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. Other consistent symptoms include myalgias, diarrhea, and smell or taste aberrancies. Although these syndromes can occur with other viral respiratory illnesses, the likelihood of COVID-19 is increased if the patient:
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. In the United States, the Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America have suggested priorities for testing high-priority individuals include
The diagnosis of COVID-19 is made by detection of SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction (RT-PCR). Various RT-PCR assays are used around the world; different assays amplify and detect different regions of the SARS-CoV-2 genome. Common gene targets include nucleocapsid (N), envelope (E), spike (S), and RNA-dependent RNA polymerase (RdRp), as well as regions in the first open reading frame.
Upper respiratory samples are the primary specimens for SARS-CoV-2 RT-PCR testing. CDC recommends collection of a nasopharyngeal swab specimen. 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 (of both nares) are acceptable alternatives for symptomatic patients if nasopharyngeal swabs are unavailable. Nasal mid-turbinate or nasal swabs can be self-collected by the patient on site.
A positive test for SARS-CoV-2 generally confirms the diagnosis of COVID-19. However, false-negative tests from upper respiratory specimens have been well documented. If initial testing is negative but the suspicion for COVID-19 remains and determining the presence of infection is important for management or infection control, it is suggested to repeat the test. In such cases, the WHO also recommends testing lower respiratory tract specimens, if possible. Infection control precautions for COVID-19 should continue while repeat evaluation is being performed.
Lower respiratory tract specimens may have higher viral loads and be more likely to yield positive tests than upper respiratory tract specimens. 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). Data from this study suggested that viral RNA levels are higher and more frequently detected in nasal compared with oral specimens, although only eight nasal swabs were tested.
The Serologic test is designed to detect antibodies (also known as immunoglobulins) against the virus that causes COVID-19. Antibodies are proteins produced by the immune system in response to an infection and are specific to that particular infection. They are found in the liquid part of blood specimens which is called serum or plasma, depending on the presence of clotting factors. The blood samples will be tested for immunoglobulin G (IgG) and immunoglobulin M (IgM).
The FDA highlights that serologic tests should not be used as the sole test to diagnose or exclude active SARS-CoV-2 infection.
This test detects IgG antibodies that develop in most patients within seven to 10 days after symptoms of COVID-19 begin. IgG antibodies remain in the blood after an infection has passed. These antibodies indicate that you may have had COVID-19 in the recent past and have developed antibodies that may protect you from future infection. It is unknown at this point how much protection antibodies might provide against another infection of COVID-19.
This test also detects IgM antibodies. IgM is usually the first antibody produced by the immune system when a virus attacks. A positive IgM test indicates that you may have been infected and that your immune system has started responding to the virus. When IgM is detected you may still be infected or you may have recently recovered from a COVID-19 infection.
The accuracy and time to antibody detection vary with the particular test used. Studies evaluating the specificity of serologic tests in a broad population are lacking; in particular, the rate of cross-reactivity with other coronaviruses is a potential concern, and IgM tests are prone to false-positive results.
Tests that identify SARS-CoV-2 antigen are under development, although rapid antigen tests for respiratory pathogens are typically less sensitive than PCR in detecting viral nucleic acid. Several manufacturers are selling rapid, point-of-care tests based on antigen testing or antibody detection, but the WHO does not recommend these tests because of accuracy concerns in the absence of validation studies.
For safety reasons, specimens from a patient with suspected or documented COVID-19 should not be submitted for viral culture.
If influenza is circulating in the community, it is reasonable to also test for influenza when testing for SARS-CoV-2, as this could have management implications.
However, detection of another viral (or bacterial) pathogen does not necessarily rule out SARS-CoV-2 in locations where there is widespread transmission. Coinfection with SARS-CoV-2 and other respiratory viruses, including influenza, has been described, but the reported frequency is variable.
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.
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.
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:
Among hospitalized patients, the proportion of critical or fatal disease is higher. In a study that included 2634 patients who had been hospitalized for COVID-19 in the New York City area, 14 percent were treated in the intensive care unit and 12 percent received invasive mechanical ventilation, and mortality among those receiving mechanical ventilation was 88 percent. However, the analysis was limited to patients who had either been discharged or died during the admission, and these patients represented fewer than half of the total population admitted with COVID-19; thus, the proportion of critically ill patients and the associated mortality rate may not accurately reflect those of the entire hospitalized population.
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:
The Centers for Disease Control and Prevention (CDC) also includes immunocompromising conditions, severe obesity (body mass index ≥40), and liver disease as potential risk factors for severe illness, although specific data regarding risks associated with these conditions are limited.
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.
Among patients with advanced age and medical comorbidities, COVID-19 is frequently severe. For example, in a SARS-CoV-2 outbreak across several long-term care facilities in Washington State, the median age of the 101 facility residents affected was 83 years, and 94 percent had a chronic underlying condition; the hospitalization and preliminary case fatality rates were 55 and 34 percent, respectively.
Males have comprised a disproportionately high number of deaths in cohorts from China, Italy, and the United States.
In a number of states in the United States, black individuals also appear to comprise a disproportionately high number of infections and deaths due to COVID-19, possibly related to underlying socioeconomic disparities.
Particular laboratory features have also been associated with worse outcomes. These include:
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 .
Patients with severe disease have also been reported to have higher viral RNA levels in respiratory specimens than those with milder disease, although this association was not observed in a different study that measured viral RNA in salivary specimens.
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, and older adults are more likely to have severe disease.
In several cohorts of hospitalized patients with confirmed COVID-19, the median age ranged from 49 to 56 years. In a report from the Chinese Center for Disease Control and Prevention that included approximately 44,500 confirmed infections, 87 percent of patients were between 30 and 79 years old. Similarly, in a modeling study based on data from mainland China, the hospitalization rate for COVID-19 increased with age, with a 1 percent rate for those 20 to 29 years old, 4 percent rate for those 50 to 59 years old, and 18 percent for those older than 80 years.
Older age is also associated with increased mortality. In a report from the Chinese Center for Disease Control and Prevention, case fatality rates were 8 and 15 percent among those aged 70 to 79 years and 80 years or older, respectively, in contrast to the 2.3 percent case fatality rate among the entire cohort. 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.
In the United States, 2449 patients diagnosed with COVID-19 between February 12 and March 16, 2020 had age, hospitalization, and intensive care unit (ICU) information available; 67 percent of cases were diagnosed in those aged ≥45 years, and, similar to findings from China, mortality was highest among older individuals, with 80 percent of deaths occurring in those aged ≥65 years.
Pneumonia appears to be the most frequent serious manifestation of infection, characterized primarily by
However, other features, including upper respiratory tract symptoms, myalgias, diarrhea, and smell or taste disorders, are also common. There are no specific clinical features that can yet reliably distinguish COVID-19 from other viral respiratory infections, although development of dyspnea several days after the onset of initial symptoms is suggestive.
Most studies describing the clinical features of COVID-19 have been performed in hospitalized populations. In a study describing 138 patients hospitalized with COVID-19 pneumonia in Wuhan, the most common clinical features at the onset of illness were:
Other cohort studies of patients with confirmed COVID-19 have reported a similar range of clinical findings. However, fever might not be a universal finding on presentation. In one study, fever was reported in almost all patients, but approximately 20 percent had a very low grade fever <100.4°F/38°C. In another study of 1099 patients from Wuhan and other areas in China, fever (defined as an axillary temperature over 99.5°F/37.5°C) was present in only 44 percent on admission but was ultimately noted in 89 percent during the hospitalization.
Although not highlighted in the initial cohort studies from China, smell and taste disorders (eg, anosmia and dysgeusia) have also been reported as common symptoms in patients with COVID-19. In a survey of 59 patients with COVID-19 in Italy, 34 percent self-reported either a smell or taste aberration and 19 percent reported both. In a survey of 202 outpatients with mild COVID-19 in Italy, 64 percent reported alterations in smell or taste, and 24 percent reported very severe alterations; smell or taste changes were reported as the only symptom in 3 percent overall and preceded symptoms in another 12 percent. Whether this finding is a distinguishing feature of COVID-19 is uncertain.
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. In a systematic review of studies reporting on gastrointestinal symptoms in patients with confirmed COVID-19, the pooled prevalence was 18 percent overall, with diarrhea, nausea/vomiting, or abdominal pain reported in 13, 10, and 9 percent, respectively.
Other reported symptoms have included
Dermatologic findings in patients with COVID-19 are not well characterized. There have been rare reports of urticarial eruptions and transient livedo reticularis. Reddish-purple nodules on the distal digits similar in appearance to pernio (chilblains) have also been anecdotally described in children and young adults with suspected COVID-19, although an association has not been clearly established.
Some patients with initially nonsevere 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. Thromboembolic complications, including pulmonary embolism and acute stroke, have also been reported.
Some patients with severe COVID-19 have laboratory evidence of an exuberant inflammatory response, similar to cytokine release syndrome, with persistent fevers, elevated inflammatory markers (eg, D-dimer, ferritin), and elevated proinflammatory cytokines; these laboratory abnormalities have been associated with critical and fatal illnesses.
Guillain-Barré syndrome has also been reported, with onset 5 to 10 days after initial symptoms.
According to the WHO, recovery time appears to be around two weeks for mild infections and three to six weeks for severe disease.