are available for coronavirus disease 2019 (COVID-19)?

What are the CDC criteria to guide evaluation and testing of patients under investigation for coronavirus disease 2019 (COVID-19)?

What are the CDC&#39;s sample collection and testing guidelines for coronavirus disease 2019 (COVID-19)?

What are the guidelines for containing hospital spread of coronavirus disease 2019 (COVID-19)?

What are the AAP guidelines for management of infants born to mothers with coronavirus disease 2019 (COVID-19)?

What are the thromboembolism prevention and treatment guidelines in patients with coronavirus disease 2019 (COVID-19)?

What are the CDC guidelines for reporting, testing, and specimen collection for coronavirus disease 2019 (COVID-19)?