Coronaviruses, Including SARS-CoV-2 and MERS-CoV
Novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China in late 2019. The most common presenting symptoms of COVID-19 in children are fever and cough; other symptoms can include shortness of breath, sore throat, headache, myalgia, fatigue, and, less frequently, rhinorrhea. Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and poor appetite may occur, with or without respiratory symptoms. Less frequently, infected people can experience anosmia (loss of smell) or ageusia (loss of taste); these occur more commonly in adolescents than in younger children. Conjunctivitis and rashes also have been reported. Children generally have mild disease or may be asymptomatic, although severe and even fatal cases have occurred. Children with obesity or medical comorbidities are at risk for more severe disease. Children from racial or ethnic minority groups may be at higher risk for severe illness. Complications include respiratory failure, acute cardiac injury, acute kidney injury, shock, coagulopathy, and multiorgan failure. Diabetic ketoacidosis and intussusception also have been reported. Laboratory findings may be normal or may include lymphopenia, leukopenia, elevated C-reactive protein or procalcitonin, and elevated alanine aminotransferase and aspartate aminotransferase. Chest imaging may be normal or there may be unilateral or bilateral lung involvement with multiple areas of consolidation and ground glass opacities.
Multisystem inflammatory syndrome in children (MIS-C) may present during or weeks following SARS-CoV-2 infection. Children present with fever, severe disease of ≥2 organ systems (cardiac, gastrointestinal tract, skin, kidney, neurologic, hematologic, or respiratory tract), and laboratory evidence of inflammation. The case definition from the Centers for Disease Control and Prevention (CDC; www.cdc.gov/mis-c/hcp/) includes no alternative diagnosis in addition to evidence of recent or concurrent SARS-CoV-2 infection or exposure to someone with known or suspected COVID-19 within the past 4 weeks. Children with MIS-C often present with severe abdominal pain, and many have features that can be similar to Kawasaki disease. Children with MIS-C may have echocardiographic abnormalities, including myocarditis and coronary artery abnormalities.
Human coronaviruses (HCoVs) 229E, OC43, NL63, and HKU1 are associated most frequently with an upper respiratory tract infection characterized by rhinorrhea, nasal congestion, sore throat, sneezing, and cough that may be associated with mild fever. Symptoms are self-limited and typically peak on day 3 or 4 of illness. These HCoV infections also may be associated with acute otitis media or asthma exacerbations. Less frequently, they are associated with lower respiratory tract infections, including bronchiolitis, croup, and pneumonia, primarily in infants and children and adults who are immunocompromised.
MERS-CoV, the virus associated with the Middle East respiratory syndrome (MERS), can cause severe disease, but asymptomatic infections and mild disease may occur. Most cases have been identified in adult males with comorbidities. Infections in children are uncommon and typically are milder. Patients initially present with fever, myalgia, and chills followed by a nonproductive cough and dyspnea a few days later. Approximately 25% of patients may experience vomiting, diarrhea, or abdominal pain. Rapid deterioration of oxygenation with progressive unilateral or bilateral airspace infiltrates on chest imaging may follow, requiring mechanical ventilation and often associated with acute renal failure. The case fatality rate is high, estimated at 36%, but may partially reflect surveillance bias for more severe disease. Surprisingly, this case-fatality rate for hospitalized patients has remained higher than 30% for all new cases since 2012 despite improved diagnostics and supportive care. Laboratory abnormalities may include thrombocytopenia, lymphopenia, and increased lactate dehydrogenase (LDH) concentration, particularly among severely infected individuals.
SARS-CoV-1 was responsible for the 2002–2003 global outbreak of SARS, which was associated with severe symptoms, although a spectrum of disease including asymptomatic infections and mild disease occurred. Infections in children were less severe than in adults and typically presented with fever, cough, and rhinorrhea. Adolescents with SARS had clinical courses more closely resembling those of adult disease, presenting with fever, myalgia, headache, and chills. No deaths in children or adolescents from SARS-CoV-1 infection were documented.
Coronaviruses are enveloped, nonsegmented, single-stranded, positive-sense RNA viruses named after their crown- or Latin “corona”-like surface projections observed on electron microscopy that correspond to large surface spike proteins. Coronaviruses are classified in the Nidovirales order. Coronaviruses are host specific and can infect humans as well as a variety of different animals, causing diverse clinical syndromes. Four distinct genera have been described: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. HCoVs 229E and NL63 belong to the genus Alphacoronavirus. HCoVs OC43 and HKU1 belong to lineage A, SARS-CoV-1 and SARS-CoV-2 belong to lineage B, and MERS-CoV belongs to lineage C of the genus Betacoronavirus.
SARS-CoV-2 emerged in Wuhan, China, near the end of 2019. Infection rapidly spread throughout Hubei province and across China. In January 2020, cases were detected outside of China (the first US case was reported on January 21, 2020). The World Health Organization (WHO) declared SARS-CoV-2 a “public health emergency of international concern” on January 30, 2020, and the United States declared a “public health emergency” the following day. A global pandemic was declared by the WHO on March 11, 2020. By March 2021, more than 112 million cases and 2.5 million deaths were reported globally, with approximately 28 million cases and 500 000 deaths in the United States. Children constitute approximately 10% of US cases. MIS-C is a rare diagnosis, with just over 2000 cases and approximately 30 deaths in the US by early February 2021; most cases occurred in children age 1-14 years, with an average age of 8 years. Additional information on COVID-19 and the fast-moving pandemic can be found at www.cdc.gov/coronavirus/2019-ncov/index.html.
SARS-CoV-2 is transmitted efficiently between people, including from presymptomatic, symptomatic, and asymptomatic people. Infection is believed to be primarily through transmission of large and small respiratory droplets and particles among people in close proximity (generally within 6 feet), although transmission can occur at larger distances. Aerosol transmission, which essentially is spread from very small droplets that can remain suspended in the air for longer periods of time, also can occur. Crowded, enclosed, and poorly ventilated spaces are particularly concerning environments for the transmission of SARS-CoV-2. Infected people are believed to be infectious 2 days prior to symptom onset through 10 days after symptom onset, with viral loads being higher earlier in the course of infection and with decreasing infectivity as time progresses. Patients with severe disease or who are severely immunocompromised may shed viable virus for longer than 10 days. Health care-associated transmission occurs with SARS-CoV-2, and strict adherence to infection prevention guidance is necessary. Outbreaks of SARS-CoV-2 infection occur readily in congregate settings (eg, long-term care facilities, group homes, prisons, shelters, congregate workplaces, dormitories) and households.
HCoVs 229E, OC43, NL63, and HKU1 can be found worldwide. They cause most disease in the winter and spring months in temperate climates. Seroprevalence data for these HCoVs suggest that exposure is common in early childhood, with approximately 90% of adults being seropositive for HCoVs 229E, OC43, and NL63 and 60% being seropositive for HCoV HKU1. The modes of transmission for HCoVs 229E, OC43, NL63, and HKU1 have not been well studied. However, on the basis of studies of other respiratory tract viruses, it is likely that transmission occurs primarily via a combination of droplet and direct and indirect contact spread. HCoVs 229E and OC43 are most likely to be transmitted during the first few days of illness, when symptoms and respiratory viral loads are at their highest.
MERS-CoV likely evolved from bat coronaviruses and infected dromedary camels, which now demonstrate seroprevalence and infection with MERS-CoV in parts of the Middle East and Africa. MERS-CoV cases continue mostly in the Middle East, primarily linked to close contact with camels or an infected person. Human-to-human transmission occurs generally in health care settings and less frequently in household settings and is believed to occur most commonly through droplet and contact spread, although airborne spread may occur. Updated figures on global cases can be found on the WHO website (www.who.int/emergencies/mers-cov/en/).
SARS-CoV-1 likely evolved from a natural reservoir of SARS-CoV-like viruses in horseshoe bats through civet cats or intermediate animal hosts in wet markets of China. Public health interventions ultimately aborted the epidemic. SARS-CoV-1 was last reported with human disease in 2004 from laboratory acquired infections.
The incubation period for SARS-CoV-2 is 2 to 14 days (median, 5 days). The incubation period for HCoV-229E is 2 to 5 days (median, 3 days). Further study is needed to confirm the incubation periods for HCoVs OC43, NL63, and HKU1. The incubation period for MERS-CoV is estimated to be 2 to 14 days (median 5 days).
Acute SARS-CoV-2 infection can be diagnosed by detection of viral RNA from a respiratory source from the upper or lower airway (eg, nasopharynx, oropharynx, nose, saliva, trachea) through reverse transcriptase-polymerase chain reaction (RT-PCR) assay (some may be multiplex assays) or through direct antigen testing for SARS-CoV-2 from a nasopharyngeal or nasal specimen. Serologic testing is not helpful for the diagnosis of acute SARS-CoV-2 infection but can be used in the diagnosis of MIS-C. Additional information on SARS-CoV-2 assays can be found on the CDC and Food and Drug Administration (FDA) websites (www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html and www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/vitro-diagnostics-euas).
Multiplex assays for respiratory pathogens are commercially available that include HCoVs 229E, OC43, NL63, and HKU1 as targets. State public health departments should be contacted for evaluation of suspected cases of MERS-CoV using RT-PCR assay. Guidance regarding testing for MERS-CoV (including specimen collection, typically upper respiratory, lower respiratory and serum) is available on the CDC MERS website (www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html).
Treatment of COVID-19 is evolving rapidly. The National Institutes of Health (www.covid19treatmentguidelines.nih.gov/) and the Infectious Diseases Society of America (www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/) have updated information on treatment for COVID-19 on their websites. As of the end of February 2021, remdesivir has received FDA approval for use in children ≥12 years (≥40 kg) and adults who are hospitalized with COVID-19, in whom the medication shortens hospitalization, and has received emergency use authorization (EUA) for use in younger children. In adults, use of dexamethasone in COVID-19 hospitalized patients requiring oxygen or invasive mechanical ventilation has improved survival. Use of convalescent plasma in children with COVID-19 is under investigation. A number of monoclonal antibody therapies are under investigation, with at least 3 (bamlanivimab, as monotherapy or in combination with etesevimab, and the combination of casirivimab and imdevimab) receiving EUA for use in infected nonhospitalized children ≥12 years (≥40 kg) and adults who are at high risk of severe COVID-19.
For the treatment of MIS-C, the American Academy of Pediatrics (https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/), CDC (www.cdc.gov/mis-c/hcp/), and American College of Rheumatology30 have developed interim guidance. As of March 2021, there are no trials evaluating efficacy of treatment options. A multidisciplinary approach, with the involvement of pediatric specialists in cardiology, rheumatology, infectious disease, hematology, immunology, and critical care, is recommended to guide individual management. In addition to supportive care, therapies have included Immune Globulin Intravenous (1–2 g/kg), steroids, biologics (anakinra), and prophylaxis or treatment of thromboses.
Infections attributable to HCoVs HKU1, OC43, 229E, and NL63 are treated with supportive care. No controlled trials have been conducted for treatment of MERS-CoV.
Isolation of the Hospitalized Patient
Airborne, droplet, and contact precautions are recommended for patients with suspected or known SARS-CoV-2 or MERS-CoV infection (including eye protection [face shield or goggles], N95 or higher respirator [or medical mask if not available], gown, and gloves; for aerosol-generating procedures, an N95 or higher respirator should be used). Airborne infection isolation rooms should be prioritized for aerosol-generating procedures. A well-ventilated single-occupancy room with a closed door may be used if aerosol-generating procedures are not performed. Detailed guidance is available on the CDC website (www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html).
For other HCoV infections, in addition to standard precautions, health care professionals should use droplet and contact precautions when examining and caring for infants and young children.
When SARS-CoV-2 is circulating in a community, control measures include use of face masks for children 2 years and older and for adults (www.cdc.gov/coronavirus/2019-ncov/more/masking-science-sars-cov2.html), keeping a 6-foot or greater distance from other people whenever possible, and hand hygiene. During the COVID-19 pandemic, jurisdictions have specific guidance and policies regarding community mitigation, and referral to state, local, and CDC websites is recommended. The AAP (https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/) and other professional organizations have also developed guidance. Practicing appropriate hand and respiratory hygiene can help curb spread of all respiratory tract viruses, including coronaviruses. Cleaning and disinfection of high-touch environmental surfaces using standard disinfectants should decrease the potential for indirect transmission of coronaviruses via fomites.
As of February 2021, 2 mRNA vaccines and 1 nonreplicating viral vector vaccine for SARS-CoV-2 have received EUA status from the FDA. Numerous additional vaccines using different platforms are in varying stages of development. Pediatric vaccine studies are underway. Recommendations for use of these vaccines in children will be issued by the CDC Advisory Committee on Immunization Practices (www.cdc.gov/vaccines/hcp/acip-recs) and the AAP.
MERS-CoV transmission within hospitals and households can be averted with case identification and the use of infection control and public health measures, including contact tracing. However, preventing the transmission of MERS-CoV from camels to humans is more challenging, given the prevalent use of camels in some Middle East countries. Most experts believe that sporadic transmission will continue until an effective MERS-CoV vaccine is found. Several candidate vaccines are currently in human trials.