29/04/2020
CLINICAL FEATURES
Incubation period — The incubation period for COVID-19 is thought to be within 14 days following exposure, with most cases occurring approximately five days after exposure [13].
In a family cluster of infections, the onset of fever and respiratory symptoms occurred approximately three to six days after presumptive exposure [28]. Similarly, in an analysis of 10 patients with confirmed COVID-19 pneumonia, the estimated mean incubation period was five days [13].
Clinical presentation — Pneumonia appears to be the most frequent serious manifestation of infection, characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest imaging [29-31]. Most infections are not severe, although many patients have had critical illness [16,28-33]. 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, 81 percent were mild (no or mild pneumonia), 14 percent were severe (eg, with dyspnea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours), and 5 percent were critical (eg, with respiratory failure, shock, or multiorgan dysfunction) [34]. The overall case-fatality rate was 2.3 percent; no deaths were reported among noncritical cases. Most of the fatal cases have occurred in patients with advanced age or underlying medical comorbidities.
In addition to respiratory symptoms, gastrointestinal symptoms (eg, nausea and diarrhea) have been reported in some patients, but these are relatively uncommon [29,31]. Asymptomatic infections have also been described [15,28,35,36], but their frequency is unknown.
In patients with COVID-19, the white blood cell count can vary. Leukopenia, leukocytosis, and lymphopenia have been reported, although lymphopenia appears most common [23]. Elevated aminotransferase levels have also been described. On admission, many patients with pneumonia have normal serum procalcitonin levels; however, in those requiring intensive care unit (ICU) care, they are more likely to be elevated [29-31].
In a study describing 138 patients with COVID-19 pneumonia in Wuhan, the median age was 56 years (interquartile range 42 to 68 years) [31]. Nearly all (99 percent) reported fever, 59 percent had a dry cough, and 35 percent had myalgias. Dyspnea developed in 31 percent after a median of five days of illness. Lymphopenia was common, and all patients had parenchymal lung abnormalities on computed tomography of the chest, including bilateral patchy shadows or ground-glass opacities. Acute respiratory distress syndrome developed in 20 percent, and mechanical ventilation was implemented in 12.3 percent. Among the six patients who died, D-dimer levels were higher and lymphopenia was more severe compared with survivors. Similar clinical features have been described in other smaller cohorts of patients from Wuhan with confirmed COVID-19 [29,30,37]. In one report of 21 patients with laboratory-confirmed COVID-19 who did not develop severe respiratory distress, lung abnormalities were most severe approximately 10 days after symptom onset [37].
Reports of cohorts in locations outside of Wuhan have described similar clinical findings, although some have suggested that milder illness may be more common [38,39]. As an example, in a study of 62 patients with COVID-19 in the Zhejiang province of China, all but one had pneumonia, but only two developed dyspnea, and only one warranted mechanical ventilation [39].
EVALUATION AND DIAGNOSIS
The approach to initial management should focus on early recognition of suspect cases, immediate isolation, and institution of infection control measures. At present, the possibility of COVID-19 should be considered primarily in patients with fever and/or lower respiratory tract symptoms who reside in or have recently (within the prior 14 days) traveled to China or who have had recent (within the prior 14 days) close contact with a confirmed or suspected case of COVID-19. When COVID-19 is suspected, infection control measures should be implemented and public health officials notified. Infection control precautions are discussed elsewhere. (See 'Infection control for suspected or confirmed cases' below.)
The specific case definitions and clinical criteria for diagnostic evaluation differ slightly between expert groups. Case definitions from the World Health Organization are found in its technical guidance online; clinical criteria for patients under investigation from the United States Centers for Disease Control and Prevention (CDC) are also found online and are summarized in the table (table 1). In mid-February 2020, the CDC stated that evaluation for COVID-19 could also be considered in patients who are severely ill when another etiology cannot be determined, even if a clear exposure has not been identified [40].
For patients who meet their criteria, in addition to testing for other respiratory pathogens, the CDC recommends collection of specimens to test for COVID-19 virus from the upper respiratory tract (nasopharyngeal and oropharyngeal swab) and, if possible, the lower respiratory tract (sputum, tracheal aspirate, or bronchoalveolar lavage). Induction of sputum is not indicated. Additional specimens (eg, stool, urine) can also be collected.
COVID-19 virus is detected by polymerase chain reaction; in the United States, testing is performed by the CDC or a CDC-qualified lab [41].
However, for safety reasons, specimens from a patient with suspected or documented COVID-19 should not be submitted for viral culture.
The importance of testing for other pathogens was highlighted in a report of 210 symptomatic patients with suspected COVID-19; 30 tested positive for another respiratory viral pathogen, and 11 tested positive for COVID-19 [16].
MANAGEMENT
Hospital care — Management of patients with suspected or documented COVID-19 consists of ensuring appropriate infection control, as below (see 'Infection control for suspected or confirmed cases' below), and supportive care. Clinical guidance can be found on the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) websites [23,42].
Supportive care for sepsis and acute respiratory distress syndrome is discussed elsewhere. (See "Evaluation and management of suspected sepsis and septic shock in adults" and "Acute respiratory distress syndrome: Supportive care and oxygenation in adults".)
The WHO and CDC recommend glucocorticoids not be used in patients with COVID-19 pneumonia unless there are other indications (eg, exacerbation of chronic obstructive pulmonary disease) [23,42]. Glucocorticoids have been associated with an increased risk for mortality in patients with influenza and delayed viral clearance in patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Although they were widely used in management of severe acute respiratory syndrome (SARS), there was no good evidence for benefit, and there was persuasive evidence of adverse short- and long-term harm [43]. (See "Treatment of seasonal influenza in adults", section on 'Adjunctive therapies' and "Middle East respiratory syndrome coronavirus: Treatment and prevention", section on 'Treatment'.)
Investigational agents are being explored for antiviral treatment of COVID-19. As an example, the manufacturer of remdesivir, a novel nucleotide analogue that has activity against COVID-19 virus and related coronaviruses (including SARS and MERS-CoV) in vitro and in animal studies [44,45], is conducting a randomized clinical trial in China to evaluate the efficacy and safety of remdesivir in COVID-19 [46]. The compassionate use of remdesivir through an investigational new drug application was described in a case report of one of the first patients with COVID-19 in the United States [47]. Any clinical impact of remdesivir on COVID-19 remains unknown.
There has also been interest in the combined protease inhibitor lopinavir-ritonavir, which is used for the treatment of HIV infection. This combined agent has in vitro activity against the SARS-CoV [48] and appears to have some activity against MERS-CoV in animal studies [49]. The use of this agent for treatment of COVID-19 has been described in case reports [50,51], but its efficacy is unclear, and it is being evaluated in larger randomized trials.
Practitioners in China should be aware of local guidelines regarding treatment and also assess their patients for eligibility in available clinical trials. A registry of international clinical trials can be found on the WHO website and at clinicaltrials.gov.
Home care — Home management may be appropriate for patients with mild infection who can be adequately isolated in the outpatient setting [23,42,52]. Management of such patients should focus on prevention of transmission to others, and monitoring for clinical deterioration, which should prompt hospitalization.
Interim recommendations on home management of patients with COVID-19 can be found on the WHO and CDC websites [52-54].
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. In one report of 138 patients with COVID-19 in China, it was estimated that 43 percent acquired infection in the hospital setting [31].
Individuals with suspected infection in the community should be advised to wear a medical mask to contain their respiratory secretions and seek medical attention. (See 'Evaluation and diagnosis' above.)
In the health care setting, the World Health Organization (WHO) and United States Centers for Disease Control and Prevention (CDC) recommendations for infection control for suspected or confirmed infections differ slightly:
●The WHO recommends standard, contact, and droplet precautions, with eye or face protection [55]. The addition of airborne precautions is warranted during aerosol-generating procedures, such as tracheal intubation, noninvasive ventilation, tracheotomy, cardiopulmonary resuscitation, manual ventilation before intubation, and bronchoscopy.
●The CDC recommends standard, contact, and airborne precautions, with eye protection [56]. If an airborne infection isolation room (ie, a single patient negative pressure room) is not readily available, the patient should wear a mask and be placed in a private room with the door closed, and any personnel entering the room should wear the appropriate personal protection equipment. Patients with suspected or confirmed COVID-19 who require hospitalization should be cared for in a facility that can provide an airborne infection isolation room.
Elements of the different types of infection control precautions are detailed in the table (table 2).
The decision to discontinue infection control precautions for patients with COVID-19 should be made on a case-by-case basis in consultation with experts in infection prevention and control and public health officials. Factors to inform this decision include resolution of clinical signs and symptoms and negative results of reverse transcription polymerase chain reaction (RT-PCR) testing for COVID-19 virus on two sequential respiratory tract specimens collected ≥24 hours apart [57].
To help reduce the spread of COVID-19 virus, environmental infection control procedures should also be implemented [52,54-56,58]. In United States health care settings, the CDC states routine cleaning and disinfection procedures are appropriate for COVID-19 virus [56]. Products approved by the Environmental Protection Agency for emerging viral pathogens should be used. Specific guidance on environmental measures, including those used in the home setting, is available on the CDC and WHO websites. Additional information is also found in a separate topic review. (See "Coronaviruses", section on 'Treatment and prevention'.)
For health care workers who have had a potential exposure to COVID-19, the CDC has provided guidelines for work restriction and monitoring. The approach depends upon the duration of exposure, the patient's symptoms, whether the patient was wearing a facemask, the type of personal protective equipment used by the provider, and whether an aerosol-generating procedure was performed.
Links to additional infection control guidelines are found below. (See 'Society guideline links' below.)
Preventing exposure in the community — The WHO advises general measures to reduce transmission of infection, including diligent hand washing, respiratory hygiene, and avoiding close contact with live or dead animals and ill individuals.
It notes that for people without respiratory symptoms, wearing a medical mask in the community is not required, even if COVID-19 is prevalent in the area; wearing a mask does not decrease the importance of other general measures to prevent infection, and it may result in unnecessary cost and supply problems [59].
Individuals who are caring for patients with suspected or documented COVID-19 at home, however, should wear a tightly fitting medical mask when in the same room as that patient.
Global public health measures — On January 30, 2020, the WHO declared the COVID-19 outbreak a public health emergency of international concern.
The WHO does not recommend international travel restrictions but does acknowledge that movement restriction may be temporarily useful in some settings. The WHO advises exit screening for international travelers from areas with ongoing transmission of COVID-19 virus to identify individuals with fever, cough, or potential high-risk exposure [60,61]. Many countries also perform entry screening (eg, temperature, assessment for signs and symptoms). More detailed travel information is available on the WHO website.
In the United States, the CDC currently recommends that individuals avoid all nonessential travel to China [62]; United States citizens returning from the Hubei Province are undergoing a 14-day quarantine, while those returning from other parts of China are undergoing screening for signs of illness on arrival (with subsequent self-monitoring) as long as there is no known high-risk exposure; foreign nationals who have been in China in the prior 14 days are temporarily suspended from entry. The CDC website provides updated guidance on travel restrictions [63], as well as risk assessment and management of persons with a suspected exposure to COVID-19.
Although many cases of COVID-19 can be detected through entry screening, some may be missed. As an example, in Germany, 114 travellers returning from Wuhan were considered to be asymptomatic during entry screening, but when tested for COVID-19 virus by RT-PCR, two tested positive [17]. However the role of asymptomatic patients in transmitting infection to others, and thus the value of PCR testing of asymptomatic individuals on entry, remains unclear. (See 'Transmission' above.)CLINICAL FEATURES
Incubation period — The incubation period for COVID-19 is thought to be within 14 days following exposure, with most cases occurring approximately five days after exposure [13].
In a family cluster of infections, the onset of fever and respiratory symptoms occurred approximately three to six days after presumptive exposure [28]. Similarly, in an analysis of 10 patients with confirmed COVID-19 pneumonia, the estimated mean incubation period was five days [13].
Clinical presentation — Pneumonia appears to be the most frequent serious manifestation of infection, characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest imaging [29-31]. Most infections are not severe, although many patients have had critical illness [16,28-33]. 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, 81 percent were mild (no or mild pneumonia), 14 percent were severe (eg, with dyspnea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours), and 5 percent were critical (eg, with respiratory failure, shock, or multiorgan dysfunction) [34]. The overall case-fatality rate was 2.3 percent; no deaths were reported among noncritical cases. Most of the fatal cases have occurred in patients with advanced age or underlying medical comorbidities.
In addition to respiratory symptoms, gastrointestinal symptoms (eg, nausea and diarrhea) have been reported in some patients, but these are relatively uncommon [29,31]. Asymptomatic infections have also been described [15,28,35,36], but their frequency is unknown.
In patients with COVID-19, the white blood cell count can vary. Leukopenia, leukocytosis, and lymphopenia have been reported, although lymphopenia appears most common [23]. Elevated aminotransferase levels have also been described. On admission, many patients with pneumonia have normal serum procalcitonin levels; however, in those requiring intensive care unit (ICU) care, they are more likely to be elevated [29-31].
In a study describing 138 patients with COVID-19 pneumonia in Wuhan, the median age was 56 years (interquartile range 42 to 68 years) [31]. Nearly all (99 percent) reported fever, 59 percent had a dry cough, and 35 percent had myalgias. Dyspnea developed in 31 percent after a median of five days of illness. Lymphopenia was common, and all patients had parenchymal lung abnormalities on computed tomography of the chest, including bilateral patchy shadows or ground-glass opacities. Acute respiratory distress syndrome developed in 20 percent, and mechanical ventilation was implemented in 12.3 percent. Among the six patients who died, D-dimer levels were higher and lymphopenia was more severe compared with survivors. Similar clinical features have been described in other smaller cohorts of patients from Wuhan with confirmed COVID-19 [29,30,37]. In one report of 21 patients with laboratory-confirmed COVID-19 who did not develop severe respiratory distress, lung abnormalities were most severe approximately 10 days after symptom onset [37].
Reports of cohorts in locations outside of Wuhan have described similar clinical findings, although some have suggested that milder illness may be more common [38,39]. As an example, in a study of 62 patients with COVID-19 in the Zhejiang province of China, all but one had pneumonia, but only two developed dyspnea, and only one warranted mechanical ventilation [39].
EVALUATION AND DIAGNOSIS
The approach to initial management should focus on early recognition of suspect cases, immediate isolation, and institution of infection control measures. At present, the possibility of COVID-19 should be considered primarily in patients with fever and/or lower respiratory tract symptoms who reside in or have recently (within the prior 14 days) traveled to China or who have had recent (within the prior 14 days) close contact with a confirmed or suspected case of COVID-19. When COVID-19 is suspected, infection control measures should be implemented and public health officials notified. Infection control precautions are discussed elsewhere. (See 'Infection control for suspected or confirmed cases' below.)
The specific case definitions and clinical criteria for diagnostic evaluation differ slightly between expert groups. Case definitions from the World Health Organization are found in its technical guidance online; clinical criteria for patients under investigation from the United States Centers for Disease Control and Prevention (CDC) are also found online and are summarized in the table (table 1). In mid-February 2020, the CDC stated that evaluation for COVID-19 could also be considered in patients who are severely ill when another etiology cannot be determined, even if a clear exposure has not been identified [40].
For patients who meet their criteria, in addition to testing for other respiratory pathogens, the CDC recommends collection of specimens to test for COVID-19 virus from the upper respiratory tract (nasopharyngeal and oropharyngeal swab) and, if possible, the lower respiratory tract (sputum, tracheal aspirate, or bronchoalveolar lavage). Induction of sputum is not indicated. Additional specimens (eg, stool, urine) can also be collected.
COVID-19 virus is detected by polymerase chain reaction; in the United States, testing is performed by the CDC or a CDC-qualified lab [41].
However, for safety reasons, specimens from a patient with suspected or documented COVID-19 should not be submitted for viral culture.
The importance of testing for other pathogens was highlighted in a report of 210 symptomatic patients with suspected COVID-19; 30 tested positive for another respiratory viral pathogen, and 11 tested positive for COVID-19 [16].
MANAGEMENT
Hospital care — Management of patients with suspected or documented COVID-19 consists of ensuring appropriate infection control, as below (see 'Infection control for suspected or confirmed cases' below), and supportive care. Clinical guidance can be found on the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) websites [23,42].
Supportive care for sepsis and acute respiratory distress syndrome is discussed elsewhere. (See "Evaluation and management of suspected sepsis and septic shock in adults" and "Acute respiratory distress syndrome: Supportive care and oxygenation in adults".)
The WHO and CDC recommend glucocorticoids not be used in patients with COVID-19 pneumonia unless there are other indications (eg, exacerbation of chronic obstructive pulmonary disease) [23,42]. Glucocorticoids have been associated with an increased risk for mortality in patients with influenza and delayed viral clearance in patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Although they were widely used in management of severe acute respiratory syndrome (SARS), there was no good evidence for benefit, and there was persuasive evidence of adverse short- and long-term harm [43]. (See "Treatment of seasonal influenza in adults", section on 'Adjunctive therapies' and "Middle East respiratory syndrome coronavirus: Treatment and prevention", section on 'Treatment'.)
Investigational agents are being explored for antiviral treatment of COVID-19. As an example, the manufacturer of remdesivir, a novel nucleotide analogue that has activity against COVID-19 virus and related coronaviruses (including SARS and MERS-CoV) in vitro and in animal studies [44,45], is conducting a randomized clinical trial in China to evaluate the efficacy and safety of remdesivir in COVID-19 [46]. The compassionate use of remdesivir through an investigational new drug application was described in a case report of one of the first patients with COVID-19 in the United States [47]. Any clinical impact of remdesivir on COVID-19 remains unknown.
There has also been interest in the combined protease inhibitor lopinavir-ritonavir, which is used for the treatment of HIV infection. This combined agent has in vitro activity against the SARS-CoV [48] and appears to have some activity against MERS-CoV in animal studies [49]. The use of this agent for treatment of COVID-19 has been described in case reports [50,51], but its efficacy is unclear, and it is being evaluated in larger randomized trials.
Practitioners in China should be aware of local guidelines regarding treatment and also assess their patients for eligibility in available clinical trials. A registry of international clinical trials can be found on the WHO website and at clinicaltrials.gov.
Home care — Home management may be appropriate for patients with mild infection who can be adequately isolated in the outpatient setting [23,42,52]. Management of such patients should focus on prevention of transmission to others, and monitoring for clinical deterioration, which should prompt hospitalization.
Interim recommendations on home management of patients with COVID-19 can be found on the WHO and CDC websites [52-54].
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. In one report of 138 patients with COVID-19 in China, it was estimated that 43 percent acquired infection in the hospital setting [31].
Individuals with suspected infection in the community should be advised to wear a medical mask to contain their respiratory secretions and seek medical attention. (See 'Evaluation and diagnosis' above.)
In the health care setting, the World Health Organization (WHO) and United States Centers for Disease Control and Prevention (CDC) recommendations for infection control for suspected or confirmed infections differ slightly:
●The WHO recommends standard, contact, and droplet precautions, with eye or face protection [55]. The addition of airborne precautions is warranted during aerosol-generating procedures, such as tracheal intubation, noninvasive ventilation, tracheotomy, cardiopulmonary resuscitation, manual ventilation before intubation, and bronchoscopy.
●The CDC recommends standard, contact, and airborne precautions, with eye protection [56]. If an airborne infection isolation room (ie, a single patient negative pressure room) is not readily available, the patient should wear a mask and be placed in a private room with the door closed, and any personnel entering the room should wear the appropriate personal protection equipment. Patients with suspected or confirmed COVID-19 who require hospitalization should be cared for in a facility that can provide an airborne infection isolation room.
Elements of the different types of infection control precautions are detailed in the table (table 2).
The decision to discontinue infection control precautions for patients with COVID-19 should be made on a case-by-case basis in consultation with experts in infection prevention and control and public health officials. Factors to inform this decision include resolution of clinical signs and symptoms and negative results of reverse transcription polymerase chain reaction (RT-PCR) testing for COVID-19 virus on two sequential respiratory tract specimens collected ≥24 hours apart [57].
To help reduce the spread of COVID-19 virus, environmental infection control procedures should also be implemented [52,54-56,58]. In United States health care settings, the CDC states routine cleaning and disinfection procedures are appropriate for COVID-19 virus [56]. Products approved by the Environmental Protection Agency for emerging viral pathogens should be used. Specific guidance on environmental measures, including those used in the home setting, is available on the CDC and WHO websites. Additional information is also found in a separate topic review. (See "Coronaviruses", section on 'Treatment and prevention'.)
For health care workers who have had a potential exposure to COVID-19, the CDC has provided guidelines for work restriction and monitoring. The approach depends upon the duration of exposure, the patient's symptoms, whether the patient was wearing a facemask, the type of personal protective equipment used by the provider, and whether an aerosol-generating procedure was performed.
Links to additional infection control guidelines are found below. (See 'Society guideline links' below.)
Preventing exposure in the community — The WHO advises general measures to reduce transmission of infection, including diligent hand washing, respiratory hygiene, and avoiding close contact with live or dead animals and ill individuals.
It notes that for people without respiratory symptoms, wearing a medical mask in the community is not required, even if COVID-19 is prevalent in the area; wearing a mask does not decrease the importance of other general measures to prevent infection, and it may result in unnecessary cost and supply problems [59].
Individuals who are caring for patients with suspected or documented COVID-19 at home, however, should wear a tightly fitting medical mask when in the same room as that patient.
Global public health measures — On January 30, 2020, the WHO declared the COVID-19 outbreak a public health emergency of international concern.
The WHO does not recommend international travel restrictions but does acknowledge that movement restriction may be temporarily useful in some settings. The WHO advises exit screening for international travelers from areas with ongoing transmission of COVID-19 virus to identify individuals with fever, cough, or potential high-risk exposure [60,61]. Many countries also perform entry screening (eg, temperature, assessment for signs and symptoms). More detailed travel information is available on the WHO website.
In the United States, the CDC currently recommends that individuals avoid all nonessential travel to China [62]; United States citizens returning from the Hubei Province are undergoing a 14-day quarantine, while those returning from other parts of China are undergoing screening for signs of illness on arrival (with subsequent self-monitoring) as long as there is no known high-risk exposure; foreign nationals who have been in China in the prior 14 days are temporarily suspended from entry. The CDC website provides updated guidance on travel restrictions [63], as well as risk assessment and management of persons with a suspected exposure to COVID-19.
Although many cases of COVID-19 can be detected through entry screening, some may be missed. As an example, in Germany, 114 travellers returning from Wuhan were considered to be asymptomatic during entry screening, but when tested for COVID-19 virus by RT-PCR, two tested positive [17]. However the role of asymptomatic patients in transmitting infection to others, and thus the value of PCR testing of asymptomatic individuals on entry, remains unclear. (See 'Transmission' above.)
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