Understanding of COVID-19 is evolving. Interim guidance has been issued by the WHO and by the United States CDC.
VIROLOGY: Full-genome sequencing and phylogenic analysis indicated that the coronavirus that causes COVID-19 is a betacoronavirus in the same subgenus as the severe acute respiratory syndrome (SARS) virus (as well as several bat coronaviruses), but in a different clade. The structure of the receptor-binding gene region is very similar to that of the SARS coronavirus, and the virus has been shown to use the same receptor, the angiotensin-converting enzyme 2 (ACE2), for cell entry.
The Middle East respiratory syndrome (MERS) virus, another betacoronavirus, appears more distantly related. The closest RNA sequence similarity is to two bat coronaviruses, and it appears likely that bats are the primary source; whether COVID-19 virus is transmitted directly from bats or through some other mechanism (eg, through an intermediate host) is unknown.
In a phylogenetic analysis of 103 strains of SARS-CoV-2 from China, two different types of SARS-CoV-2 were identified, designated type L (accounting for 70 percent of the strains) and type S (accounting for 30 percent). The L type predominated during the early days of the epidemic in China, but accounted for a lower proportion of strains outside of Wuhan than in Wuhan. The clinical implications of these findings are uncertain.
EPIDEMIOLOGY
Geographic distribution — Globally, more than 7,00,000 confirmed cases of COVID-19 have been reported. Since the first reports of cases from Wuhan, a city in the Hubei Province of China, at the end of 2019, more than 80,000 COVID-19 cases have been reported in China, with the majority of those from Hubei and surrounding provinces. A joint World Health Organization (WHO)-China fact-finding mission estimated that the epidemic in China peaked between late January and early February 2020, and the rate of new cases decreased substantially by early March.
However, cases have been reported in all continents, except for Antarctica, and have been steadily rising in many countries. These include the United States, most countries in Western Europe (including the United Kingdom), and Iran.
Immunity — Antibodies to the virus are induced in those who have become infected. Preliminary evidence suggests that some of these antibodies are protective, but this remains to be definitively established. Moreover, it is unknown whether all infected patients mount a protective immune response and how long any protective effect will last.
Data on protective immunity following COVID-19 are emerging but still in very early stages. One study derived monoclonal antibodies from convalescent patients’ B-cells that targeted the receptor-binding domain of the spike protein and had neutralizing activity in a pseudovirus model; another reported that rhesus macaques infected with SARS-CoV-2 did not develop reinfection following recovery and rechallenge. However, neither of these studies has been published in a peer reviewed journal, and further confirmation of these findings is needed.
CLINICAL FEATURES
Incubation period — The incubation period for COVID-19 is thought to be within 14 days following exposure, with most cases occurring approximately four to five days after exposure.
In a study of 1099 patients with confirmed symptomatic COVID-19, the median incubation period was four days (interquartile range two to seven days).
Using data from 181 publicly reported, confirmed cases in China with identifiable exposure, one modeling study estimated that symptoms would develop in 2.5 percent of infected individuals within 2.2 days and in 97.5 percent of infected individuals within 11.5 days. The median incubation period in this study was 5.1 days.
Spectrum of illness severity — The spectrum of symptomatic infection ranges from mild to critical; most infections are not severe. Specifically, in a report from the Chinese Center for Disease Control and Prevention that included approximately 44,500 confirmed infections with an estimation of disease severity:
●Mild (no or mild pneumonia) was reported in 81 percent.
●Severe disease (eg, with dyspnea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours) was reported in 14 percent.
●Critical disease (eg, with respiratory failure, shock, or multiorgan dysfunction) was reported in 5 percent.
●The overall case fatality rate was 2.3 percent; no deaths were reported among noncritical cases.
According to a joint World Health Organization (WHO)-China fact-finding mission, the case-fatality rate ranged from 5.8 percent in Wuhan to 0.7 percent in the rest of China. Most of the fatal cases occurred in patients with advanced age or underlying medical comorbidities
The proportion of severe or fatal infections may vary by location. As an example, in Italy, 12 percent of all detected COVID-19 cases and 16 percent of all hospitalized patients were admitted to the intensive care unit; the estimated case fatality rate was 7.2 percent in mid-March. In contrast, the estimated case fatality rate in mid-March in South Korea was 0.9 percent. This may be related to distinct demographics of infection; in Italy, the median age of patients with infection was 64 years, whereas in Korea the median age was in the 40s.
Risk factors for severe illness — Severe illness can occur in otherwise healthy individuals of any age, but it predominantly occurs in adults with advanced age or underlying medical comorbidities.
Comorbidities that have been associated with severe illness and mortality include :
●Cardiovascular disease
●Diabetes mellitus
●Hypertension
●Chronic lung disease
●Cancer
●Chronic kidney disease
In a subset of 355 patients who died with COVID-19 in Italy, the mean number of pre-existing comorbidities was 2.7, and only 3 patients had no underlying condition.
Particular laboratory features have also been associated with worse outcomes. These include:
●Lymphopenia
●Elevated liver enzymes
●Elevated lactate dehydrogenase (LDH)
●Elevated inflammatory markers (eg, C-reactive protein [CRP], ferritin)
●Elevated D-dimer (>1 mcg/mL)
●Elevated prothrombin time (PT)
●Elevated troponin
●Elevated creatine phosphokinase (CPK)
●Acute kidney injury
As an example, in one study, progressive decline in the lymphocyte count and rise in the D-dimer over time were observed in nonsurvivors compared with more stable levels in survivors.
Impact of age — Individuals of any age can acquire severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, although adults of middle age and older are most commonly affected.
In Chin, Older age was also associated with increased mortality, with case fatality rates of 8 and 15 percent among those aged 70 to 79 years and 80 years or older, respectively. Similar findings were reported from Italy, with case fatality rates of 12 and 20 percent among those aged 70 to 79 years and 80 years or older, respectively. Similarly, in the United States, mortality was highest among older individuals, with 80 percent of deaths occurring in those aged ≥65 years.
In the large Chinese report described above, only 2 percent of infections were in individuals younger than 20 years old. Similarly, in South Korea, only 6.3 percent of nearly 8000 infections were in those younger than 20 years old. In a small study of 10 children in China, clinical illness was mild; 8 had fever, which resolved within 24 hours, 6 had cough, 4 had sore throat, 4 had evidence of focal pneumonia on CT, and none required supplemental oxygen. In another study of six children aged 1 to 7 years who were hospitalized in Wuhan with COVID-19, all had fever >102.2°F/39°C and cough, four had imaging evidence of viral pneumonia, and one was admitted to the intensive care unit; all children recovered.
Asymptomatic infections — Asymptomatic infections have also been described, but their frequency is unknown.
In a COVID-19 outbreak on a cruise ship where nearly all passengers and staff were screened for SARS-CoV-2, approximately 17 percent of the population on board tested positive as of February 20; about half of the 619 confirmed COVID-19 cases were asymptomatic at the time of diagnosis. A modeling study estimated that 18 percent were true asymptomatic cases (ie, did not go on to develop symptoms).
Clinical manifestations
Initial presentation — Pneumonia appears to be the most frequent serious manifestation of infection, characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest Xray. There are no specific clinical features that can yet reliably distinguish COVID-19 from other viral respiratory infections.
In a study describing 138 patients with COVID-19 pneumonia in Wuhan, the most common clinical features at the onset of illness were :
●Fever in 99 percent
●Fatigue in 70 percent
●Dry cough in 59 percent
●Anorexia in 40 percent
●Myalgias in 35 percent
●Dyspnea in 31 percent
●Sputum production in 27 percent
Other, less common symptoms have included headache, sore throat, and rhinorrhea. In addition to respiratory symptoms, gastrointestinal symptoms (eg, nausea and diarrhea) have also been reported; and in some patients, they may be the presenting complaint.
Course and complications —Some patients with initially mild symptoms may progress over the course of a week. In one study of 138 patients hospitalized in Wuhan for pneumonia due to SARS-CoV-2, dyspnea developed after a median of five days since the onset of symptoms, and hospital admission occurred after a median of seven days of symptoms. In another study, the median time to dyspnea was eight days.
Acute respiratory distress syndrome (ARDS) is a major complication in patients with severe disease and can manifest shortly after the onset of dyspnea. In the study of 138 patients described above, ARDS developed in 20 percent a median of eight days after the onset of symptoms; mechanical ventilation was implemented in 12.3 percent]. In another study of 201 hospitalized patients with COVID-19 in Wuhan, 41 percent developed ARDS; age greater than 65 years, diabetes mellitus, and hypertension were each associated with ARDS.
Other complications have included arrhythmias, acute cardiac injury, and shock. In one study, these were reported in 17, 7, and 9 percent, respectively. In a series of 21 severely ill patients admitted to the ICU in the United States, one-third developed cardiomyopathy.
According to the WHO, recovery time appears to be around two weeks for mild infections and three to six weeks for severe disease.
EVALUATION AND DIAGNOSIS
Clinical suspicion and criteria for testing — The possibility of COVID-19 should be considered primarily in patients with new onset fever and/or respiratory tract symptoms (eg, cough, dyspnea). It should also be considered in patients with severe lower respiratory tract illness without any clear cause. Although these syndromes can occur with other viral respiratory illnesses, the likelihood of COVID-19 is increased if the patient:
●Resides in or has traveled within the prior 14 days to a location where there is community transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or
●Has had close contact with a confirmed or suspected case of COVID-19 in the prior 14 days, including through work in health care settings. Close contact includes being within approximately six feet (about two meters) of a patient for a prolonged period of time while not wearing personal protective equipment (PPE) or having direct contact with infectious secretions while not wearing PPE.
The diagnosis cannot be definitively made without microbiologic testing, but limited capacity may preclude testing all patients with suspected COVID-19. Local health departments may have specific criteria for testing.
Laboratory testing — Patients who meet the testing criteria discussed above should undergo testing for SARS-CoV-2 (the virus that causes COVID-19) in addition to testing for other respiratory pathogens.
In the United States, the CDC recommends collection of a nasopharyngeal swab specimen to test for SARS-CoV-2. An oropharyngeal swab can be collected but is not essential; if collected, it should be placed in the same container as the nasopharyngeal specimen. Oropharyngeal, nasal mid-turbinate, or nasal swabs are acceptable alternatives if nasopharyngeal swabs are unavailable.
Expectorated sputum should be collected from patients with productive cough; induction of sputum is not recommended. A lower respiratory tract aspirate or bronchoalveolar lavage should be collected from patients who are intubated.
In a study of 205 patients with COVID-19 who were sampled at various sites, the highest rates of positive viral RNA tests were reported from bronchoalveolar lavage (95 percent, 14 of 15 specimens) and sputum (72 percent, 72 of 104 specimens), compared with oropharyngeal swab (32 percent, 126 of 398 specimens).
S-CoV-2 RNA is detected by reverse-transcription polymerase chain reaction (RT-PCR). A positive test for SARS-CoV-2 generally confirms the diagnosis of COVID-19, although false-positive tests are possible.
If initial testing is negative but the suspicion for COVID-19 remains, the WHO recommends resampling and testing from multiple respiratory tract sites. The accuracy and predictive values of SARS-CoV-2 testing have not been systematically evaluated. Negative RT-PCR tests on oropharyngeal swabs despite CT findings suggestive of viral pneumonia have been reported in some patients who ultimately tested positive for SARS-CoV-2. Serologic tests, once generally available, should be able to identify patients who have either current or previous infection but a negative PCR test.
For safety reasons, specimens from a patient with suspected or documented COVID-19 should not be submitted for viral culture.
MANAGEMENT
Home care — Home management is appropriate for patients with mild infection who can be adequately isolated in the outpatient setting . Management of such patients should focus on prevention of transmission to others and monitoring for clinical deterioration, which should prompt hospitalization.
Outpatients with COVID-19 should stay at home and try to separate themselves from other people and animals in the household. They should wear a facemask when in the same room (or vehicle) as other people and when presenting to health care settings. Disinfection of frequently touched surfaces is also important.The optimal duration of home isolation is uncertain.
●When a test-based strategy is used, patients may discontinue home isolation when there is:
•Resolution of fever without the use of fever-reducing medications AND
•Improvement in respiratory symptoms (eg, cough, shortness of breath) AND
•Negative results of a US FDA Authorized molecular assay for COVID-19 from at least two consecutive nasopharyngeal swab specimens collected ≥24 hours apart (total of two negative specimens)
●When a non-test-based strategy is used, patients may discontinue home isolation when the following criteria are met:
•At least seven days have passed since symptoms first appeared AND
•At least three days (72 hours) have passed since recovery of symptoms (defined as resolution of fever without the use of fever-reducing medications and improvement in respiratory symptoms [eg, cough, shortness of breath])
In some cases, patients may have had laboratory-confirmed COVID-19, but they did not have any symptoms when they were tested. In such patients, home isolation may be discontinued when at least seven days have passed since the date of their first positive COVID-19 test so long as there was no evidence of subsequent illness.
Hospital care — Some patients with suspected or documented COVID-19 have severe disease that warrants hospital care. Patients with severe disease often need oxygenation support. High-flow oxygen and noninvasive positive pressure ventilation have been used, but the safety of these measures is uncertain, and they should be considered aerosol-generating procedures that warrant specific isolation precautions.
Some patients may develop acute respiratory distress syndrome and warrant intubation with mechanical ventilation.
PREVENTION
Infection control for suspected or confirmed cases — Infection control to limit transmission is an essential component of care in patients with suspected or documented COVID-19.
Individuals with suspected infection in the community should be advised to wear a medical mask to contain their respiratory secretions prior to seeking medical attention. In the health care setting, the World Health Organization (WHO) and CDC recommendations for infection control for suspected or confirmed infections differ slightly:
- The WHO recommends standard, contact, and droplet precautions (ie, gown, gloves, and mask), with eye or face protection. The addition of airborne precautions (ie, respirator) is warranted during aerosol-generating procedures (as detailed below).
- The CDC recommends that patients with suspected or confirmed COVID-19 be placed in a single-occupancy room with a closed door and dedicated bathroom. The patient should wear a facemask if being transported out of the room (eg, for studies that cannot be performed in the room). An airborne infection isolation room (ie, a single-patient negative pressure room) should be reserved for patients undergoing aerosol-generating procedures.
Any personnel entering the room of a patient with suspected or confirmed COVID-19 should wear the appropriate personal protective equipment (PPE): gown, gloves, eye protection, and a respirator (eg, an N95 respirator). If supply of respirators is limited, the CDC acknowledges that facemasks are an acceptable alternative (in addition to contact precautions and eye protection), but respirators should be worn during aerosol-generating procedures.
Aerosol-generating procedures include tracheal intubation, noninvasive ventilation, tracheotomy, cardiopulmonary resuscitation, manual ventilation before intubation, upper endoscopy, and bronchoscopy. The CDC does not consider nasopharyngeal or oropharyngeal specimen collection an aerosol-generating procedure that warrants an airborne isolation room, but it should be performed in a single-occupancy room with the door closed, and any personnel in the room should wear a respirator (or if unavailable, a facemask).
Preventing exposure in the community — The following general measures are recommended to reduce transmission of infection:
●Diligent hand washing, particularly after touching surfaces in public. Use of hand sanitizer that contains at least 60 percent alcohol is a reasonable alternative if the hands are not visibly dirty.
●Respiratory hygiene (eg, covering the cough or sneeze).
●Avoiding touching the face (in particular eyes, nose, and mouth).
●Avoiding crowds (particularly in poorly ventilated spaces) if possible and avoiding close contact with ill individuals.
●Cleaning and disinfecting objects and surfaces that are frequently touched.
In particular, older adults and individuals with chronic medical conditions should be encouraged to follow these measures.
Women who choose not to breastfeed must take similar precautions to prevent transmission through close contact when formula is used.
Managing chronic medications
Patients receiving ACE inhibitors/ARBs — Patients receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should continue treatment with these agents.
Patients receiving immunomodulatory agents — Immunocompromised patients with COVID-19 are at increased risk for severe disease, and the decision to discontinue steroid, biologics, or other immuno-suppressive drugs in the setting of infection must be determined on a case-by-case basis.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
SUMMARY AND RECOMMENDATIONS
●The possibility of COVID-19 should be considered primarily in patients with fever and/or respiratory tract symptoms who reside in or have traveled to areas with community transmission or who have had recent close contact with a confirmed or suspected case of COVID-19. Clinicians should also be aware of the possibility of COVID-19 in patients with severe respiratory illness when no other etiology can be identified.
●In addition to testing for other respiratory pathogens, a nasopharyngeal swab specimen should be collected for reverse-transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2.
●Upon suspicion of COVID-19, CDC recommends a single-occupancy room for patients and gown, gloves, eye protection, and a respirator (or facemask as an alternative) for health care personnel.
●Management consists of supportive care, although investigational approaches are being evaluated. Home management may be possible for patients with mild illness who can be adequately isolated in the outpatient setting.
●To reduce the risk of transmission in the community, individuals should be advised to wash hands diligently, practice respiratory hygiene (eg, cover their cough), and avoid crowds and close contact with ill individuals, if possible. Facemasks are not routinely recommended for asymptomatic individuals to prevent exposure in the community. Social distancing is advised, particularly in locations that have community transmission.