Numerous coronaviruses, first discovered in domestic poultry in the 1930s, cause respiratory, gastrointestinal, liver, and neurologic diseases in animals. Only 7 coronaviruses are known to cause disease in humans.
Four of the 7 coronaviruses most frequently cause symptoms of the common cold. Coronaviruses 229E, OC43, NL63, and HKU1 cause about 15 to 30% of cases of the common cold. Rarely, severe lower respiratory tract infections, including bronchiolitis and pneumonia, can occur, primarily in infants, older people, and the immunocompromised.
Three of the 7 coronaviruses cause much more severe, and sometimes fatal, respiratory infections in humans than other coronaviruses and have caused major outbreaks of deadly pneumonia in the 21st century:
SARS-CoV-2 is a novel coronavirus identified as the cause of coronavirus disease 2019 (COVID-19) that began in Wuhan, China in late 2019 and spread worldwide.
MERS-CoV was identified in 2012 as the cause of Middle East respiratory syndrome (MERS).
SARS-CoV was identified in 2003 as the cause of an outbreak of severe acute respiratory syndrome (SARS) that began in China near the end of 2002.
These coronaviruses that cause severe respiratory infections are zoonotic pathogens, which begin in infected animals and are transmitted from animals to people. SARS-CoV-2 has significant person-to-person transmission.
COVID-19 was first reported in late 2019 in Wuhan, China and has since spread extensively worldwide. For current information on the number of cases and fatalities, see the Centers for Disease Control and Prevention: 2019 Novel Coronavirus and the World Health Organization's Novel Coronavirus (COVID-2019) situation reports.
Early COVID-19 cases were linked to a live animal market in Wuhan, China, suggesting that the virus was initially transmitted from animals to humans. The virus spreads by close person-to-person contact, mainly via respiratory droplets produced when an infected person coughs, sneezes, sings, exercises, or talks. Large respiratory droplets spread within 6 feet of a contagious person, but SARS-CoV-2 can sometimes be spread more than 20 feet via small respiratory particle aerosols that can linger in air for several hours and infect people separated by distances previously considered safe. Although there has been no evidence that these small respiratory particles pose an efficient means of transmission, it appears to be possible under certain conditions. Spread of the virus could also occur via contact with a surface contaminated by respiratory droplets. It is known that asymptomatic and presymptomatic people, as well as symptomatic patients, can transmit the virus, making it difficult to control an outbreak.
A person is most contagious for the several days before and after the onset of symptoms, at which time the viral load in respiratory secretions is greatest. The SARS-CoV-2 virus spreads easily between people. In general, the closer and longer the interaction with an infected person, the higher the risk of virus spread.
Super-spreader events or situations played an extraordinary role in driving the 2003 SARS outbreak and also play a major role in the current COVID-19 outbreak. Super-spreading situations are those in which a small number of cases contribute a large proportion of the disease's transmission. This is probably due to a combination of biological, environmental, and behavioral factors.
Situations with high risk of transmission include congregate living facilities (eg, nursing homes, long-term care facilities, prisons, ships) as well as crowded, poorly ventilated environments such as indoor religious services, gyms, bars, night clubs, indoor restaurants, and meat-packing facilities. Such situations involve high population density and often difficulty in maintaining avoidance precautions. The residents of nursing homes are also at high risk of severe disease because of age and underlying medical disorders.
Quarantine and isolation measures are being applied in an attempt to limit the local, regional, and global spread of this outbreak. See also Centers for Disease Control and Prevention (CDC) discussion of Contact Tracing for COVID-19 which includes quarantine and isolation recommendations.
A close contact is a person who
Other situations that could be taken into account in considering whether a person is a close contact include whether the person had direct physical contact with the sick person (eg, hugged or kissed them, shared eating or drinking utensils) or if the infected person was likely to be generating significant respiratory aerosols (eg, was sneezing, coughing, singing, shouting). The CDC recommends not taking into account whether the contact person was wearing a mask.
Quarantine is meant to separate and restrict the movement of close contacts who were exposed to a contagious person to see if they become sick. The recommended duration is based on the incubation period of the pathogen, which is up to 14 days for the SARS-CoV-2 virus. (Also see CDC: When to Quarantine.) The following people should quarantine for 14 days after their last exposure:
Isolation is meant to separate people who are contagious from those who are susceptible. The recommended duration is based on the patient's symptoms as well as data on the time course of recovery of live SARS-CoV-2 virus from upper respiratory secretion. (Also see CDC: Duration of Isolation and Precautions for Adults with COVID-19.) The following people should isolate:
Isolation and precautions for patients who had mild to moderate symptoms can be discontinued for most patients 10 days after symptom onset provided they have been afebrile for ≥ 24 hours without the use of fever-reducing drugs and whose other symptoms are significantly improving. Asymptomatic patients can discontinue isolation 10 days after the date of their first positive SARS-CoV-2 diagnostic test.
Strict adherence to these measures have been successful at controlling the spread of infection in select areas.
People with COVID-19 may have few to no symptoms, although some become severely ill and die. Symptoms can include
The incubation time (ie, from exposure to symptom onset) ranges from 2 to 14 days, with a median of 4 to 5 days. The majority of infected people (likely 80%) will have no symptoms or mild disease. The risk of serious disease and death in COVID-19 cases increases with age, in people who smoke, and in people with other serious medical disorders, such as cancer, heart, lung, kidney, or liver disease, diabetes, immunocompromising conditions, sickle cell disease, or obesity (1, 2). Severe disease is characterized by dyspnea, hypoxia, and extensive lung involvement on imaging. This can progress to respiratory failure requiring mechanical ventilation, shock, multiorgan failure, and death.
In addition to respiratory disease that can progress to acute respiratory distress syndrome (ARDS) and death, other serious complications include the following:
Guillain-Barré syndrome (rare)
A rare postinfectious inflammatory syndrome termed multisystem inflammatory syndrome in children (MIS-C) has been observed as a rare complication of SARS-CoV-2 infection. It has features similar to Kawasaki disease or toxic shock syndrome. Children with MIS-C most commonly present with fever, tachycardia, and gastrointestinal symptoms with signs of systemic inflammation. Cases meeting the following criteria should be reported to the Centers for Disease Control and Prevention (CDC) as suspected MIS-C: individuals < 21 years old with fever > 24 hours, laboratory evidence of inflammation, signs of ≥ 2 organs involved, and laboratory or epidemiologic association with SARS-CoV-2 infection (3). A similar multisystem inflammatory syndrome in young and middle-aged adults (MIS-A) also has been reported (4).
In most patients, symptoms resolve over about a week. However, some patients clinically deteriorate after a week, progressing to severe disease including ARDS. Even patients with mild illness (about one third in one study) may have persistent symptoms including dyspnea, cough, and malaise, which can last for weeks or even months. More prolonged illness appears to be more common in those with severe disease. Viral PCR tests in patients may remain positive for at least 3 months regardless of symptoms. However, even patients with lingering symptoms are generally not considered infectious, as virus is rarely if ever able to be cultured from the upper respiratory tract of patients after 10 days of illness.
Although infection with coronaviruses is generally believed to confer some degree of immunity to reinfection, the duration and effectiveness of immunity following COVID-19 remain unknown. Researchers have demonstrated the presence of neutralizing antibodies in most patients following SARS-CoV-2 infection. These antibody titers appear to wane over time; the clinical significance of this is unclear. However, recently, a very small number of cases have been reported in which a genetically different strain of SARS-CoV-2 was identified in recovered patients who manifested recurrent symptoms of COVID-19 (or a few who were asymptomatic). The fact that a genetically different strain was detected strongly suggests that these few cases represent reinfection rather than reactivation of disease. This is more likely to occur >3 months after the initial infection but may be considered if symptoms recur as soon as 45 days after the initial infection (see CDC: Investigative Criteria for Suspected SARS-CoV-2 Reinfection).
1. Centers for Disease Control and Prevention: Symptoms and Testing
2. Centers for Disease Control and Prevention: People at Increased Risk and Other People Who Need to Take Extra Precautions
3. Feldstein LR, Rose EB, Horwitz SM, et al: Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 383(4):334-346, 2020. doi:10.1056/NEJMoa2021680
4. Morris SB, Schwartz NG, Patel P, et al: Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection — United Kingdom and United States, March–August 2020. MMWR Morb Mortal Wkly Rep 69:1450–1456, 2020. doi: 10.15585/mmwr.mm6940e1
Diagnostic testing for COVID-19 is becoming increasingly available through commercial and hospital-based laboratories in addition to public health laboratories. Point-of-care antigen detection and PCR-based assays are also commercially available. These assays typically are less sensitive than standard RT-PCR assays and may not be approved for use in asymptomatic individuals or after 5 to 7 days of symptoms.
For initial diagnostic testing for COVID-19, the CDC recommends collecting and testing a single upper respiratory specimen. The following are acceptable specimens:
A nasopharyngeal specimen collected by a healthcare professional (preferred specimen if available)
An oropharyngeal (throat) specimen collected by a healthcare professional
A nasal mid-turbinate swab collect by a healthcare professional or by a supervised onsite self-collection (using a flocked tapered swab)
An anterior nares specimen collect by a healthcare professional or by onsite or home self-collection (using a flocked or spun polyester swab)
A nasopharyngeal wash/aspirate or nasal wash/aspirate specimen collected by a healthcare professional
A saliva specimen collected by supervised self-collection
Refer to accepting laboratory's collection instructions, because not all testing platforms and laboratories may be able to test all specimen types. For nasopharyngeal and oropharyngeal specimens, use only synthetic fiber swabs with plastic or wire shafts. Do not use calcium alginate swabs or swabs with wooden shafts, as they may contain substances that inactivate some viruses and inhibit PCR testing. The swabs should be placed immediately into a sterile transport tube containing 2 to 3 mL of either viral transport medium, Amies transport medium, or sterile saline, unless using a test designed to analyze the specimen directly, such as a point-of-care test. Maintain proper infection control when collecting specimens.
The CDC also recommends testing lower respiratory tract specimens, if available. For patients for whom it is clinically indicated (eg, those receiving invasive mechanical ventilation), a lower respiratory tract aspirate or bronchoalveolar lavage sample should be collected and tested as a lower respiratory tract specimen. Collection of sputum should be done only for those patients with productive coughs. Induction of sputum is not recommended. (See CDC: Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019.) For biosafety reasons, the CDC recommends local institutions do not attempt to isolate the virus in cell culture or do initial characterization of viral agents in patients suspected of having COVID-19 infection.
SARS-CoV-2 diagnostic testing is becoming more available in the US, and previous restrictions on patient selection for testing are being relaxed. SARS-CoV-2 tests are recommended to diagnose acute infection of both symptomatic and asymptomatic individuals and to guide contact tracing, treatment options, and isolation requirements. Clinicians should use their judgment as to whether a patient's symptoms and signs are compatible with COVID-19 and whether testing would impact the care of the patient or public health measures. Decision to test may also take into account the local epidemiology of COVID-19, the course of illness, and the patient's epidemiologic factors such as close contact with a confirmed COVID-19 case within 14 days of symptom onset. Clinicians are also encouraged to test for other causes of similar respiratory illness (eg, influenza) if epidemiologically appropriate. Asymptomatic patients may also be candidates for testing based on local public health guidance. (See CDC: Overview of Testing for SARS-CoV-2.)
Positive test results need to be reported to local and state health departments, and patients require strict isolation at home or in a healthcare facility.
NOTE: Serologic, or antibody, testing should not be used to diagnose acute COVID-19 illness, because antibodies most commonly become detectable only 1 to 3 weeks after symptom onset. Antibody tests help determine whether the person being tested was previously infected and are important for surveillance and epidemiologic studies.
Routine laboratory findings for those with more severe disease include lymphopenia as well as less specific findings of elevated aminotransaminase (ALT, AST) levels, elevated lactate dehydrogenase (LDH) levels, D-dimer, ferritin, and elevated inflammatory markers such as C-reactive protein.
Chest imaging findings can be normal with mild disease and increase with increasing severity of the illness. Typical findings are consistent with viral pneumonia and include ground-glass opacities and consolidation on either chest x-ray or chest CT. Chest imaging is not recommended as a routine screening tool for COVID-19.
Treatment of COVID-19 depends on the severity of illness. The CDC definitions of severity are as follows:
Mild illness: Patients who have any signs and symptoms of COVID-19 (eg, fever, cough, sore throat, malaise, headache, muscle pain) but without shortness of breath, dyspnea, or abnormal chest imaging
Moderate illness: Patients who have evidence of lower respiratory disease by clinical assessment or imaging, and an oxygen saturation (SpO2) ≥ 94% on room air at sea level
Severe illness: Patients who have respiratory rate > 30 breaths per minute, SpO2 < 94% on room air at sea level (or, for patients with chronic hypoxemia, a > 3% decrease from baseline), ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mmHg, or lung infiltrates > 50%
Critical illness: Patients who have respiratory failure, septic shock, and/or multiple organ dysfunction
Treatment of COVID-19 is mainly supportive. Many treatment clinical trials are currently registered, but data on effective therapy remain sparse. The antiviral agent remdesivir is the only treatment approved by the US Food and Drug Administration (FDA) for COVID-19. It is approved for use in patients ≥12 years of age and ≥ 40 kg who require hospitalization for COVID-19. It also remains available through an FDA emergency use authorization for hospitalized pediatric patients ≥ 3.5 kg and not otherwise covered under the approval, regardless of age. Current national guidelines caution against the use of therapeutic agents outside of clinical trials with the exception of remdesivir and dexamethasone (see National Institutes of Health (NIH) COVID-19 Treatment Guidelines and Infectious Diseases Society of America (IDSA) Guidelines on the Treatment and Management of Patients with COVID-19). For each therapeutic agent, the benefits must be weighed against possible risks for each patient.
The NIH treatment guidelines recommend using dexamethasone (at a dose of 6 mg once per day for up to 10 days or until hospital discharge, whichever comes first) in patients with COVID-19 who are mechanically ventilated or require supplemental oxygen but recommend against using dexamethasone in patients who do not require supplemental oxygen. If dexamethasone is not available, other glucocorticoids (eg, prednisone, methylprednisolone, hydrocortisone) may be used.
The NIH recommends using remdesivir for 5 days or until hospital discharge, whichever comes first, in hospitalized patients with COVID-19 who require supplemental oxygen but who do not require oxygen delivery through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
Numerous immune-based therapies have been used and are under evaluation in clinical trials. Currently, there are insufficient data to recommend the use of convalescent plasma or SARS-COV-2-specific blood-derived or monoclonal antibody therapy outside of clinical trials. The NIH treatment guidelines recommend against the use of nonspecific immunoglobulin (IVIG), and the treatment guidelines recommend against the use of mesenchymal stem cell therapy. Additional immunomodulatory therapies, including interferons, kinase inhibitors, and interleukin inhibitors have been used, but there are insufficient data to recommend their routine use outside of clinical trials. Other drugs that have been used include azithromycin and antiretrovirals. There are also insufficient data to support the use of these agents outside of clinical trials. Multiple clinical trials of the HIV retroviral lopinavir/ritonavir and the anti-malaria drugs chloroquine and hydroxychloroquine have shown these drugs to be without benefit. There are also no randomized clinical trials documenting the usefulness of the anti-parasite drug ivermectin for the prevention or treatment of COVID-19.
Toxicities associated with chloroquine and hydroxychloroquine led to an NIH recommendation that they not be used for treatment of COVID-19 in hospitalized patients. In nonhospitalized patients, the NIH guidelines recommend against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19 outside of a clinical trial.
Supportive therapy may include critical care management with mechanical ventilation and vasopressor support. Early goals of care discussions are recommended. For patients with severe respiratory failure, extracorporeal membrane oxygenation (ECMO) may be considered. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score developed based on a study of 2355 adult patients with severe acute respiratory failure treated by ECMO from 2000 to 2012 (1) predicts survival in adults receiving ECMO for respiratory failure and may help in the selection of COVID-19 patients for ECMO treatment but is not a substitute for clinical assessment and judgment. A study on the use of ECMO in 1035 patients with acute hypoxic respiratory failure due to COVID-19 found that the death rate was less than 40%, which is comparable to results in non-COVID-19 patients with acute hypoxic respiratory failure (2).
Complications of COVID-19 illness should also be treated as they arise. Hospitalized patients with COVID-19 may be at increased risk for thromboembolic events. Pharmacologic prophylaxis should be given as per hospital guidelines, and a high clinical suspicion for thromboembolic events should be maintained. Therapeutic anticoagulation should be started if there is a high suspicion of thromboembolism and confirmatory imaging could not be obtained.
Drugs such as angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy should be continued if needed for concomitant medical conditions but not started as treatment for COVID-19. There is no evidence that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is linked to worse outcomes, and either acetaminophen or NSAIDs can be used during the treatment of COVID-19.
Respiratory management of the nonintubated and intubated COVID-19 patient should take into consideration the tendency toward hypoxia. Nonpharmacologic adjunctive measures such as frequent repositioning and ambulation may be helpful. Therapeutic decisions should be made to best manage the patient, but also consider the risk of exposure to healthcare workers and best use of resources. Intubation is a time of particular risk of healthcare provider exposure to infectious aerosols and should be done with extreme care.
Schmidt M, Bailey M, Sheldrake J, et al: Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med 189(11):1374-1382, 2014. doi:10.1164/rccm.201311-2023OC
Barbaro RP, MacLaren G, Boonstra PS, et al: Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet, 2020. [Epub ahead of print] doi: 10.1016/S0140-6736(20)32008-0
To help prevent spread of SARS-CoV-2 from suspected cases, health care practitioners should use standard, contact, and airborne or droplet precautions with eye protection. Airborne precautions are particularly relevant for patients undergoing aerosol-generating procedures. Patients with respiratory symptoms should be identified and masked immediately upon entry to any healthcare facility. Strategies to monitor and conserve personal protective equipment (PPE) supplies should be considered; tools are available through the CDC. (See CDC: Infection Control Guidance for Healthcare Professionals about Coronavirus.)
To best way to prevent illness is for people to avoid exposure to the virus. The following steps are recommended by the CDC:
Areas of sustained transmission will vary as the outbreak proceeds. For areas inside the US, clinicians should consult state or local health departments. Cases have been reported in all states. The CDC advises that travel increases the chance of getting and spreading COVID-19 and recommends avoiding all cruise ship travel due to the global pandemic; for current information see CDC: Coronavirus Disease 2019 Information for Travel.
As of November 2020, there is no approved vaccine for SARS-CoV-2 in the US. Numerous vaccine candidates with different mechanisms of action are under development and many have entered clinical trials. A few are nearing the end of phase 3 trials, but it is unclear when they will be available outside of clinical trials. Some vaccine manufacturers have indicated they will likely apply for emergency use authorization after phase 3 data collection and preliminary analysis are complete. China and Russia have each approved a vaccine well before completion of trials.
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
MERS-CoV infection was first reported in September 2012 in Saudi Arabia, but an outbreak in April 2012 in Jordan was confirmed retrospectively. Through 2019, worldwide, nearly 2500 cases of MERS-CoV infection (with at least 850 related deaths) have been reported from 27 countries; all cases of MERS have been linked through travel to or residence in countries in and near the Arabian Peninsula, with > 80% involving Saudi Arabia. The largest known outbreak of MERS outside the Arabian Peninsula occurred in the Republic of Korea in 2015. The outbreak was associated with a traveler returning from the Arabian Peninsula. Cases have also been confirmed in countries throughout Europe, Asia, North Africa, the Middle East, and the United States in patients who were either transferred there for care or became ill after returning from the Middle East.
Preliminary seroprevalence studies indicate that the infection is not widespread in Saudi Arabia.
The World Health Organization considers the risk of contracting MERS-CoV infection to be very low for pilgrims traveling to Saudi Arabia for Umrah and Hajj. For additional information about pilgrimages to the Middle East, see World-travel advice on MERS-CoV for pilgrimages .
Median age of patients with MERS-CoV is 56 years, and the male:female ratio is about 1.6:1. Infection tends to be more severe in older patients and in patients with a preexisting disorder such as diabetes, a chronic heart disorder, or a chronic renal disorder.
MERS-CoV may be transmitted from person to person via direct contact, respiratory droplets (particles > 5 micrometers), or aerosols (particles < 5 micrometers). Person-to-person transmission has been established by the development of infection in people whose only risk was close contact with people who had MERS.
The reservoir of MERS-CoV is thought to be dromedary camels, but the mechanism of transmission from camels to humans is unknown. Most reported cases involved direct human-to-human transmission in health care settings. If MERS is suspected in a patient, infection control measures must be initiated promptly to prevent transmission in health care settings.
The incubation period for MERS-CoV is about 5 days.
Most reported cases have involved severe respiratory illness requiring hospitalization, with a case fatality rate of about 35%; however, at least 21% of patients had mild or no symptoms. Fever, chills, myalgia, and cough are common. Gastrointestinal symptoms (eg, diarrhea, vomiting, abdominal pain) occur in about one third of patients. Manifestations may be severe enough to require treatment in an intensive care unit, but recently, the proportion of such cases has declined sharply.
MERS should be suspected in patients who have an unexplained acute febrile lower respiratory infection and who have had either of the following within 14 days of symptom onset:
MERS should also be suspected in patients who have had close contact with a patient with suspected MERS and who have a fever whether they have respiratory symptoms or not.
The most recent recommendations are available from the Centers for Disease Control and Prevention (MERS: Interim Guidance for Healthcare Professionals).
Testing should include real-time RT-PCR testing of upper and lower respiratory secretions, ideally taken from different sites and at different times. Serum should be obtained from patients and from all, even asymptomatic close contacts, including health care workers (to help identify mild or asymptomatic MERS). Serum is obtained immediately after MERS is suspected or after contacts are exposed (acute serum) and 3 to 4 weeks later (convalescent serum). Testing is done at state health departments or the Centers for Disease Control and Prevention.
In all patients, chest imaging detects abnormalities, which may be subtle or extensive, unilateral or bilateral. In some patients, levels of LDH and AST are elevated and/or levels of platelets and lymphocytes are low. A few patients have acute kidney injury. Disseminated intravascular coagulation and hemolysis may develop.
SARS is much more severe than other coronavirus infections. SARS is an influenza-like illness that occasionally leads to progressively severe respiratory insufficiency.
SARS-CoV was first detected in the Guangdong province of China in November 2002 and subsequently spread to > 30 countries. In this outbreak, > 8000 cases were reported worldwide, with 774 deaths (about a 10% case fatality rate, which varied significantly by age, ranging from < 1% in people ≤ 24 years to > 50% in those ≥ 65 years). The SARS-CoV outbreak was the first time that the Centers for Disease Control and Prevention advised against travel to a region. This outbreak subsided, and no new cases have been identified since 2004. The immediate source was presumed to be civet cats, that were being sold for food in a live-animal market and had likely been infected through contact with a bat before they were captured for sale. Bats are frequent hosts of coronaviruses.
SARS-CoV is transmitted from person to person by close personal contact. It is thought to be transmitted most readily by respiratory droplets produced when an infected person coughs or sneezes.
Diagnosis of SARS is made clinically, and treatment is supportive. Coordination of prompt and rigid infection control practices helped control the 2002 outbreak rapidly.
Although no new cases have been reported since 2004, SARS should not be considered eliminated because the causative virus has an animal reservoir from which it conceivably could reemerge.