Practice Essentials
Coronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus 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 CDC estimates that SARS-CoV-2 entered the United States in late January or early February 2020, establishing low-level community spread before being noticed. [8] Since that time, the United States has experienced widespread infections, with nearly 63.4 million reported cases and over 842,000 deaths reported as of January 13, 2022, according to the CDC. According to the CDC, 75% of people who have died of the virus in the United States as of December 29, 2021 (ie, about 608,000 of the 820,000) are aged 65 years or older. According to the New York Times, the CDC reports that one in 100 older Americans has died from the virus. For people younger than 65, the ratio is about 1 in 1,400.
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 to abate the spread of COVID-19. [9]
The CDC had postulated that large numbers of patients could require 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) are the most important response strategy for delaying viral spread and reducing disease impact. Unfortunately, these concerns have been proven accurate.
The feasibility and implications of suppression and mitigation strategies have been rigorously analyzed and are being encouraged or enforced by many governments to slow or halt viral transmission. Population-wide social distancing plus other interventions (eg, home self-isolation, school and business closures) are strongly advised. These policies may be required for long periods to avoid rebound viral transmission. [10]
As the United States is experiencing another surge of COVID-19 infections, the CDC has intensified its recommendations for transmission mitigation. They recommend all unvaccinated individuals wear masks in public indoor settings. On the basis of evidence regarding emerging variants of concern (See Virology), CDC recommends that persons who are fully vaccinated also wear masks in public indoor settings in areas with substantial or high transmission. Fully vaccinated individuals might consider wearing a mask in public indoor areas, regardless of transmission level, if they or someone in their home is immunocompromised, is at increased risk for severe disease, or is unvaccinated (including children younger than 12 years who are ineligible for vaccination). [11]
The CDC recommends physical distancing, avoiding nonessential indoor spaces, postponing travel until fully vaccinated, enhanced ventilation, and hand hygiene. [12, 13]
According to the CDC, individuals at high risk for 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.
The CDC has published a summary of evidence of comorbidities that are supported by meta-analysis/systematic review that have a significant association with risk of severe COVID-19 illness. These include the following conditions [14] :
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Cancer
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Cerebrovascular disease
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Chronic kidney disease
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COPD (chronic obstructive pulmonary disease)
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Diabetes mellitus, type 1 and type 2
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Heart conditions (eg, heart failure, coronary artery disease, cardiomyopathies)
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Immunocompromised state from solid organ transplant
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Obesity (BMI 30 kg/m 2 or greater)
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Pregnancy
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Smoking, current or former
Comorbidities that are supported by mostly observational (eg, cohort, case-control, or cross-sectional) studies include [14] :
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Children with certain underlying conditions
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Down syndrome
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HIV (human immunodeficiency virus)
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Neurologic conditions, including dementia
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Overweight (BMI 25 to less than 30 kg/m 2)
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Other lung disease (including interstitial lung disease, pulmonary fibrosis, pulmonary hypertension)
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Sickle cell disease
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Solid organ or blood stem cell transplantation
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Substance use disorders
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Use of corticosteroids or other immunosuppressive medications
Comorbidities that are supported by mostly case series, case reports, or, if other study design or the sample size is small include [14] :
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Cystic fibrosis
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Thalassemia
Comorbidities supported by mixed evidence include [14] :
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Asthma
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Hypertension
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Immune deficiencies
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Liver disease
Such individuals should consider the following precautions [14] :
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Stock up on supplies.
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Avoid close contact with sick people.
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Wash hands often.
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Stay home as much as possible in locations where COVID-19 is spreading.
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Develop a plan in case of illness.
Signs and symptoms
Presentations of COVID-19 range from asymptomatic/mild symptoms to severe illness and mortality. Symptoms may develop 2 days to 2 weeks after exposure to the virus. [15] In a pooled analysis of 181 confirmed cases of COVID-19 outside Wuhan, China, the mean incubation period was 5.1 days and 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 CDC (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. Multiple reports from around the globe have subsequently confirmed these patterns of presentation. [17]
The following symptoms may indicate COVID-19 [15] :
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Fever or chills
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Cough
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Shortness of breath or difficulty breathing
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Fatigue
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Muscle or body aches
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Headache
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New loss of taste or smell
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Sore throat
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Congestion or runny nose
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Nausea or vomiting
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Diarrhea
Other reported symptoms have included the following:
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Sputum production
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Malaise
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Respiratory distress
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Neurologic (eg, headache, altered mentality)
The most common serious manifestation of COVID-19 appears to be pneumonia.
A complete or partial loss of the sense of smell (anosmia) has been reported as a potential history finding in patients eventually diagnosed with COVID-19. [18] 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. [19]
Diagnosis
COVID-19 should be considered a possibility (1) in 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 or antigen) testing is required for definitive diagnosis.
Patients who do not require emergency care are encouraged to contact their healthcare provider by phone. Patients with suspected COVID-19 who present to a healthcare facility should trigger infection-control measures. These patients should be evaluated in a private room with the door closed (an airborne infection isolation room is ideal) and instructed to wear a surgical mask. All other standard contact and airborne precautions should be observed, and treating healthcare personnel should wear eye protection. [20]
Management
Utilization of programs established by the FDA to allow clinicians access to investigational therapies during the pandemic has been essential. The expanded access (EA) and emergency use authorization (EUA) programs allowed for rapid deployment of potential therapies for investigation and investigational therapies with emerging evidence. A review by Rizk et al describes the role for each of these measures and their importance to providing medical countermeasures in the event of infectious disease and other threats. [21]
Remdesivir, an antiviral agent, was the first drug to gain full FDA approval for treatment of COVID-19 in October 2020. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. [22] An emergency use authorization (EUA) remains in place to treat children younger than 12 years who weigh at least 3.5 kg. [23]
The first vaccine to gain full FDA approval was mRNA-COVID-19 vaccine (Comirnaty; Pfizer) in August 2021.
EUAs have been issued for other vaccines, monoclonal-directed antibodies, convalescent plasma, baricitinib (a Janus kinase inhibitor), and tocilizumab (an interleukin-6 inhibitor) in the United States. A full list of EUAs and access to the Fact Sheets for Healthcare Providers is available from the FDA.
Use of corticosteroids improves survival in hospitalized patients with severe COVID-19 disease requiring supplemental oxygen, with the greatest benefit shown in those requiring mechanical ventilation. [24]
Infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases. [25]
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. [25, 26, 27, 28, 29]
Background
Coronaviruses comprise a vast family of viruses, seven of which are known to cause disease in humans. Some coronaviruses that typically infect animals have evolved 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) also are caused by coronaviruses that “jumped” from animals to humans. More than 8000 individuals developed SARS, nearly 800 of whom died of the illness (mortality rate, approximately 10%), before it was controlled in 2003. [30] MERS continues to resurface in sporadic cases. A total of 2465 laboratory-confirmed cases of MERS have been reported since 2012, resulting in 850 deaths (mortality rate, 34.5%). [31]
Route of Transmission
The principal mode by which people are infected with SARS-CoV-2 is through exposure to respiratory droplets carrying infectious virus (generally within a space of 6 feet). Additional methods include contact transmission (eg, shaking hands) and airborne transmission of droplets that linger in the air over long distances (usually greater than 6 feet). [32, 33, 34] Virus released in respiratory secretions (eg, during coughing, sneezing, talking) can infect other individuals via contact with mucous membranes.
On July 9, 2020, the WHO 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. [34]
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. [32] 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. [35]
In a separate study, Chin and colleagues found 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 2. 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).” [36] Contact with fomites is thought to be less significant than person-to-person spread as a means of transmission. [32]
Viral shedding
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 to 37 days, with a median of 20 days. [37] 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. [38] In an evaluation of patients recovering from severe COVID-19, Zhou and colleagues found a median shedding duration of 31 days (range, 18-48 days). [39] 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. [40] These findings were incorporated into the CDC guidance on the duration of isolation following COVID-19 infection.
Additionally, patients with profound immunosuppression (eg, following hematopoietic stem-cell transplantation, receiving cellular therapies) may shed viable SARS-CoV-2 for at least 2 months. [41, 42]
SARS-CoV-2 has been found in the semen of men with acute infection, as well as in some male patients who have recovered. [43]
Asymptomatic/presymptomatic SARS-CoV-2 infection and its role in transmission
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 USS Theodore Roosevelt and Charles de Gaulle aircraft carriers, among several others. Almost half (40-45%) of SARS-CoV-2 infections were asymptomatic. [44]
Utilizing a decision analytical model, Johansson et al from the CDC assessed transmission from presymptomatic, never symptomatic, and symptomatic individuals across various scenarios to determine the infectious period of transmitting SARS-CoV-2. Results from their base case determined 59% of all transmission came from asymptomatic transmission, 35% from presymptomatic individuals and 24% from individuals who never developed symptoms. They estimate at least 50% of new SARSCoV-2 infections originated from exposure to individuals with infection, but without symptoms. [45]
Zou and colleagues 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. [46]
Epidemiology
Coronavirus outbreak and pandemic
As of January 14, 2022, confirmed COVID-19 infections numbered over 318.6 million individuals worldwide and have resulted in over 5.5 million deaths. [47]
In the United States, nearly 63.4 million reported cases of COVID-19 have been confirmed as of January 13, 2022, resulting in over 842,000 deaths. [48] The pandemic caused approximately 375,000 deaths in the United States during 2020. The age-adjusted death rate increased by 15.9% in 2020, making it the third leading cause of death after heart disease and cancer. [49] Beginning in late March 2020, the United States had more confirmed infections than any other country in the world. [47, 50] The United States also has the most confirmed deaths in the world, followed by Brazil, India, and Mexico. [47]
An interactive map of confirmed cases can be found here.
Health disparities
Communities of color have been disproportionally devastated by COVID-19 in the United States and in Europe. Data from New Orleans illustrated these disparities. African Americans represent 31% of the population but 76.9% of the hospitalizations and 70.8% of the deaths. [51]
The reasons are still being elucidated, but data suggest the cumulative effects of health disparities are the driving force. The prevalence of chronic (high- risk) medical conditions is higher, and access to healthcare may be less available. Finally, socioeconomic status may decrease the ability to isolate and avoid infection. [52, 53]
The overall age-adjusted death rate increased by 15.9% in 2020. Death rates were highest among non-Hispanic Black persons and non-Hispanic American Indian or Alaska Native persons. [49]
CDC maintains a COVID-19 Data Tracker for near real time updates.
Young Adults
Outcomes from COVID-19 disease in young adults have been described by Cunningham and colleagues. Of 3200 adults aged 18 to 34 years hospitalized in the United States with COVID-19, 21% were admitted to the ICU, 10% required mechanical ventilation, and 3% died. Comorbidities included obesity (33%; 25% overall were morbidly obese), diabetes (18%), and hypertension (16%). Independent predictors of death or mechanical ventilation included hypertension, male sex, and morbid obesity. Young adults with multiple risk factors for poor outcomes from COVID-19 compared similarly to middle-aged adults without such risk factors. [54]
A study from South Korea found that older children and adolescents are more likely to transmit SARS CoV-19 to family members than are younger children. The researchers reported that the highest infection rate (18.6%) was in household contacts of patients with COVID-19 aged 10 to 19 years, and the lowest rate (5.3%) was in household contacts of those aged 0 to 9 years. [55] Teenagers have been the source of clusters of cases, illustrating the role of older children. [56]
COVID-19 in children
Data continue to emerge regarding the incidence and effects of COVID-19, especially for severe disease. A severe multisystem inflammatory syndrome linked to COVID-19 infection has been described in children. [57, 58, 59, 60]
The American Academy of Pediatrics (AAP) reports children represent 17.4% of all cases in the 49 states reporting by age; over 8.4 million children have tested positive in the United States since the onset of the pandemic as of January 6, 2022. This represents an overall rate of 11,255 cases per 100,000 children. During the 2-week period of December 23, 2021 to January 6, 2022, there was a 12% increase in the cumulated number of children who tested positive, representing 905,587 new cases. In the week from December 30, 2021 to January 6, 2022, cases in children numbered 580,247 and represented 17.3% of the new weekly cases. Children were 1.7% to 4.3% of total reported hospitalizations, and 0.1% to 1.6% of all child COVID-19 cases resulted in hospitalization. [61]
AAP has issued interim guidance for follow-up care of children following a SARS-CoV-2 infection.
In the United States, a modeling study found one child loses a parent or caregiver for every four COVID-19 associated deaths. From April 1, 2020 through June 30, 2021, more than 140,000 children younger than 18 years in the United States lost a parent, custodial grandparent, or grandparent caregiver who provided the child’s home and basic needs, including love, security, and daily care. Overall, the study shows that approximately one of 500 children in the United States has experienced COVID-19-associated orphanhood or the death of a grandparent caregiver. The study also revealed racial, ethnic, and geographic disparities in COVID-19-associated death of caregivers – children of racial and ethnic minorities accounted for 65% of those who lost a primary caregiver due to the pandemic. [62]
In September 2020, the CDC published the demographics of SARS-CoV-2-associated deaths among persons aged 21 years and younger. At the time of publication, approximately 6.5 million cases of SARS-CoV-2 infection and 190,000 associated deaths were reported in the United States. Persons younger than 21 years constitute 26% of the US population. [63]
Clinical characteristics and outcomes of hospitalized children and adolescents aged 1 month to 21 years with COVID-19 in the New York City area have been described. These observations alerted clinicians to rare, but severe illness in children. Of 67 children who tested positive for COVID-19, 21 (31.3%) were managed as outpatients. Among 46 hospitalized patients, 33 (72%) were admitted to the general pediatric medical unit and 13 (28%) to the pediatric intensive care unit (PICU). Obesity and asthma were highly prevalent, but not significantly associated with PICU admission (P = .99).
Admission to the pediatric intensive care unit (PICU) was significantly associated with higher C-reactive protein, procalcitonin, and pro-B type natriuretic peptide levels and platelet counts (P < .05 for all). Patients in the PICU were more likely to require high-flow nasal cannula (P = .0001) and were more likely to have received remdesivir through compassionate release (P < .05). Severe sepsis and septic shock syndromes were observed in seven (53.8%) patients in the PICU. ARDS was observed in 10 (77%) PICU patients, six (46.2%) of whom required invasive mechanical ventilation for a median of 9 days. Of the 13 patients in the PICU, eight (61.5%) were discharged home, and four (30.7%) patients remained hospitalized on ventilatory support at Day 14. One patient died after withdrawal of life-sustaining therapy associated with metastatic cancer. [64]
A case series of 91 children who tested positive for COVID-19 in South Korea showed 22% were asymptomatic during the entire observation period. Among 71 symptomatic cases, 47 children (66%) had unrecognized symptoms before diagnosis, 18 (25%) developed symptoms after diagnosis, and six (9%) were diagnosed at the time of symptom onset. Twenty-two children (24%) had lower respiratory tract infections. The mean (SD) duration of the presence of SARS-CoV-2 RNA in upper respiratory samples was 17.6 (6.7) days. These results lend more data to unapparent infections in children that may be associated with silent COVID-19 community transmission. [65]
An Expert Consensus Statement has been published that discusses diagnosis, treatment, and prevention of COVID-19 in children.
Multisystem inflammatory syndrome in children
Media reports and a health alert from the New York State Department of Health drew initial attention to a newly recognized multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Since then, MIS-C cases have been reported across the United States and Europe, and the American Academy of Pediatrics has published interim guidance.
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. The CDC case definition requires:
An individual younger than 21 years presenting with fever ≥38.0°C for ≥24 hours, laboratory evidence of inflammation (including an elevated C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase [LDH], or interleukin 6 [IL-6], elevated neutrophils, reduced lymphocytes, and low albumin), and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological); AND
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No alternative plausible diagnoses; AND
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Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.
Jiang and colleagues reviewed the literature on MIS-C noting the multiple organ system involvement. Unlike classic Kawasaki Disease, the children tended to be older and those of Asian ethnicity tended to be spared. [66]
A case series compared 539 patients who had MIS-C with 577 children and adolescents who had severe COVID-19. The patients with MIS-C were typically younger (predominantly aged 6-12 years) and more likely to be non-Hispanic Black. They were less likely to have an underlying chronic medical condition, such as obesity. Severe cardiovascular or mucocutaneous involvement was more common in those with MIS-C. Patients with MIS-C also had higher neutrophil to lymphocyte ratios, higher CRP levels, and lower platelet counts than those with severe COVID-19. [67]
COVID-19 in pregnant individuals and neonates
The US COVID-19 PRIORITY study (Pregnancy coRonavIrus Outcomes RegIsTrY) pregnancy registry is open; the study has a dashboard for real time data.
The CDC COVID-NET data published in September 2020 reported that among 598 hospitalized pregnant patients with COVID-19, 55% were asymptomatic at admission. Severe illness occurred among symptomatic pregnant patients, including intensive care unit admissions (16%), mechanical ventilation (8%), and death (1%). Pregnancy losses occurred for 2% of pregnancies completed during COVID-19-associated hospitalizations, and were experienced by both symptomatic and asymptomatic individuals. [68]
A multicenter study involving 16 Spanish hospitals reported outcomes of 242 pregnant patients diagnosed with COVID-19 during the third trimester from March 13 to May 31, 2020. They and their 248 newborns were monitored until the infant was 1 month old. Pregnant patients with COVID-19 who were hospitalized had a higher risk for cesarean birth (P = 0.027). Newborns whose mothers were hospitalized for COVID-19 infection had a higher risk for premature delivery (P = 0.006). No infants died and no vertical or horizontal transmission was detected. Exclusive breastfeeding was reported for 41.7% of infants at discharge and 40.4% at 1 month. [69]
A cohort study of pregnant patients (n = 64) with severe or critical COVID-19 disease hospitalized at 12 US institutions between March 5, 2020, and April 20, 2020 has been published. At the time of the study, most (81%) received hydroxychloroquine; 7% of those with severe disease and 65% with critical disease received remdesivir. All of those with critical disease received either prophylactic or therapeutic anticoagulation. One case of maternal cardiac arrest occurred, but there were no cases of cardiomyopathy or death. Half (n = 32) delivered during their hospitalization (34% severe group; 85% critical group). Additionally, 88% with critical disease delivered preterm during their disease course, with 16 of 17 (94%) pregnant women giving birth through cesarean delivery. Overall, 15 of 20 (75%) with critical disease delivered preterm. There were no stillbirths or neonatal deaths or cases of vertical transmission. [70]
Adhikari and colleagues published a cohort study evaluating 252 pregnant patients with COVID-19 in Texas. Maternal illness at initial presentation was asymptomatic or mild in 95% of them, and 3% developed severe or critical illness. Compared with COVID negative pregnancies, there was no difference in the composite primary outcome of preterm birth, preeclampsia with severe features, or cesarean delivery for abnormal fetal heart rate. Early neonatal SARS-CoV-2 infection occurred in six of 188 tested infants,(3%) primarily born to asymptomatic or mildly symptomatic mothers. There were no placental pathologic differences by illness severity. [71]
Breastfeeding
A study by Chambers and colleagues found human milk is unlikely to transmit SARS-CoV-2 from infected mothers to infants. The study included 64 milk samples provided by 18 mothers infected with COVID-19. Samples were collected before and after COVID-19 diagnosis. No replication-competent virus was detectable in any of their milk samples compared with samples of human milk that were experimentally infected with SARS-CoV-2. [72]
Mothers or birthing parents who have been infected with SARS CoV-2 may have neutralizing antibodies expressed in their milk. In an evaluation of 37 milk samples from 18 women, 76% contained SARS-CoV-2-specific IgA, and 80% had SARS-CoV-2-specific IgG. 62% of the milk samples were able to neutralize SARS-CoV-2 infectivity in vitro. These results support recommendations to continue breastfeeding/chestfeeding with masking during mild-to-moderate maternal COVID-19 illness. [73]
COVID-19 in patients with HIV
Data for people with HIV and coronavirus are emerging. A multicenter registry has published outcomes for 286 patients with HIV who tested positive for COVID-19 between April 1 and July 1, 2020. Patient characteristics included mean age of 51.4 years, 25.9% were female, and 75.4% were African-American or Hispanic. Most patients (94.3%) were on antiretroviral therapy, 88.7% had HIV virologic suppression, and 80.8% had comorbidities. Within 30 days of positive SARS-CoV-2 testing, 164 (57.3%) patients were hospitalized, and 47 (16.5%) required ICU admission. Mortality rates were 9.4% (27/286) overall, 16.5% (27/164) among those hospitalized, and 51.5% (24/47) among those admitted to an ICU. [74]
Multiple case series have subsequently been published. Most suggest similar outcomes in patients living with HIV as the general patient population. [75, 76] Severe COVID-19 has been seen, however, suggesting that neither antiretroviral therapy of HIV infection are protective. [74, 77]
COVID-19 in clinicians
Among a sample of healthcare providers who routinely cared for patients with COVID-19 in 13 US academic medical centers from February 1, 2020, 6% had evidence of previous SARS-CoV-2 infection, with considerable variation by location that generally correlated with community cumulative incidence. Among participants who had positive test results for SARS-CoV-2 antibodies, approximately one third did not recall any symptoms consistent with an acute viral illness in the preceding months, nearly one half did not suspect that they previously had COVID-19, and approximately two thirds did not have a previous positive test result demonstrating an acute SARS-CoV-2 infection. [78]
Prognosis
During January to December 2020, the estimated 2020 age-adjusted death rate increased for the first time since 2017, with an increase of 15.9% compared with 2019, from 715.2 to 828.7 deaths per 100,000 population. COVID-19 was the underlying or a contributing cause of 377,883 deaths (91.5 deaths per 100,000). COVID-19 death rates were highest among males, older adults, non-Hispanic American Indian or Alaska Native (AI/AN) persons, and Hispanic persons. Age-adjusted death rates was highest among Black (1105.3) and AI/AN persons (1024). [49]
COVID-19 deaths per 100,000 population in 2020 by age [49]
< 1 year: 1.1
1-4 years: 0.2
5-14 years: 0.2
15-24 years: 1.4
25-34 years: 5.5
35-44 years: 15.8
45-54 years: 44.2
55-64 years: 105.1
65-74 years: 249.2
75-84 years: 635.8
85 years or older: 1,797.8
Mortality and diabetes
Type 1 and type 2 diabetes are both independently associated with a significant increased odds of in-hospital death with COVID-19. In a nationwide analysis in England of 61,414,470 individuals in the registry alive as of February 19, 2020, 0.4% had a recorded diagnosis of type 1 diabetes and 4.7% of type 2 diabetes. A total of 23,804 COVID-19 deaths in England were reported as of May 11, 2020; one third were in people with diabetes, including 31.4% with type 2 diabetes and 1.5% with type 1 diabetes. Upon multivariate adjustment, the odds of in-hospital COVID-19 death were 3.5 for those with type 1 diabetes and 2.03 for those with type 2 diabetes, compared with deaths among individuals without known diabetes. Further adjustment for cardiovascular comorbidities found the odds ratios were still significantly elevated in both type 1 (2.86) and type 2 (1.81) diabetes. [79]
The CDC estimates diabetes is associated with a 20% increased odds of in-hospital mortality. [49]
Hospitalization and cardiometabolic conditions
O’Hearn et al estimate nearly two in three adults hospitalized for COVID-19 in the United States have associated cardiometabolic conditions including total obesity (BMI 30 kg/m2 or greater), diabetes mellitus, hypertension, and heart failure. [80]
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. 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. [1] SARS-CoV-2 is a group 2b beta-coronavirus that has at least 70% similarity in genetic sequence to SARS-CoV. [31] Like MERS-CoV and SARS-CoV, SARS-CoV-2 originated in bats. [1]
VIral variants emerge when the virus develops one or more mutations that differentiate it from the predominant virus variants circulating in a population. The CDC surveillance of SARS-CoV-2 variants includes US COVID-19 cases caused by variants. The site also includes which mutations are associated with particular variants. The CDC has launched a genomic surveillance dashboard and a website tracking US COVID-19 case trends caused by variants. Researchers are studying how variants may or may not alter the extent of protection by available vaccines.
Variants of Concern in the United States
As mentioned, viruses such as SARS-CoV-2 are constantly changing. Among the hundreds of variants detected in the first year of the pandemic, the ones that are most concerning are the so-called variants of concern (VOCs). Researchers are continually studying how variants may or may not alter the extent of protection by avaible vaccines and antibody-directed therapies.
Omicron
The omicron variant (B.1.1.529), initially identified in South Africa, was declared a variant of concern in the United States by the CDC November 30, 2021. This VOC contains several dozen mutations, including a large number in the spike gene, more than previous VOCs. These mutations include several associated with increased transmission. The omicron variant has quickly become dominant in the United States. As of January 8, 2022 it accounts for over 98% of circulating virus, compared with less than 8% on December 11, 2021.
Antiviral agent effectiveness
An in vitro study published in December 2021 indicate that remdesivir, nirmatrelvir, molnupiravir, EIDD-1931, and GS-441524 (oral prodrug of remdesivir) retain their activity against the VOCs alpha, beta, gamma, delta, and omicron. [81]
Monoclonal antibody effectiveness
Data analyzed by the FDA and NIH in mid-December 2021 found tixagevimab plus cilgavimab (Evusheld) and sotrovimab retain their neutralizing activity against the omicron variant. However, casirivimab plus imdevimab (REGN-COV) and bamlanivimab plus etesevimab lose most of their effectiveness when exposed in laboratory tests to omicron. [82, 83, 84]
Vaccine effectiveness
A preprinted, nonpeer reviewed article of routine surveillance data from South Africa suggests the Omicron variant may evade immunity from prior infection. Among 2,796,982 individuals with laboratory-confirmed SARS-CoV-2 who had a positive test result for SARS-CoV-2 at least 90 days before November 27, 2021, there were 35,670 suspected reinfections identified. [85]
In another preprinted article, neutralization performed with sera from double or triple BNT162b2-vaccinated individuals (6, 0.5 or 3 months after last vaccination/booster) revealed an 11.4-, 37.0- and 24.5-fold reduction, respectively. Sera from double mRNA-1273-vaccinated and additionally BNT162b2-vaccinated individuals (sampled 6 or 0.5 months after last vaccination/booster) showed a 20- and 22.7-fold reduction in the neutralization capacity. [84]
Delta
The delta variant (B.1.617.2) that was first identified in India became the dominant variant in the United States in mid-July 2021. This variant increases ACE binding and transmissibility. An approximate 6.8-fold decreased neutralization for mRNA vaccines and convalescent plasma was observed with the delta variant. [86, 87] However, a study completed by Public Health England found the BNT162b2 vaccine was only slightly reduced from 93.7% with the B.1.1.7 variant to 88% for the delta variant 2 weeks after the second dose. [88] As the omicron variant transmission increased rapidly in December 2021, the delta variant now accounts for less than 2% of cases in the United States.
Mutations
Viral mutations may naturally occur anywhere in the SARS-CoV-2 genome. Unlike the human DNA genome, which is slow to mutate, RNA viruses can readily, and quickly, mutate. A mutation may alter the viral function (eg, enhance receptor binding), or may have no discernable function.
Mutations have been identified for the receptor-binding domain (RBD) on the spike protein of SARS-CoV-2. Several of these mutations display higher binding affinity to human ACE2, likely owing to enhanced structural stabilization of the RBD. Whether a mutation enhances viral transmission is a question to explore. Possible mechanisms of increased transmissibility include increased viral shedding, longer contagious interval, increased infectivity, or increased environmental stability.
Table 1. Examples of mutations and resulting actions (Open Table in a new window)
Mutation |
Actions |
Variants with Mutation |
N501Y |
Increased viral load |
Alpha UK (B.1.117) |
Del69-70 |
Increased ACE binding |
Alpha UK (B.1.117); Omicron (B.1.1.529) |
E484K |
Increased transmission and virulence; decreased neutralization by vaccines and monoclonal antibodies When combined with other mutations, may result in an escape mutation |
Beta South Africa (B.1.351), Gamma Brazil (P1), and Iota NYC (B.1.526 and B.1.526.1) |
L452R |
Monoclonal antibodies may be less effective |
B.1.526.1, Epsilon California (B.1.427 and B.1.429), and Delta India (B.1.617 linages and sub-lineages) |
D614G |
Increased transmission |
One of the first documented mutations in the United States after initially circulating in Europe. Included in nearly all variants of interest and variants of concern, including Delta and Omicron |
Older Variants Monitored in the United States
Alpha
The CDC tracks variant proportions circulating in the United States and estimates the B.1.1.7 variant (Alpha) that was first detected in the United Kingdom accounted for over 44% of cases from January 2 to March 27, 2021. On April 7, 2021, the CDC announced B.1.1.7 was the dominant strain circulating in the United States. It was the dominant strain until mid-July 2021, when the Delta variant became the dominant strain.
A novel spike mutation with deletions of (delta)69/delta(70) has been shown to occur de novo on multiple occasions and to be maintained through sustained transmission in association with other mutations. [89] This is the source of intense scrutiny in Europe, especially in the United Kingdom. A recent VOC – 202012/01 (201/501Y.V1) contains the deletion 69-70 as well as several other mutations including: N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. The variant is being investigated as a cause of rapid increase in case numbers, possibly due to increased viral loads and transmissibility. The N501Y mutation seems to increase viral loads 0.5 log. [90]
Additionally, VOC-202012/01 has mutations that appear to account for its enhanced transmission. The N501Y replacement on the spike protein has been shown to increase ACE2 binding and cell infectivity in animal models. The deletion at positions 69 and 70 of the spike protein (delta69-70) has been associated with diagnostic test failure for the ThermoFisher TaqPath probe targeting the spike protein. Therefore, British labs are using this test failure to identify the variant. [91]
Surveillance data from the UK national community testing (“Pillar 2”) showed a rapid increase in S-gene target failures (SGTF) in PCR testing for SARS-CoV-2 in November and December 2020. The R0 of this variant seems higher. At the same time that the transmission of the wild type virus was dropping, the variant increased, suggesting that the same recommendations (eg, masks, social distancing) may not be enough. The UK variant is also infecting more children (aged 19 years and younger) than the wild type, indicating that it may be more transmissible in children. This has raised concerns because a relative sparing of children has been observed to date. This variant is hypothesized to have a stronger ACE binding than the original variant, which was felt to have trouble infecting younger individuals as they express ACE to a lesser degree. [91]
Beta
The E484K mutation was found initially in the South Africa VOC (B.1.351 [Beta]) and also with the Brazil variants in late 2020, and was observed in the UK variant in early February 2021.
Position 484 and 501 mutations that are both present in the South African variant, and the combination is a concern that immune escape may occur. These mutations, among others, have combined to create the VOC B.1.351. The mutation at the 501 position changes the shape of the RBD by rotating it by 20 degrees to allow deeper binding. The mutation at the 484 position changes the RBD to a positive charge, and allows a higher affinity to the ACE2 receptor. [92]
Gamma
The Brazil VOC P.1 (Gamma) was responsible for an enormous second surge of infections. Sabino et al describe resurgence of COVID-19 in Manaus, Brazil in January 2021, despite a high seroprevalence. A study of blood donors indicated that 76% of the population had been infected with SARS-CoV-2 by October 2020. Hospitalizations for COVID-19 in Manaus numbered 3431 in January 1 to 19, 2021 compared with 552 for December 1 to 19, 2020. Hospitalizations had remained stable and low for 7 months prior to December 2020. Several postulated variables regarding this resurgence include waning titers to the original viral lineage and the high prevalence of the P.1 variant, which was first discovered in Manaus. [93] In addition, researchers are monitoring emergence of a second variant in Brazil, P.2, identified in Rio de Janeiro. As of September 21, 2021, the CDC lists P.2 as a variant being monitored.
Epsilon
VOCs B.1.427 (Epsilon) and B.1.429 (Epsilon) emerged in California. These variants accounted for 2.9% and 6.9% of variants circulating in the United States between January 2 to March 27, 2021. An approximate 20% increase in transmission has been observed with this variant.
-
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 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 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 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.
-
Axial chest CT demonstrates patchy ground-glass opacities with peripheral distribution.
-
Coronal reconstruction chest CT of the same patient above, showing patchy ground-glass opacities.
-
Axial chest CT shows bilateral patchy consolidations (arrows), some with peripheral ground-glass opacity. Findings are in peripheral and subpleural distribution.
Tables
Mutation |
Actions |
Variants with Mutation |
N501Y |
Increased viral load |
Alpha UK (B.1.117) |
Del69-70 |
Increased ACE binding |
Alpha UK (B.1.117); Omicron (B.1.1.529) |
E484K |
Increased transmission and virulence; decreased neutralization by vaccines and monoclonal antibodies When combined with other mutations, may result in an escape mutation |
Beta South Africa (B.1.351), Gamma Brazil (P1), and Iota NYC (B.1.526 and B.1.526.1) |
L452R |
Monoclonal antibodies may be less effective |
B.1.526.1, Epsilon California (B.1.427 and B.1.429), and Delta India (B.1.617 linages and sub-lineages) |
D614G |
Increased transmission |
One of the first documented mutations in the United States after initially circulating in Europe. Included in nearly all variants of interest and variants of concern, including Delta and Omicron |
| Therapy | Description |
|---|---|
| Ifenprodil (NP-120; Algernon Pharmaceuticals) [243] | 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. The phase 2b part of the 2b/3 study completed enrollment mid-December 2020. Key findings were no mortality at Day 15 in ifenprodil treated patients compared with 3.3% in those in the standard of care (SOC) group. Oxygenation returned to normal at day 4 compared with day 9 in the treated vs SOC groups respectively. |
| Eculizumab (Soliris; Alexion) [244] | 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) [245] | Monoclonal antibody that is a C5 complement inhibitor. Phase 3 randomized controlled trial in hospitalized adults with severe pneumonia or acute ARDS requiring mechanical ventilation was initiated in April 2020, but was paused in January 2021 owing to initial outcomes not showing efficacy. Another phase 3 trial (TACTIC-R) in the UK is studying use of earlier immune modulation in preventing disease progression. |
| ATYR1923 (aTyr Pharma, Inc) [246] | 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) [247] | 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. |
| Dociparstat sodium (DSTAT; Chimerix) [248] | 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) [249, 250] | Orally administered 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. As of December 2020, the phase 2/3 trial has enrolled more than 60% of participants, who are hospitalized patients with severe COVID-19 who have developed pneumonia and require supplemental oxygen. |
| Tranexamic acid (LB1148; Leading BioSciences, Inc) [251] | 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) [252] | Recombinant sialidase drug is a fusion protein that cleaves sialic receptors. Phase 3 substudy for COVID-19 added to existing study for parainfluenza infection. |
| AT-001 (Applied Therapeutics) [253] | Aldose reductase inhibitor shown to prevent oxidative damage to cardiomyocytes and to decrease oxidative-induced damage. |
| CM4620-IE (Auxora; CalciMedica, Inc) [254] | 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) [255] | 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) [256] | 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. An interim analysis indicated that the trial was unlikely to meet its prespecified primary endpoint across the entire patient population studied, and has since been discontinued. However, the results demonstrated encouraging antiviral and anti-inflammatory activity for a subset of treated patients with low baseline LDH or D-dimer. |
| EDP1815 (Evelo Biosciences; Rutgers University; Robert Wood Johnson University Hospital) [257, 258] | 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. |
| VERU-111 (Veru, Inc) [259] | Microtubule depolymerization agent that has broad antiviral activity and has strong anti-inflammatory effects. As of August 2020, a phase 2 trial is underway for hospitalized patients with COVID-19 at high risk for ARDS. |
| Vascular leakage therapy (Q BioMed; Mannin Research) [260] | Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction. |
| Trans sodium crocetinate (TSC; Diffusion Pharmaceuticals) [261, 262] | 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) [263] | 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) [264] | Deuterated form of pirfenidone, an approved anti-inflammatory and anti-fibrotic drug. Inhibits TGF-beta and TNF-alpha. Phase 2 trial initiated in December 2020 for long COVID syndrome to evaluate use for serious respiratory complications, including inflammation and fibrosis, that persist following resolution of SARS-CoV-2 infection. |
| OP-101 (Ashvattha Therapeutics) [265] | Selectively targets reactive macrophages to reduce inflammation and oxidative stress. |
| Vidofludimus calcium (IMU-838; Immunic Therapeutics) [266, 267] | 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) [268] | 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) [269] | Randomized, open-label study (CardioLink-9; n = 100) focuses on reduction of circulating proinflammatory biomarkers (eg, high-sensitivity C-reactive protein [hsCRP, D-dimer) in COVID-infected outpatients. Patients in the icosapent ethyl group received a loading dose of 8 g/day for 3 days followed by 4 g/day for 11 days plus usual care. Icosapent ethyl showed a 25% reduction in hsCRP (p = 0.011) and a reduction in D-dimer (p = 0.048). Additionally, icosapent ethyl resulted in a significant 52% reduction of the total FLU-PRO prevalence score (flulike symptoms) compared with 24% reduction in the usual care group (p = 0.003). |
| Prazosin (Johns Hopkins) [270, 271] | 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) [272] | 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 results of IV Ampion or standard of care (eg, remdesivir and/or convalescent plasma) were evaluated in September 2020. IND granted for phase 1 trial of inhaled Ampion in September 2020. |
| Losmapimod (Fulcrum Therapeutics) [273] | 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) [274] | 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) [275] | 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 (Vyrologix; CytoDyn) [276, 277] | CCR5 antagonist. A phase 2 trial for mild-to-moderate COVID-19 is ongoing. The phase 3 trial in severe-to-critical patients is fully enrolled (n = 390) as of December 2020 and an open-label extension trial has been added to the protocol. 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) [278] | 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) [279] | 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.) [280] | 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. |
| Piclidenoson (Can-Fite BioPharma) [281] | 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) [282] | 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) [283] | 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. |
| BLD-2660 (Blade Therapeutics) [284] | Antifibrotic agent. Targets a specific group of cysteine proteases called dimeric calpains (calpains 1, 2 and 9). Overactivity of dimeric calpains lead to inflammation and fibrosis. Phase 2 trial (CONQUER) in hospitalized patients (n = 120) with COVID pneumonia completed in September 2020. |
| EC-18 (Enzychem Lifesciences) [285] | Preclinical studies observed EC-18 to control neutrophil infiltration, thereby modulating the inflammatory cytokine and chemokine signaling. A phase 2 multicenter, randomized, double-blind, placebo-controlled study is being initiated in the US to evaluate the safety and efficacy of EC-18 in preventing the progression of COVID-19 infection to severe pneumonia or ARD. |
| SBI-101 (Sentien Biotechnologies) [286] | Biologic/device combination product designed to regulate inflammation and promote repair of injured tissue using allogeneic human mesenchymal stromal cells. The phase 1/2 study integrates SBI-101 into the renal replacement circuit for treatment up to 24 hours in patients with ARDS and acute kidney injury requiring renal replacement therapy (RRT). |
| Bacille Calmette-Guérin (BCG) vaccine (Baylor, Texas A&M, and Harvard Universities; MD Anderson and Cedars-Sinai Medical Centers) [287] | Areas with existing BCG vaccination programs appear to have lower incidence and mortality from COVID19. Study administers BCG vaccine to healthcare workers to see if reduces infection and disease severity during SARS-CoV-2 epidemic. |
| ARDS-003 (Tetra Bio-Pharma) [288] | Cannabinoid that specifically targets CB2 receptor. Phase 1 clinical trial planned to evaluate anti-inflammatory properties and reduce cytokine release to prevent ARDS. |
| CAP-1002 (Capricor Therapeutics) [289] | CAP-1002 consists of allogeneic cardiosphere-derived cells (CDCs), a type of cardiac cell therapy that has been shown in preclinical and clinical studies to exert potent immunomodulatory activity. CDCs releasing exosomes that are taken up largely by macrophages and T-cells and begin a cycle of repair. A phase 2 trial (INSPIRE) in hospitalized patients with severe or critical COVID-19 was initiated in late 2020. |
| Icatibant (Firazyr; Takeda Pharmaceuticals) [139] | Competitive antagonist selective for bradykinin B2 receptor. Bradykinin formation results in vascular leakage and edema. Part of the I-SPY COVID-19 clinical trial. |
| Razuprotafib (AKB-9778; Aerpio Pharmaceuticals) [139] | Tie2 activator that enhances endothelial function and stabilizes blood vessels, including pulmonary and renal vasculature. SC razuprotafib restores Tie2 activation and improves vascular stability in multiple animal models of vascular injury and inflammation, including lipopolysaccharide-induced pulmonary and renal injury, polymicrobial sepsis, and IL-2 induced cytokine storm. Part of the I-SPY COVID-19 clinical trial. |
| Fenretinide (LAU-7b; Laurent Pharmaceuticals) [290] | Synthetic retinoid shown to address the complex links between fatty acids metabolism and inflammatory signaling, which is distinct from the retinoid class MOA. Believed to work by modulating key membrane lipids in conjunction with proinflammatory pathways (eg, ERK1/2, NF-kappa-B, and cPLA2) needed for coronavirus entry, replication, and host defense evasion. It may also have antiviral properties. The phase 2 RESOLUTION trial in Canada has also gained FDA approval in August 2020 for an IND in the US. |
| Ebselen (SPI-1005; Sound Pharmaceuticals) [291] | Anti-inflammatory molecule that mimics and induces glutathione peroxidase. It reduces reactive oxygen and nitrogen species by first binding them to selenocysteine, and then reducing the selenic acid intermediate through a reduction with glutathione. May also inhibit viral replication. Phase 2 studies for moderate and severe COVID-19 infection initiated in Fall 2020. |
| Fostamatinib (Tavalisse; Rigel Pharmaceuticals) [216] | Spleen tyrosine kinase (SYK) inhibitor that reduces signaling by Fc gamma receptor (FcγR) and c-type lectin receptor (CLR), which are drivers of proinflammatory cytokine release. It also reduces mucin-1 protein abundance, which is a biomarker used to predict ARDS development. Part of the NIH ACTIV-4 Host Tissue phase 3 trial. |
| Vadadustat (Akebia Therapeutics) [292] | Oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor designed to mimic the physiologic effect of altitude on oxygen availability and increased RBC production. Approved in Japan for anemia owing to chronic kidney disease (in phase 3 trials in US). Phase 2 trial initiated at U of Texas Health Center in Houston for prevention and treatment of ARDS in hospitalized patients with COVID-19. |
| Ultramicronized palmitoylethanolamide (PEA; FSD201; FSD Pharma) [293] | Fatty acid amide studied for its anti-inflammatory and analgesic actions. Phase 2a trial expected to begin in October 2020 for hospitalized patients with documented COVID-19 disease. |
| EB05 (Edesa Biotech) [294] | Toll-like receptor 4 (TLR4) inhibitor. TLR4 is a key component of the innate immune system which functions to detect molecules generated by pathogens, acting upstream of cytokine storm and IL-6-mediated acute lung injury. |
| Fluvoxamine (Luvox) [295] | Preliminary double, randomized study of nonhospitalized adults with COVID-19 in community living environment showed no clinical deterioration at Day 15 compared with those taking placebo. Limited sample size with short follow-up. Clinical efficacy would require larger randomized trial. Theorized mechanisms include Sigma-1 receptor (S1R) activation (an endoplasmic reticulum chaperone protein), anti-inflammatory actions owing to S1R stimulation of inositol-requiring enzyme 1 alpha, and SSRI inhibition of platelet activation. Several trials are evaluating fluvoxamine’s use for early treatment of COVID, including the TOGETHER clinical trial in Canada, COVID OUT trial at the University of Minnesota, and the Stop COVID 2 trial at Washington University. Fluvoxamine is also part of the NIH ACTIV-6 phase 3 trial. |
| Lanadelumab (Takeda) [296] | mAb that targets kallikrein. Inhibits kallikrein proteolytic activity to control excess bradykinin. Part of the COVID R&D alliance (Amgen, UCB SA, Takeda) to identify drugs that can reduce severity of COVID-19 in hospitalized patients by moderating the immune system. |
| Zilucoplan (UCB SA) [296] | Macrocyclic peptide inhibitor of complement C5. Part of the COVID R&D alliance (Amgen, UCB SA, Takeda) to identify drugs that can reduce severity of COVID-19 in hospitalized patients by moderating the immune system. |
| CRV431 (Hepion) [297] | Binds cyclophilin A, which blocks the binding of cyclophilin A to specific receptors on inflammatory cells. This decreases infiltration of the cells into the tissue and production of harmful inflammatory molecules, resulting in reduced lung inflammation. Phase 2 trial starting late 2020. |
| Ensifentrine (Verona Pharma) [298] | Phosphodiesterase (PDE) 3 and 4 inhibitor. Elicits both bronchodilator and anti-inflammatory activities. Delivered via pressurized metered-dose inhaler. Phase 2 trial in 45 patients completed January 2021. |
| TZLS-501 (Tiziana Life Sciences) [299] | Anti-interleukin-6 receptor monoclonal antibody in early development. |
| Apabetalone (Resverlogix Corp) [300] | Bromodomain and extra-terminal domain (BET) protein function is required for inflammation. BET inhibitors reversibly bind the bromodomains of BET proteins and prevent the protein-protein interaction between BET proteins and acetylated histones and transcription factors. Apabetalone, a BET inhibitor, reduces the expression of both ACE2 and DPP4 at the surface of human lung epithelial cells. Initiating open-label trials mid-2021 for apabetalone plus standard of care. |
| Therapy | Comment |
|---|---|
| Merimepodib (antiviral; BioSig Technologies) [384] | Phase 2 trial in combination with remdesivir in advanced disease (NCT04410354). |
| Acalabrutinib (Calquence; AstraZeneca) [385] | Phase 2 trial (CALAVI US) of Bruton kinase inhibitor in hospitalized patients to ameliorate excessive inflammation (NCT04380688). |
| Ruxolitinib (Jakafi) [386] | Data from the RUXCOVID study (n = 432) showed treatment with ruxolitinib plus standard-of-care did not prevent complications in patients with COVID-19 associated cytokine storm. |
| Umifenovir (Arbidol) [379, 387] | 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. 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. 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. |
| Colchicine | UK RECOVERY trial stopped the colchicine arm upon advice from its independent data monitoring committee for lack of efficacy in hospitalized patients with COVID-19. |
| Ciclesonide inhaled (Alvesco) [388] | Phase 3 outpatient randomized controlled trial demonstrated that ciclesonide did not achieve the primary efficacy endpoint of reduced time to alleviation of all COVID-19–related symptoms. |
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- Guidelines Summary
- CDC Evaluating and Testing Persons Under Investigation (PUI) for COVID-19 Clinical Guidelines
- CDC Sample Collection and Testing Guidelines for COVID-19
- Guidance for Hospitals on Containing Spread of COVID-19
- American Academy of Pediatrics Guidance on Management of Infants Born to Mothers with COVID-19
- NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines
- Infectious Diseases Society of America (IDSA) Management Guidelines
- Thromboembolism Prevention and Treatment
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- Medication
- Questions & Answers
- Media Gallery
- Tables
- References
