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Coronavirus SARS-CoV2 infection (COVID-19)

Essential Evidence


Authors:
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia
Mindy A. Smith, MD, MS, Clinical Professor, Department of Family Medicine, Michigan State University
Henry C. Barry, MD, MD, MS, Professor Emeritus, Michigan State University
Pete Yunyongying, MD, FACP, Associate Professor , Carle-Illinois College of Medicine, University of Illinois
John Hickner MD, MS, Professor Emeritus, University of Illinois-Chicago

Editor:
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia

Last updated: 2020-09-28 © 2020 John Wiley & Sons, Inc.

Overall Bottom Line

  • EDITOR'S NOTE: This topic has been made freely available and is being updated regularly. We are at times linking to preprint servers and providing direct links to articles where possible, and most of this literature has been made freely available. As preprint work becomes peer reviewed and formally published, we will update the citations. Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.
  • Suspect COVID-19 when the virus is circulating in the population and a patient reports signs and symptoms of respiratory tract infection, or less commonly fever and neurologic symptoms or thrombosis. Most common symptoms are fever, cough, myalgias, and dyspnea; loss of taste and smell are also common. Approximately 40% of all patients are asymptomatic but appear to be as infectious as symptomatic patients. B
  • Preventive measures include hand washing, surface cleaning, case isolation, quarantine of contacts for 14 days, school and university closures, and general social distancing/sheltering at home. Modeling indicates that only by doing all of these measures can the number of severe cases requiring ventilation not overwhelm hospitals.B
  • Mask and isolate patients on presentation to a healthcare facility and obtain PCR from nasopharynx and oropharynx. Also test for influenza and strep throat if clinically suspected. C
  • The combination of age and CRP can be used to identify patients at low, moderate and high risk of severe illness (see Prognosis section below).B
  • Patients can be considered cured using a test-based strategy (recovery from fever without antipyretics and without respiratory symptoms plus 2 negative PCR tests 24 hours apart). For outpatients in settings where tests are not widely available, the CDC recommends that isolation be maintained for at least 10 days after illness onset and at least 3 days (72 hours) after recovery, defined as: at least 3 days free of fever without antipyretics, 3 days without respiratory symptoms, and at least 7 days after onset of symptoms. C
  • Treatment is primarily supportive and includes monitoring oxygen saturation.
  • Remdesivir shortens the duration of hospitalization (11 vs. 15 days) and may reduce mortality slightly.108B
  • Corticosteroids have been shown in a large UK trial with 6425 patients to be highly effective at reducing mortality in patients with COVID-19 who are mechanically ventilated (NNT = 7) or who are on oxygen (NNT = 20) but not in hospitalized patients not requiring oxygen.161 Their use also decreases the likelihood of requiring mechanical ventilation.171B
  • Multiple randomized controlled trials have confirmed that hydroxychloroquine is not effective for severe disease, mild disease, early disease, or as post-exposure prophylaxis, and is associated with a higher risk of adverse events.173105A
  • The overall infection fatality rate is estimated to be 0.5% to 0.9% and is higher in older patients and those with comorbidities.65 As of September 24th, the Johns Hopkins Center for Health Security reports that there have been 984,813 deaths and 32,356,829 confirmed cases worldwide, 203,147 deaths and 6,997,468 confirmed cases in the US (2.9% case fatality ratio), 9,304 deaths and 151,982 confirmed cases in Canada (6.1% case fatality ratio), and 42,025 deaths and 425,765 confirmed cases in the UK (9.9% case fatality ratio). Mortality rates per 100,000 are 62.0 in the US, 25.1 in Canada, and 63.2 in the UK. These rates are higher than the true case and infected fatality rates due to the large number of undiagnosed mild and asymptomatic cases. B

Background

  • COVID-19 (coronavirus disease 2019) is a viral lower respiratory infection first reported in Wuhan City, China that has rapidly spread to become a pandemic. It is caused by novel coronavirus named 2019-nCoV and more recently SARS-CoV2.

Incidence

  • Information about incidence and the case fatality rate are evolving. Peak incidence predictions nationally and by state for the US are provided by the modeling group at the University of Washington.
  • Several other Web sites and the Johns Hopkins Coronavirus Resource Center provide detailed information on new cases, total cases, and deaths that are updated daily.
  • In a study in Los Angeles County, California, researchers invited a random sample of 1952 adult residents, 863 of whom agreed to be tested. Thirty-five (4%) individuals tested positive; after adjusting for the sensitivity and specificity of the test and population weighting they estimated 4.6% of adults had been infected, roughly a 50-fold increase in the number actually diagnosed.113
  • In a study of 220 women admitted for delivery in New York in late March/early April 2020, all were tested and 15.4% were positive for SARS-CoV2, most of whom were asymptomatic.60
  • A Swiss study sampled 2766 participants who were demographically similar to the overall population of the Geneva Canton for antibodies to COVID-19. After accounting for test accuracy and other factors, the range of seroprevalence during the first 4 weeks of the study ranged from 4.8% to 10.9%. Prevalence was highest in those 20 to 49 years of age, and they estimate 11.6 infections in the community for each confirmed case.129
  • The CDC has begun a series of seroprevalence studies in 6 states, using blood specimens obtained for reasons other than COVID-19 testing (preprint server, not peer-reviewed). They used an antibody test that is 96% sensitive and 99.3% specific, and adjusted the results to account for false negatives and false positives. In the most recent report, age and sex-standardized positive rates were 1.1% in Washington, 1.9% in south Florida, 2.2% in Utah, 2.4% in Minneapolis-St. Paul, 2.7% in Missouri, 3.2% in Philadelphia, 4.9% in Connecticut, 5.8% in Louisiana, and 6.9% in the metro New York City region. Based on the number of confirmed cases, they estimate a range of 6 to 24 total cases per confirmed case, with 4 of 6 jurisdictions having 10.8 to 11.9 total cases per confirmed case. These estimates are based on data collected from mid-March to late May, so current conditions may reflect a higher seroprevalence and lower ratio of undetected to confirmed cases.152
  • The rate of infection and hospitalization is higher for Black, Hispanic/Latino, and American Indian/Alaska Native than would be expected from their proportion in the general population.168
  • Among children admitted for an ENT procedure who were asymptomatic, between 0% and 0.8% tested positive for SARS-CoV-2.169

Other Impact

  • Based on modeling by the COVID-19 research unit at Imperial College in London, the case fatality ratio is estimated to be 0.9% overall (95% credible interval 0.4% to 1.4%). It is lowest in children (0.002%) and is higher with increasing age (0.08% for 30 to 39, 0.60% for 50 to 59, 2.2% for 60 to 69, 5.1% for 70 to 79 and 9.3% for 80 and older). Mortality is also higher in those with comorbidities such as hypertension, diabetes and chronic cardiopulmonary conditions. To some extent, this may be a matter of confounding as these conditions are more common in older persons.
  • The day-to-day mortality estimates are likely to change as the epidemic evolves, as there is currently incomplete case ascertainment, especially in the US, while some infected persons who will die in the subsequent 2 weeks are not yet counted in the fatality data. Data from Italy and China found similar case-fatality rates when stratified by age, with the exception of a higher rate in Italy for those 80 years and older. Since data were not reported for those 90 and older in China, this could still represent an effect of greater age in Italy within this group.
  • Undercounting the deaths from COVID is likely. A report updated on September 11, 2020 estimated over 263,000 excess deaths globally. This was based on comparing current overall mortality trends in multiple countries with historical data.
  • Based on CDC weekly death data, during a 6-week period early in 2020, the US experienced 87,000 more deaths than what would be expected based on data from the previous six years for the same time frame.178
  • Using excess mortality data, in New York City COVID-19 was more deadly in March through May of 2020 than the 1918 flu epidemic was during its peak months.162

Causes of the Condition

  • The cause of COVID-19 is the novel coronavirus SARS-CoV-2.
  • Coronaviruses are enveloped, single-stranded RNA viruses that include those that caused a large-scale epidemic of severe acute respiratory syndrome (SARS) in 2002-3 and the Middle-Eastern Respiratory Syndrome (MERS), a persistent epidemic in the Arabian Peninsula since 2012. There also several widely circulating species that cause mild respiratory tract infections in humans.74

Pathophysiology

  • COVID-19 infection ("COronaVirus Disease 2019") is caused by the novel coronarvirus SARS-CoV-2. It is the 7th coronavirus reported to cause disease in humans.
  • Like SARS-CoV, SARS-CoV-2 is in the subgenus sarbecovirus. The genome has been sequenced and it is more closely related genetically to SARS than to MERS (Middle Eastern Respiratory Syndrome).16
  • COVID-19 appears to cause a prothrombotic state with microthrombi identified in multiple organs including the lungs, kidneys, heart, and liver, based on autopsy studies. In addition, megakaryocytes (bone marrow cells responsible for producing platelets) were found in higher than usual numbers in the lungs and heart.146
  • Incubation period
  • The incubation period is a median of 5 days, and 97.5% who develop symptoms will do so within 11.5 days. About 1% may develop symptoms more than 14 days after exposure.36
  • Duration of viral shedding and infectiousness
  • The median duration of viral shedding in survivors is 20 days, based on early data from Wuhan City, China.18
  • A systematic review of 8 studies reporting on viral shedding found that 40.5% (significant heterogeneity) of patients with COVID-19 shed the virus in their stools.128
  • Based on a series of 94 patients, researchers estimated that 44% (95% CI 25% to 69%) were infected by presymptomatic or asymptomatic index patients. Shedding declined over a median 21-day period. They estimate that patients were infectious 2.3 days prior to symptom onset (95% CI 0.8 to 3.0 days), with a peak infectiousness at 0.7 days prior to symptom onset (95% CI -0.2 to 2.0 days).115
  • A South Korean study of 193 symptomatic and 110 asymptomatic individuals found that they tested positive for 17 to 19 days, with little difference between symptomatic and asymptomatic persons.179
  • Among 96 consecutive patients hospitalized with COVID-19, 22 had mild disease and 74 had severe disease. The patients had daily PCR assays of sputum, saliva, blood, urine and stool. Among the 3497 samples, SARS-CoV-2 RNA was detected in 59% of the patients. The median duration of fecal shedding of SARS-CoV-2 RNA was 22 days compared with 18 days in the respiratory samples and 16 days in the serum samples. It was detected in only a single urine sample. Patients with severe disease shed virus for 1 week longer than those with mild disease (21 days vs. 14 days, respectively).68
  • In a case-control study, compared to patients without GI symptoms, the 107 patients who had presented with GI symptoms had a longer duration of viral shedding (41 vs. 32 days).135
  • Transmission of virus
  • It is thought that the virus is spread mainly through respiratory droplets and via aerosols, especially by those in close contact typically defined as less than 6 feet or 2 meters. However, the virus can be spread by asymptomatic persons.27
  • In Singapore, a country where there was very careful contact tracing, researchers estimated that 10 of 157 (6.4%) locally-acquired cases were infected by someone who was presymptomatic (e.g. 1 to 3 days before symptom onset) based on contact with the presymptomatic individual and no contact with any symptomatic persons.114 A modeling study estimated even higher rates of infection from persons with mild or asymptomatic disease, due to greater activity levels.48
  • Researchers reported a cluster of 10 COVID-19 cases that were most likely spread from one infected person at a restaurant in Guangzhou, China. The investigators could find no other exposures to COVID-19 for the other two infected families. After careful contact tracing and assessment of the physical environment, the researchers hypothesize that the infection may have been spread by the air-conditioning unit. If so, this report has significant implications as countries open up restaurants and other business venues requiring close physical proximity.64
  • In an Italian study that tested the entire town of Vo', persons were infectious for between 3.6 to 6.5 days, with infectiousness peaking on the day of symptom onset.145 A Taiwanese study similarly found that persons were infectious for about 5 to 6 days.78
  • In Taiwan, based on contact tracing of 2761 close contacts of 100 patients confirmed with COVID-19, there were 22 secondary infections, an attack rate of 0.7% (95% CI, 0.4%-1.0%) The attack rate was highest among the 1,818 individuals exposed within 5 days of symptom onset (1.0%) compared to those with later exposure (0 cases from 852 contacts). The rate was also highest among household contacts (4.6%) and non-household family contacts (5.3%). Contacts with only pre-symptomatic exposure had a 0.9% incidence of infection. This study suggests that isolation of infected individuals is insufficient to halt transmission of COVID-19.78
  • A large South Korean contact tracing study found that the transmission rate was 11.8% for 10,592 household contacts of infected persons, compared to only 1.9% for non-household contacts. Transmission was lowest for young children age 0 to 9 years (5.3%), highest for older children age 10 to 19 years (18.6%), and was somewhere in between for adults, increasing with increasing age.155
  • Two studies examined household transmission in adults and children. In a Swiss study, adult household contacts were suspected or confirmed to have COVID-19 infection before the study child in 79% (31/39) of cases. The study child deveIoped symptoms before any other household contact in only 8% (3/39) of households.159 In a similar international study of COVID-19 transmission in 31 household clusters from China, Singapore, South Korea, Japan and Iran, the investigators found that a child the first (index) case in only 3 of the 31 (9.7%) household clusters. (preprint server, not peer reviewed)
  • The virus can also remain on surfaces like cardboard (up to 24 hours) and steel or plastic (up to 72 hours). However, it is not known how long before the level of viral pathogen on the surface is below the amount needed to cause human infection, nor the effect of environmental factors on duration.28
  • A series of 116 patients with COVID-19 found that coinfection was fairly uncommon, most often with rhinovirus (6.9%), RSV (5.2%) and other coronaviruses (4.3%).58
  • The CDC performed a case-control study that included 154 who tested positive and 160 who tested negative. Case-patients were more likely to have reported dining at a restaurant (adjusted odds ratio [aOR] = 2.4, 95% CI = 1.5–3.8) in the 2 weeks before illness onset than controls. When the analysis was restricted to the 225 participants who did not report recent close contact with a person with known COVID-19, cases were more likely than were controls to have dined at a restaurant (aOR = 2.8, 95% CI = 1.9–4.3) or going to a bar/coffee shop (aOR = 3.9, 95% CI = 1.5–10.1).175

Risk Factors

Risk Factor
Living in or traveling to an endemic area for SARS-CoV-2
Risk factors for severe COVID-19 infection include increasing age, comorbidities (diabetes, COPD, asthma, heart disease), elevated CRP, LDH, ALT or AST, decreased albumin, lymphopenia, and neutrophilia.

Screening and Prevention

Bottom Line

  • Guidelines
  • The Johns Hopkins Center for Health Security has created guidance for state and local governments with regards to re-opening the economy.
  • CDC provides guidance for healthcare facilities and clinics.
  • The World Health Organization provides guidance regarding surveillance for SARS-CoV-2 infection in various settings.
  • Post-exposure prophylaxis
  • Researchers randomized 821 persons with a moderate-risk or high-risk exposure to someone with confirmed COVID-19 within the previous 4 days to receive HCQ or matching placebo. The primary outcome was laboratory confirmed or clinically suspected COVID-19 (testing was not yet widely available) in the next 14 days. There was no difference between groups in the primary outcome, with 49/414 (11.8%) reporting infection in the HCQ group and 58/407 (14.3%) in the placebo group (risk difference -2.4%, 95% CI -7.0 to 2.2). The findings were the same at 5, 10 and 14 days. 105
  • Vaccines
  • Multiple vaccine trials have begun initial human testing. The New York Times maintains a "Coronavirus Vaccine Tracker". As of September 25, 2020 5 vaccines were approved for limited human use, 11 were in Phase 3 trials, 14 in Phase 2 trials, and 27 in Phase 1 trials.
  • Published reports of Phase 2 trials generally report good antibody response, including evidence of both humoral and cellular immunity, with acceptable adverse effects.154153
  • Coronaviruses make use of a large envelope protein called the spike to engage host cell receptors and catalyze membrane fusion. In a recent study using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, investigators identified neutralizing cross-reactive single-domain camelid antibodies that can attach to and neutralize the viruses’ spike protein and may serve as potential therapeutic candidate for human vaccines.83
  • A variety of approaches are being used, including inactivated or weakened coronavirus, viral vector vaccines, nucleic acid vaccines (DNA and RNA), mRNA, and protein-based vaccines. These approaches are explained in a graphical article in Nature.
  • In a computational model, a vaccine must have high effectiveness (at least 60%) and high uptake (at least 75%) to single-handedly stop a pandemic.180
  • Physical ("social") distancing
  • Frequent, adequate handwashing for 20 seconds using warm, soapy water is strongly recommended. A simple online intervention to educate patients has been evaluated and has been demonstrated to decrease transmission of respiratory tract infections in a large trial with 20,066 patients. The "GermDefence" site from this study has been adapted for COVID-19 and is freely available.47
  • Based on modeling of COVID-19, to significantly decrease spread of the disease a combination of several measures need to be in place to avoid overwhelming hospital and ICU capacity: school and university closure, case isolation, and general social distancing of no less than 6 feet/2 meters for no more than 10 minutes.
  • Physical distancing has been broadly mandated around the world. A Cochrane review of 29 studies (10 modeling studies of COVID-19, 4 observational, and 15 modeling studies of SARS or MERS) has concluded that these measures are consistently effective in slowing the spread of an epidemic. It is most effective when implemented early and in conjunction with other measures like closing schools and restricting travel.55
  • A comprehensive analysis determined incidence rate ratios before and after various distancing measures (school closures, workplace closures, restrictions on mass gatherings, public transportation closure and lock-down orders) were implemented in 149 countries. They found that implementation resulted in a 13% reduction in the incidence rate ratio.156
  • A meta-analysis sponsored by WHO identified 172 observational studies of non-pharmaceutical interventions in healthcare and community settings. They found lower risk of infection with distancing (-10.2%, moderate certainty), facemask use (-14.3%, low certainty), and eye protection (-10.6%).121
  • A Web site tracks the current status of stay-at-home orders by US state.
  • Researchers at the University of Toronto (preprint, not peer-reviewed) concluded that a 10% decrease in mobility resulted in an 11% decrease in the average daily growth rate of the epidemic.
  • Early in the outbreak in China when restrictions on public gathering and emphasis on distancing was increased, the basic reproductive number (R0 or "R naught") went from about 3.0 before public measures were put in place to only 0.3 by the time all measures were in place. R0 is the mean number of persons infected by an infected case and values less than 1 generally reflect outbreak containment.116
  • A time series study from Harvard (preprint, not peer reviewed) found increases in doubling time that corresponded to implementation of statewide distancing measures.
  • A prospective cohort study of 144 geopolitical regions worldwide found little or no association with latitude, temperature, or relative humidity but strong associations with physical distancing, school closures, and banning mass gatherings.86
  • A hyperlocal study in the American Journal of Preventive Medicine compared Clarke County, Georgia which had early, strict distancing with surrounding counties that implemented it later. Cases grew more quickly in surrounding counties. The doubling time also began increasing about 2 weeks earlier in Clarke County, in line with when distancing was enforced (doubling time is the number of days for cases to double, so higher is better).
  • A study applying econometric approaches to the question of whether non-pharmaceutical interventions are effective studied 1717 administrative units in six countries. Their modeling concludes that implementation of all policy measures (such as school closures, social isolation guidelines, travel bans) resulted in reductions in the rate of growth of cases, with larger reductions in Iran, China, South Korea and Italy and smaller reductions in the US and France. They estimate that these measures reduced the number of confirmed cases in those 6 countries by over 60 million, with a reduction of confirmed cases in the US by 4.8 million and total cases by 60 million (assuming that many cases were asymptomatic or never confirmed).127
  • Contact tracing and isolation
  • Early detection and screening of contacts is important to prevent the spread of COVID-19 infection early during an outbreak. It is not feasible later.7
  • Contacts of COVID-19 exposed individuals should quarantine for 14 days with daily monitoring for fever and other symptoms. Persons living alone should have daily virtual contact with someone who can obtain help in the event of worsening
  • Some countries such as Taiwan and Singapore had success with early and aggressive implementation of contact tracing. A report from Taiwan on 100 index cases and 2761 close contacts found a 0.7% rate of secondary infections, all occurring with exposure during the first 5 days of symptoms. Of 852 close contacts after 5 days there were no secondary infections.78
  • An outbreak in Beijing was contained within one month using a combination of rapid response, extensive testing, quick results reporting, and comprehensive contact.166
  • Digital approaches to contact tracing using mobile phones have been developed.130
  • Facemasks
  • Surgical masks
  • During the 2003 SARS outbreak in Taiwan, wearing surgical face masks on entering the hospital, on hospital wards and in out-patient clinics prevented nearly all cases of SARS among healthcare workers.75
  • None of 41 healthcare workers who had exposure to aerosol-generating procedures for at least 10 minutes at a distance of less than 2 meters of a patient with COVID-19 became ill; most (85%) were wearing a surgical mask and the remainder were wearing N95 masks.76
  • A study of exhaled breath of patients infected with seasonal coronavirus found some evidence that surgical face masks reduce spread of both droplet particles greater than 5 microns and aerosol particles ≤5 microns in diameter.
  • A single RCT from 2015 comparing surgical masks with cloth masks with no mask found that cloth masks had the highest rates of respiratory infection.71
  • Cloth masks
  • The CDC recommended on April 2nd, 2020 that members of the public wear home-made face masks when in a public place where appropriate physical distancing may be difficult, such as a grocery store or pharmacy. Instructions for making masks are provided. However, it is not known whether this will provide a net benefit, and concern has been expressed that it might lead to abandonment of physical distancing measures by some persons. The National Academy of Science concluded that homemade masks have a filtration rate ranging from 0% to 50%.
  • A comparison of 2-layer cotton masks also found that a surgical mask was much more effective.63
  • However, another review of the evidence for cloth masks found very little high-level evidence of their effectiveness in other viral infections. Given what is thought to be a higher rate of asymptomatic transmission with COVID-19, these may not apply.72
  • A Chinese study found that rigorous use of face masks and daily use of disinfectants in the home reduced transmission within a household. This is particularly relevant for households where older or vulnerable family members may reside.104
  • A study used laser interferometry (peer reviewed but not yet in PubMed) to assess droplet spread from 14 different style masks and found that a variety of cotton or polypropylene masks provided reasonable good efficacy, but that knitted masks, bandannas, and fleece gaiters were much less effective, if at all.
  • Droplet spread
  • In a laser-base study, respiratory droplets generated during normal speech travel between 5 to 7.5 cm and ranged in size from 20 to 500 micrometers. With louder speech, droplets travel farther. Using a damp washcloth resulted in dramatic reductions in number and size of droplets as well as the distance traveled. The authors are clear to report they did not assess viral transmission.61
  • The same team using similar methods determined that louder speech also generates thousands of oral fluid droplets per second and that in a closed, stagnant air environment the droplets linger in the air for 8 to 14 minutes.98
  • Consistent with these in vitro experiments, a study from China determined that, among 10,980 confirmed cases, only a single cluster of two patients contracted COVID-19 outdoors (preprint server, not peer-reviewed, use caution).
  • School and university outbreaks
  • During a heatwave, students and teachers were excused from facemasks, resulting in a large outbreak in the school. It was also clear from the physical layout that distancing was not possible. Overall, 13% of students and 17% of staff tested positive, and 43% of students and 75% of staff were symptomatic.151
  • The first large US university to return to in person instruction in early August (University of North Carolina at Chapel Hill) was forced to pivot to online instruction after 4 clusters with over 130 students in the first week of classes.
  • Surface decontamination
  • Surface decontamination using 60% or higher ethanol, 0.5% or higher hydrogen peroxide, or a dilute bleach (0.1% sodium hypochlorite) is recommended given persistence of the virus on surfaces.45
  • Personal Protective Equipment (PPE) for healthcare workers
  • Healthcare personnel doing procedures that may generate aerosols should use a fitted respirator mask (N95) as well as face shield, gloves, and gown. (Surviving Sepsis Campaign Guidelines, 3/26/20).
  • Some studies have compared N95 masks with standard medical masks for prevention of influenza in healthcare workers.444342 They have found little difference, but in these studies poor fit and lack of compliance with N95 masks was common. These studies cannot be applied to the COVID-19 epidemic where the motivation to comply with proper fit and adhere to consistent usage is much higher than in a study of influenza prevention.
  • N95 respirators can be decontaminated and re-used in times of shortage up to 3 times, based on one study, using either UV radiation or vaporized hydrogen peroxide. Use of 70% ethanol was found to be acceptable for decontamination once, but additional decontamination with ethanol resulted in a sharp drop in mask filtration performance.138
  • In a study of 420 healthcare workers sent to Wuhan for a 6-week period to care for COVID-19 patients (16 hours/week average in ICU), none tested positive after two weeks of quarantine upon their return home.132
  • In a study of healthcare workers doing home visits in India, the attack rate was 12/62 (19%) prior to use of face shields and 0/50 (0%) after their use was initiated.163
  • Measures recommended by front-line physicians based on personal experience include the following (personal communication, Hannah Ferenchick, MD, ED/critical care physician in Detroit, MI):
    • Scrubs only, no undershirts, minimize work jackets. If long hair, consider hairnet. If male, shave beard to improve N95 fit.
    • N95 for all encounters, often limited to one per shift, with surgical mask over N95 in case of soiling.
    • Eye protection (eye shield, helmet, welding glasses/goggles, and welding style face shield PLUS goggles for intubation or other high-risk procedures.
    • Phone in plastic sandwich bag.
    • Minimize objects close to patient (not taking pen/paper into rooms, minimize phone contact, try not to use own stethoscope).
    • Disinfect all workspaces prior to shift, including computer keyboard and mouse, desktop, phones, etc.
    • Do not eat with hands, do not touch face with hands while at work, throw away water bottles during shift and do not take home.
    • At work after shift: return dirty scrubs, change into clothes or clean scrubs, disinfect phone/badge/face shield/eye wear, place personal PPE in plastic bag without other objects, and disinfect personal stethoscope and place in bag without other objects.
    • Car: "Home" shoes kept in trunk, change out of "work" shoes and place in trunk, place personal PPE in trunk until next shift.
    • Home: Take off work purse, place in closet away from other clothes, disinfect phone again, wash hands and shower immediately. Some are choosing to isolate at home as well, and/or using garage to dump clothes.

Diagnosis

Bottom Line

  • Suspect severe coronavirus infection in persons with fever, cough, and other respiratory symptoms, or less commonly fever and neurologic symptoms or thrombosis when the virus is circulating in the community. C
  • RT-PCR of multiple specimens is the most appropriate diagnostic testing method. Testing should be carried out according to guidelines from and in consultation with public health authorities.8B

Differential Diagnosis

Diagnosis
Community-acquired pneumonia caused by strep, influenza, legionella, mycoplasma, or other viruses
COPD exacerbation
Acute pulmonary edema
Interstitial lung disease
Hantavirus pulmonary syndrome
Opportunistic infections causing pneumonia-complicating HIV infection (pneumocystis carinii, histoplasmosis, or disseminated varicella pneumonia)

Diagnostic Criteria

  • The WHO R&D Blueprint Group recommends classifying patients with regards to disease severity as follows:
    • 1: Not hospitalized
    • 2: Hospitalized, not requiring supplemental oxygen
    • 3: Hospitalized, requiring supplemental oxygen
    • 4: Hospitalized requiring nasal high-flow oxygen, non-invasive mechanical ventilation, or both
    • 5: Hospitalized, requiring invasive mechanical ventilation, ECMO or both
    • 6: Death
  • The WHO defines several clinical syndromes:
    • Mild illness: uncomplicated upper RTI as well as non-specific symptoms such as fever, cough, fatigue, anorexia, myalgias, sore throat, dyspnea, nasal congestion, and headache. Rarely patients may present with diarrhea, nausea or vomiting.
    • Pneumonia (non-severe): Pneumonia but no need for supplemental oxygen and no signs of severe pneumonia. In child characterized by cough with tachypnea >60 bpm for <2 months; ≥50 bpm for 2 to 11 months; ≥40 bpm for 1 to 5 years.
    • Severe pneumonia: Adult or adolescent: fever or suspected RTI plus one of respiratory rate >30 bpm, severe respiratory distress, or O2 sat ≥93% on room air. Children with cough or difficulty breathing and at least one of O2 sat <90%, severe distress with grunting or severe retractions; inability to feed or drink, lethargy or unconsciousness, or seizures.
    • Acute respiratory distress syndrome: CXR or chest CT with bilateral opacities; respiratory failure not fully explained by cardiac failure or fluid overload; impaired oxygenation.
      • Oxygen impairment in adults: Mild ARDS: 200 mmHg <PaO2/FiO2 ≤300 mmHg (with PEEP or CPAP ≥5 cmH2O, or non-ventilated); Moderate ARDS: 100 mmHg <PaO2/FiO2 ≤200 mmHg (with PEEP ≥5 cmH2O, or non-ventilated); Severe ARDS: PaO2/FiO2 ≤100 mmHg (with PEEP ≥5 cmH2O, or non-ventilated); When PaO2 is not available, SpO2/FiO2 ≤315 suggests ARDS (including in non-ventilated patients)
      • Oxygen impairment in children (OI = oxygenation index and OSI = oxygenation Index using SpO2. Use PaO2-based metric when available. If PaO2 not available, wean FiO2 to maintain SpO2 ≤97% to calculate OSI or SpO2/FiO2 ratio): Bilevel ( NIV or CPAP) ≥5 cmH2O via full face mask: PaO2/FiO2 ≤300 mmHg or SpO2/FiO2 ≤264; Mild ARDS (invasively ventilated): 4 ≤OI <8 or 5 ≤OSI <7.5; Moderate ARDS (invasively ventilated): 8 ≤OI <16 or 7.5 ≤OSI <12.3; Severe ARDS (invasively ventilated): OI ≥16 or OSI ≥12.3.
    • Sepsis: In adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia. In children: suspected or proven infection and ≥2 age based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count. Severe sepsis in children is defined as sepsis accompanied by cardiovascular dysfunction, ARDS, or 2 or more organ dysfunctions.181

Using the History and Physical

  • Suspect COVID-19 when the virus is circulating in the population and a patient reports signs and symptoms of respiratory tract infection. Most common symptoms are fever, cough, myalgias, and dyspnea.
  • In the first 1099 patients in China, the median age was 47 years and 58% were male. Fever (89%), cough (68%), myalgias (15%), and dyspnea (19%) were common symptoms. In addition, 5% of patients had nausea or vomiting, and 4% had diarrhea.15
  • A systematic review of 43 Chinese studies with 3600 patients reported the following frequency of symptoms: fever 83%, cough 60%, fatigue 38%, myalgias 28%, dyspnea 25%, and diarrhea 8.4% (see Table 1).102
  • Cough is typically dry; the WHO/China report found that 67% had a dry or nonproductive cough while the remainder had a productive cough with thick phlegm.
  • In a series of 202 Italian outpatients with mild to moderate COVID-9 infection, 64% reported alteration of taste or smell, and 101 of 130 with altered taste or smell described it as moderate, severe, or very severe.99 A Swiss study confirmed this, finding it in 62% of COVID-19 patients. Median day of onset was day 3, and it was most often moderate to severe. It was more common in younger and female patients.100 It is thought that anosmia occurs because the coronavirus attaches to ACE2 receptors which are very common in the nasal epithelium and olfactory bulb.
  • The increased blood clotting observed in cases of COVID-19 has caused strokes (see Prognosis | Complications) and small vessel lesions presenting as swollen, discolored toes or fingers. Lesions are similar to pernio, a vascular inflammatory disorder seen in cold, moist climates. Skin lesions are thought to be present in up to 20% of cases and have been seen in symptomatic and asymptomatic patients.
  • A systematic review of 12 studies found that GI manifestations occurred in 3.9% of patients.128
  • A study of 215 consecutive patients hospitalized for COVID-19 in China found CNS manifestations (dizziness, headache, impaired consciousness, stroke, ataxia or seizure) in 25%, while 9% had peripheral nervous system manifestations (altered taste or smell, visual impairment, neuropathic pain).122
  • In a study of 91 children with COVID-19 identified by contact tracing in South Korea, 2% remained asymptomatic, 60% had respiratory symptoms, and 55% had non-specific systemic symptoms. Viral shedding was 14 to 20 days, longer in those who were more symptomatic.170
  • Asymptomatic infections
  • A review identified 16 cohorts of COVID-19 positive individuals from Iceland, Italy, Greece, France, Japan, Argentina, and the United States, (including four ship outbreaks) ranging in size from 76 to 13,080 individuals. The percentage of people who tested positive but were asymptomatic at the time of testing ranged from a low of 6.3% in nursing home residents to highs 87.8% of occupants in a Boston homeless shelter, 87.9% on an obstetric service in New York City, and 96% of 3146 3,146 inmates in state prison systems in Arkansas, North Carolina, Ohio and Virginia. The three cohorts that came from representative samples of the population suggest the rate of asymptomatic infection is in the range of 40% to 45%. It appears that asymptomatic infection is more common in younger persons.126 A study that included over 85% of persons living in the Italian town of Vo' found that 42% of infections were asymptomatic. However, asymptomatic persons were shown to spread the infection and had similar viral loads to symptomatic persons.145
  • Infants and children
  • Infants and children generally have milder illness and a milder clinical presentation. In one series of 171 children with confirmed infection with COVID-19, 41% had fever, and 16% had no signs or symptoms. Only 3 required ICU support, all of whom had serious comorbidities (hydronephrosis, leukemia, and intussusception).29 See the Managing Special Populations section for a description of characteristics of children with the multisystem inflammatory syndrome.

Selecting Diagnostic Tests

  • PCR testing
  • Infection should be confirmed by PCR testing using a nasopharyngeal swab. The WHO provides guidance regarding how to prioritize testing when resources or supplies are limited.
  • Specimens for PCR testing should be obtained from the nasopharynx and oropharynx; if upper respiratory specimens are negative but clinical suspicion remains, obtain specimens from the lower respiratory tract as well (WHO interim guidance, May 27, 2020).
  • After brief training, 530 symptomatic patients were asked to collect tongue, nasal, and mid-turbinate samples, in that order. Afterwards, trained staff collected swab samples from the nasopharynx and at least one additional location. Using the staff-collected sample as “the gold standard,” self-collected samples were 90% sensitive (one-sided 97.5% CI 78 to 100.0) for tongue samples, 94% sensitive (97.5% CI 84 to 100.0) for nasal samples, and 96% sensitive (97.5% CI 87 to 100.0) for mid-turbinate samples.117 This study suggests that patient-collected samples are reasonably accurate and have the potential to decrease the frequency of exposing staff to potentially infectious material.
  • There are many reports of patients with an initially negative PCR who subsequently test positive. A Chinese study of PCR in patients with suspected COVID-19 and typical CT findings found a sensitivity of only 59%. It is not clear whether this low sensitivity is also a problem with the tests in North America and Europe.49
  • A study (preprint, non peer-reviewed) of 30 patients who had repeated PCR testing for COVID-19. They found that the sensitivity was highest at the time of symptom onset (>90%) but declined to 50% at 15 days and essentially 0% at one month.
  • A test awaiting FDA approval is 93% sensitive and 98% specific (LR+62, LR- 0.07) is simpler to perform and generates results in less than an hour. 182
  • In a Chinese study of 51 patients eventually diagnosed with COVID-19, 15 (29%) had a negative PCR but positive CT at initial presentation; PCR became positive for these patients over the next 1-7 days. Only one patient had a positive PCR and negative CT which became positive for viral pneumonia 3 days later.62
  • Saliva testing
  • Sensitivity for detection of SARS-CoV-2 appears to be similar in saliva as in nasopharyngeal swabs.18379 A Japanese study found that saliva was positive in 8 of 9 specimens positive by NP swab, and was negative in 66 of 67 samples negative by NP swab.139 A smaller Italian study with 25 patients found perfect agreement between salivary and NP sampling.140
  • A study from Yale University (preprint server, non peer-reviewed) took paired saliva samples with NP swabs from 29 inpatients every 3 days for a total of 121 samples. They found that viral titers using PCR were higher in saliva, with fewer false negatives. A total of 8 patients were negative using NP swab but positive using saliva, compared to only 3 who were positive using NP but negative using saliva. In 5 patients, NP swabs went from negative to positive over time, but this did not occur in the saliva samples of any patients.
  • Rutgers has received an emergency use authorization from the FDA for their PCR test for SARS-CoV-2 in saliva.
  • After brief training, 530 patients were asked to collect tongue, nasal, and mid-turbinate samples, in that order. Afterwards, trained staff collected swab samples from the nasopharynx and at least one additional location. Compared with samples collected by trained staff, the patient-collected specimens had high sensitivity (90-96%). 117
  • Antibody (IgG and IgM) tests
  • The FDA requires that antibody tests be at least 90% sensitive and 95% specific. These test characteristics lead to an unacceptably high false positive rate in low prevalence situations.
  • A meta-analysis identified 40 studies of IgG and/or IgM antibody tests for SARS-CoV-2. The overall risk of bias was high for almost all studies. Based on 15 studies of ELISA assays, they found the following test characteristics: sensitivity 84%, specificity 98%, LR+ 42, LR- 0.16. Based on 17 studies of lateral flow immunoassays, they found sensitivity 66%, specificity 97%, LR+ 22, LR- 0.35. Finally, based on 13 studies of chemiluminescent immunoassays they found sensitivity 98%, specificity 97% to 98%, LR+ 49, LR- 0.02. These values reflect testing 3 or more weeks following symptom onset.150
  • A rapid systematic review from the National Academies estimates that IgM can be detected a median of 5 days after symptom onset and IgG a median of 14 days (range 10 to 18 days) after symptom onset.
  • Researchers in New York (preprint server, non peer reviewed) in New York identified 624 patients with previous PCR confirmed SARS-CoV-2 infection who were volunteering to provide convalescent sera. All received an IgG test that was 92% sensitive and more than 99% specific. At the initial testing, 82% were strongly positive, 7% weakly positive, and 11% were negative. Strongly positive patients (IgG titer >1:320) were referred for donation of sera, while weakly positive or those who were initially negative for IgG returned at least a week later for retesting. Of those who were weakly positive or negative, 64 returned a median of 13 days later and at that time 57 were strongly positive, 4 weakly positive and 3 negative. The median duration from onset of symptoms to development of IgG antibodies is 24 days, with a range of 7 to 50 days. This suggests that the vast majority of patients develop a vigorous antibody response. Testing for IgG and IgM antibodies should be delayed until at least 3 weeks after symptom onset, repeated in 1 to 2 weeks if initially negative.
  • An Icelandic study tracked persons who had recovered from COVID-19, and found that antibody levels persisted for at least 4 months at high levels.177
  • Other blood tests
  • In early reports of hospitalized patients in Wuhan City, lymphocytopenia was common (83%). The median white cell count was 3700 in patients with severe disease and 4900 in those with non-severe disease. The median lymphocyte count was 800 in severe disease and 1000 in non-severe disease.15
  • C-reactive protein, d-dimer, interleukin-6, and LDH are commonly elevated. Lymphopenia and neutrophilia are commonly seen. These blood tests also serve as risk factors for poor outcomes.
  • A systematic review of 43 studies with 3600 Chinese patients found that the most common laboratory findings in patients sick enough to be admitted to hospital were elevated c-reactive protein (69%), elevated lactate dehydrogenase (52%) and elevated d-dimer (29%) (see Table 1).102
  • Imaging
  • A systematic review of 43 studies with 3600 Chinese patients found that he most common imaging findings in patients sick enough to be admitted to hospital were ground glass opacities on chest CT (80%) and bilateral pneumonia (73%). The absence of radiographic findings was reported in 18% with mild disease and 3% with severe disease in early reports.10215
  • Up to half of patients may have normal CT findings in the first 2 days after onset of flu-like symptoms. Early radiologic changes include peripheral focal or multi-focal ground glass opacities. Late radiologic findings may include crazy paving (ground-glass opacity with superimposed interlobular septal thickening and intralobular septal thickening) and consolidation peaking 9 to 13 days after onset of symptoms, followed by slow clearing over the next month.37
  • A retrospective review of CT scans in 21 Chinese patients without severe respiratory distress identified 4 stages: 1) early stage (0 to 4 days after onset) with ground glass opacities; 2) progressive stage (5 to 8 days) with rapid spread to involve multiple lobes with ground glass opacities, crazy-paving pattern, and consolidation; 3) peak stage (9 to 13 days) with increased findings and dense consolidation; and 4) absorption stage (14+ days) with consolidation gradually absorbed over the next month or more, with no further crazy-paving pattern.85
  • These radiographic findings may persist for a month after recovery. It is not clear at this point whether they will persist longer.17

Approach to the Patient

Treatment

Bottom Line

  • Treatment is primarily supportive, with clinical trials of antiviral drugs, anti-malarials, and other drugs ongoing.C
  • Corticosteroids have been shown in the UK recovery trial with 6425 patients to be highly effective at reducing mortality in patients with COVID-19 who are mechanically ventilated (NNT = 7) or who are on oxygen (NNT = 20) but not in hospitalized patients not requiring oxygen.161B
  • A single open-label RCT concluded that remdesivir shortens the duration of hospitalization from 15 to 11 days; there was a non-significant reduction in mortality as well (7.1% vs. 11.9%, p = 0.059).108B
  • Multiple randomized controlled trials have confirmed that hydroxychloroquine is not effective for severe disease, mild disease, early disease, or as post-exposure prophylaxis.105A

Drug Therapy

  • Sites to link patients with trials have been developed and are active.
  • IDSA guidelines recommend that chloroquine, hydroxychloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, and convalescent plasma only be used in the context of a clinical trial.
  • A regularly updated "living systematic review" concluded (9/11/20) that only glucocorticoids have been shown to reduce mortality and the need for mechanical ventilation, and that remdesivir decreased the duration of symptoms without causing harm.165
  • Antiviral drugs
  • The Adaptive COVID-19 Treatment Trial (ACTT) multicenter, multinational study recruited 1063 hospitalized patients with SARS-CoV-2 infection and evidence of lung involvement. They were randomized to remdesivir (200 mg IV on day 1 and then 100 mg IV daily for up to 10 days or hospital discharge) or matching placebo injection. The primary outcome was time to recovery, which was significantly faster in the remdesivir group (11 vs. 15 days, p <0.001). Clinical improvement was also more likely in the remdesivir group using a 7-category ordinal scale. There was also a trend toward lower mortality in the remdesivir group (7.1% vs. 11.9%, p = 0.059, NNT = 21). Harms or other outcomes such as need for mechanical ventilation were not reported. 108
  • Another study randomized 397 patients to 5 days or 10 days of therapy and concluded that there was no difference in the likelihood of clinical improvement. The study did not mask or conceal allocation, and as a result a larger number of sicker patients ended up in the 10-day group. In the unadjusted analysis the 5-day group did better, but this difference was no longer significant after adjusting for baseline differences.118
  • Chinese researchers randomly assigned 237 patients hospitalized with COVID-19 pneumonia and hypoxia who were within 12 days of symptom onset to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days in a 2:1 ratio. The treating teams were allowed to administer other therapies. In this study, there was no statistically significant improvement in time to recovery. While about ⅔ of patients in each group reported adverse events, more remdesivir-treated patients stopped treatment early due to adverse events than did placebo-treated patients (12% vs. 5%). They found no difference in mortality (12% vs. 13%). 109
  • A randomized trial in 199 hospitalized patients with severe COVID-19 infection found no benefit from lopinavir-ritonavir. There was no difference in time to clinical improvement (16 days median in both groups. There was a small but non-significant reduction in mortality in the treatment group (19.2% vs. 25.0%, p = NS).26
  • A study (preprint, not peer-reviewed) randomized 236 patients to favipiravir or arbidol. There was no difference between groups with regards to need for mechanical ventilation or clinical recovery at 7 days.
  • The Janus associated kinase inhibitor ruxolitinib 5 mg twice daily was studied in a small placebo-controlled randomized trial of 43 patients with severe COVID-19. The time to clinical improvement, assessed in a non-blinded manner, was 12 days in the treatment group and 15 days in the placebo group. There were 3 deaths in the treatment group and 0 in the placebo group. While perhaps promising, the small sample size makes it impossible to draw conclusions about efficacy.111
  • Monoclonal antibodies
  • Studies are underway using tofacitinib, a Janus kinase inhibitor, and other anti-inflammatory drugs, as well as efforts to develop monoclonal antibody-based drugs specific to SARS-CoV2.147
  • Corticosteroids
  • The UK RECOVERY trial randomized over 11,500 hospitalized patients with COVID-19 to one of 6 arms: azithromycin, lopinavir-ritonavir, tocilizumab, convalescent plasma, low dose dexamethasone (6 mg once daily for 10 days), or usual care. This study reports the results for the primary outcome of 28-day mortality between 2104 patients randomized to low dose dexamethasone and 4321 patients randomized to usual care. The primary outcome of 28-day mortality was significantly reduced overall (22.9% vs 25.7%, rate ratio 0.83, 95% CI 0.75-0.93, NNT = 36). The degree of benefit was strongly associated with the severity of illness. For patients requiring mechanical ventilation mortality reduction was greatest (29.3% vs 41.4%, RR 0.64, 95% CI 0.51-0.81, NNT = 8), while patients requiring oxygen but not mechanically ventilated benefitted somewhat less (23.3% vs 26.2%, RR 0.82, 95% CI 0.72-0.94, NNT = 35). No benefit, and in fact a trend toward harm, was observed for hospitalized patients not requiring oxygen or mechanical ventilation (mortality 17.8% vs 14.0%, RR 1.19, 95% CI 0.91-1.55). 161
  • The efficacy of corticosteroids for reducing mortality in patients requiring mechanical ventilation or oxygen was also supported by a meta-analysis of 7 trials with over 1700 patients.172
  • A retrospective cohort of patients with ARDS found a lower risk of death with methylprednisolone (46% vs. 62%), but the analysis did not control for possible confounders and only included 84 patients.20
  • The REMAP-CAP trial randomized 384 patients to fixed dose hydrocortisone, shock dependent dosing of hydrocortisone, or no cortisone. The mean organ support-free days was 11.5 days for the fixed dose hydrocortisone group, 9.5 days for the shock-dependent hydrocortisone group and 6 days for the no hydrocortisone group.171
  • WHO suggests that corticosteroids may be considered for patients with COVID-19 and sepsis or septic shock, a conditional recommendation that preceded the results of the RECOVERY trial.23
  • The Infectious Disease Society of America guidelines do not recommend corticosteroids for treating patients with COVID-19 pneumonia (conditional recommendation based on low certainty evidence). It recommends that their use be considered for patients with COVID-19 and ARDS.
  • Antibiotics
  • There is insufficient evidence to recommend azithromycin for treatment of COVID-19; trials are ongoing.
  • For patients who are mechanically ventilated and in respiratory failure, Surviving Sepsis Campaign guidelines recommend that empiric antimicrobial therapy be considered based on expert opinion.
  • Anticoagulants and antiplatelet agents
  • Among 2,773 COVID patients hospitalized in New York City, 786 patients received systemic anticoagulation (SAC). After adjusting for important confounders, there was no overall survival benefit of SAC (22.5% vs. 22.8%). However, for patients treated with SAC who required mechanical ventilation (N = 395) receiving SAC was associated with a much lower mortality rate (29.1% vs. 62.7%, p <0.05, NNT = 3). Significant bleeding was slightly more common with anticoagulation (3.0% vs. 1.9%). These results suggest that ventilator-requiring COVID-19 patients may benefit substantially from anticoagulation.88
  • Another observational study also found an association between heparin use and decreased mortality but only in patients with an elevated sepsis score (40 vs. 64%, p = 0.03, NNT = 4) or d-dimer greater than 6x upper limit of normal (33% vs. 52%, p = 0.02, NNT = 5).89
  • Chloroquine and hydroxychloroquine
  • There was initially interest and widespread use of hydroxychloroquine (HCQ) for COVID-19. However, randomized trials to date have all been negative, with no effect on mortality, viral shedding, or symptom duration.95 and well-designed observational studies have also failed to find any benefit. However, they do find harm, primarily prolonged QT intervals and cardiac arrhythmia and in some cases increased mortality.
  • Randomized trials of HCQ
  • The UK RECOVERY Trial (preprint server, not peer reviewed) randomized hospitalized patients to HCQ (n=1561) or usual care (n=3155). Patients in the HCQ group got two 800 mg loading doses 6 hours apart, followed by 400 mg twice daily for up to 9 days. There was no difference between groups with regards to 28-day mortality (26.8% HCQ vs 25.0% usual care, rate ratio 1.09, 95% CI 0.96-1.23). Patients in the HCQ group had a longer time to hospital discharge (16 vs 13 days) and were less likely to be discharged alive within 28 days (60.3% vs. 62.8%, RR 0.92, 95% CI 0.85-0.99, NNT = 40). Patients in the HCQ group were also more likely to experience the combined outcome of mechanical ventilation or death (29.8% vs. 26.5%, RR 1.12, 95% CI 1.01-1.25, NNT = 30).
  • A Brazilian study randomized 665 hospitalized patients to HCQ (400 mg twice daily), HCQ plus azithromycin 500 mg daily, or usual care. Of 665 patients, 504 had confirmed COVID-19 and made up the primary study population. They found no difference between groups for any outcomes including length of stay or mortality (although there were only 2 deaths).149
  • A Spanish study randomized 293 outpatients with onset of symptomatic COVID-19 less than 5 days previously to HCQ 800 mg on day 1 and 400 mg once daily for 6 more days. There was no difference in viral loads at 3 and 7 days, or in symptoms or days to resolution. Adverse events were more common in the HCQ group.157
  • A US study randomized symptomatic outpatients with confirmed or suspected COVID-19 (mostly epidemiologically linked cases) to HCQ 800 mg loading dose followed by 600 mg per day for 4 days or placebo. There was no difference between groups in symptoms duration or severity, hospitalizations, or deaths.158
  • A Chinese study randomized 150 hospitalized patients with largely mild/moderate COVID-19 to HCQ 1200 mg loading dose on days 1 to 3, followed by 800 mg daily for 11 more days plus usual care or usual care alone. There was no difference in negative seroconversion rates at multiple timepoints, no difference in symptom alleviation at 28 days, and no difference in median time to symptom alleviation (19 vs. 21 days). There were more adverse events in the HCQ group (30% vs. 9%, most commonly diarrhea).95
  • A pilot study published in the Journal of ZheJiang University (not in PubMed) randomized 30 patients with COVID-19 infection of unknown severity to hydroxychloroquine (HCQ) 400 mg per day for 5 days + usual care versus usual care only. At 7 days, there was no difference in the rates of negative viral swabs by PCR (87% in the HCQ group versus 93% in the control group). There was also no difference regarding incidence of severe disease (1 patient in the HCQ group and none in the usual care group), time to discharge, and time to being afebrile.
  • Observational studies of HCQ
  • A French study evaluated nasal swabs in 11 patients treated with HCQ and azithromycin. One died, and nasopharyngeal swabs remained positive in 8 out of 10 patients 5 to 6 days after treatment initiation.52
  • A French observational study compared 84 patients receiving HCQ with 89 who did not, adjusting for known confounders using propensity score matching. They found no difference in any clinical outcomes.96
  • Researchers identified 97 patients who had been given hydroxychloroquine (HCQ), 113 who had been given HCA plus azithromycin (AZ), and 158 who had not received HCQ at US VA hospitals. They used propensity score matching to identify patients who looked similar other than whether or not they received HCQ (or HCQ + AZ) and one had not received HCQ. In the unadjusted analysis, the risk of death was 19.9% in the HCQ alone group, 25.7% in the HCQ+AZ group, 10.0% in the no HCQ group, and 12.7% in those receiving neither drug. After propensity score matching, there was no difference in mortality between groups. There was an association between use of HCQ plus azithromycin with an increased risk of cardiac arrest (adjusted OR 2.13, 95% CI 1.12 - 4.05).91
  • A large observational study of 1376 patients hospitalized in New York with COVID-19 did propensity score matching to compare those receiving HCQ (59%) with those who did not. They analyzed the data several different ways but found no association between HCQ use and need for intubation or death.87
  • A multi-center, retrospective observational study included 2,541 hospitalized patients in Detroit with COVID-19. In-hospital mortality was lower among those receiving HCQ + azithromycin (157/783 [20.1%; 95% CI 17.3%-23.0%]) or HCQ alone (162/1202 [13.5%; 95% CI 11.6%-15.5%]) compared to azithromycin alone (33/147 [22.4%; 95% CI 16.0%-30.1%]) or neither drug (108/409 [26.4%; 95% CI 22.2%-31.0%]). The hazard ratio for HCQ alone vs. neither drug was 0.34 (95% CI 0.25-0.46).148
  • Harms of HCQ
  • A Brazilian study randomized 81 patients to high-dose chloroquine (600 mg twice daily for 10 days) or low-dose chloroquine (450 mg twice daily on day 1 and once daily on days 2 to 5). The high-dose group had a high rate of prolonged QT (25%) and a trend toward higher mortality than the low-dose group and overall mortality similar to historical control rates of death in untreated patients.141
  • A living systematic review in BMJ confirmed an increased risk of adverse events with HCQ.165
  • Guidance from American College of Cardiology regarding HCQ: withhold if QTc >500 msec or known congenital long QT syndrome; monitor QT interval, withdraw if >500 msec; correct hypokalemia to >4 mEq/L and hypomagnesemia to >2 mg/dl; avoid other QT prolonging agents if feasible.57
  • Bacillus Calmette-Guerin (BCG) and MMR vaccination
  • In Israel, BCG was no longer routinely administered after 1982. A study compared COVID-19 infection rates in patients born 3 years before and 3 years after this cutoff, and found no difference in infection rates (11.7% vaccinated vs. 10.4% unvaccinated).90
  • Based on homology of genetic sequences between rubella (and to some extent measles and mumps) viruses, it has been proposed that MMR vaccination may be protective. Ecologic data comparing highly vaccinated populations such as Hong Kong and populations with low rates like Belgium suggest an association. However, this evidence is quite preliminary with no patient level observational data (preprint server, not peer-reviewed).
  • Other medications
  • In a small Greek trial, 105 hospitalized COVID-19 patients were randomized to receive colchicine or standard medical therapy for up to 3 weeks. The primary clinical outcome was time from baseline to clinical deterioration, defined as a 2-grade deterioration on a 7-point ordinal scale. Mean event-free survival time was 18.6 days in the control group vs 20.7 in the colchicine group (log rank P = .03). Fewer patients in the colchicine group had clinical deterioration (1.8% vs. 14%, p = 0.02). A larger trial is needed to see if colchicine leads to meaningful clinical benefit for COVID-19 patients.137
  • A formulation of vasoactive intestinal peptide (VIP) called aviptadil is in Phase 1 trials for treatment of severe COVID-19, following case reports of benefit.
  • ACE inhibitor and angiotensin receptor blockers
  • Because the SARS-CoV2 virus binds human angiotensin converting enzyme (ACE)-2 receptors, it has been hypothesized that the increased risk in patients with hypertension may be due to use of ACE inhibitors increasing the number of these receptors.33 Others hypothesize that ACE inhibitors and angiotensin receptor blockers (ARBs) might be useful as therapy.4632Current guidance recommends continuing ACE inhibitors and ARBs in patients with COVID-19 infection.
  • A case-control study in Spain matched 1139 patients with COVID-19 taking ACEI or ARB each with 10 controls taking other anti-hypertensives. There was no difference between groups with regards to the likelihood of requiring hospital admission.101
  • Among 18,472 patients who had COVID-19 testing at the Cleveland Clinic, 1735 (9.4%) tested positive. The researchers performed a propensity-weighted analysis to attempt to adjust for known confounders, comparing those on ACEI/ARB with those not taking one. While patients taking an ACEI had a slightly lower risk of infection and patients taking an ARB had a slightly higher risk of COVID-19, the differences were small and not statistically significant. However, patients on ACEIs were more likely to be hospitalized (OR 1.8, 95% CI 1.2-2.8) or go to the intensive care unit (ICU, OR 1.8, 95% CI 1.1-2.9). While patients taking ARBs were also at higher risk of hospitalization (OR 1.6, 95% CI 1.04-2.5), there was no association with going to the ICU. The use of ACEIs or ARBs was not associated with the use of mechanical ventilation.119
  • Among 12,594 patients in New York who were tested for COVID-19, 5894 (46.8%) were positive and 1002 (17.0%) had severe illness. Antihypertensive medication (ACEI, ARB, beta-blockers, calcium-channel blockers, or thiazide diuretics) use was higher in the COVID-infected patients than in those who tested negative. However, using a propensity analysis to account for known confounders, the authors found no association between any antihypertensive class and contracting COVID-19 or in the risk of having severe disease.80
  • A Danish cohort study found no difference in COVID-19 mortality among 4480 patients when comparing those taking vs not taking an ACEI or ARB after adjusting for age and comorbidities. In fact, the non-significant trend was for lower mortality in ACEI/ARB users (hazard ratio 0.83, 95% CI 0.67 - 1.03). The same researchers also found no difference in the likelihood of becoming infected in a nested case-control study with 571 COVID-19 patients compared to 5710 age and sex matched controls.131
  • In a retrospective, single institution study in Wuhan, China, 126 patients with COVID-19 and preexisting hypertension, of whom 43 were on ARBs/ACEIs, were age- and sex-matched to 125 patients with COVID-19 patients without hypertension. Patients with hypertension appeared to be more likely than those without to have critical illness (18.3% vs. 11.2%) and die in hospital (10.3% vs. 6.4%), but these differences were not statistically significant. Among those with hypertension, the group on ARBs/ACEIs compared to those on other agents had a marginally lower proportion of critical patients (9.3% [4 of 43] vs. 22.9% [19 of 83]; p = 0.061) and a lower but not statistically different death rate (4.7% [2 of 43] vs. 13.3% [11 of 83]; p = 0.283) despite similar blood pressures. Interestingly, patients in the ARBs/ACEIs group had significantly lower concentrations of C-reactive protein and procalcitonin than those with hypertension on other agents. 84

Other Treatment

  • Guidelines are available from the World Health Organization, Infectious Disease Society of America, and Massachusetts General Hospital.
  • Guidance for using telehealth consultations was published in BMJ and includes a suggested algorithm.59 CDC also provides guidance for telehealth consultations.
  • Oxygen supplementation
  • Adults: Give supplemental oxygen to patients with severe acute respiratory infection (SARI) and respiratory distress, hypoxemia or shock, with a target O2 of >94% (WHO interim guidance March 13, 2020).
  • Children: Give supplemental oxygen with target O2 of >90%. If emergency signs such as obstructed breathing or apnea, severe respiratory distress, central cyanosis, shock, coma or convulsion provide airway management and oxygen to target O2 >94%. (WHO interim guidance 3/13/2020).
  • The Surviving Sepsis Campaign Guidelines recommend supplemental oxygen if SpO2 <90% and to maintain it at no higher than 96%. If needed, high flow nasal cannula is recommended over noninvasive positive pressure ventilation depending on availability.
  • Use of prone positioning appears to improve oxygenation in patients with COVID-19 who are in respiratory distress, preventing the need for intubation and mechanical ventilation in many patients.142 Randomized trials are lacking.77 Use of home pulse oximetry should be considered, if available, for patients recovering from COVID-19 at home as hypoxic patients do not always feel dyspneic and may wait too long at home before coming in for help.
  • Clinical trials to evaluate nitric oxide as a treatment for patients with COVID-19 and ARDS are underway, as well as trials to evaluate the efficacy of nitric oxide inhalation for healthcare personnel to prevent infection.
  • Convalescent plasma
  • Use of convalescent plasma from recovered COVID-19 patients has been proposed but remains untested. Studies in patients recovering from MERS-CoV found that they did not have enough antibodies to be useful for therapeutic use.30
  • An underpowered open-label trial in China randomized 103 hospitalized patients to receive convalescent serum or usual care. The study was terminated after seven days of no new cases in the participating centers. While clinical improvement was observed in 52% of treated patients compared with 43% of controls, this was not statistically significant. Among the 46 patients with severe COVID infections, clinical improvement occurred significantly more often with convalescent plasma (91% vs. 68%, p = 0.03, NNT = 5). Overall, the 28-day mortality rate was lower in the treated patients than in the controls (15.7% vs. 24.0%, respectively) but this relatively large difference was not statistically significant.120
  • A case series identified 5 patients with severe COVID-19 pneumonia and ARDS who were mechanically ventilated with PaO2/FIO2 <300. They were all given convalescent plasma; fever resolved in 4 of 5 within 3 days, and ARDS resolved in 4 of 5 12 days after the transfusion. At the time of writing, 3 had been discharged from the hospital and 2 were in stable condition. While promising, clinical trials are needed given the small number of patients and uncontrolled design.70
  • A report on a large series of critically-ill patients who underwent treatment with convalescent sera for COVID-19 found that safety was excellent. In 5000 patients, they found only 36 serious adverse events in the four hours after transfusion (0.7%), including 4 deaths, 11 episodes of transfusion related acute lung injury, and 7 cases of transfusion-associated circulatory overload. Only 2 of the 36 events were definitely felt to be related to the transfusion by the treating physician.143
  • Stem cell therapy
  • Several companies are investigating stem cell therapy with trials getting underway.
  • Sepsis and shock
  • See detailed recommendations in the WHO interim guidance document and the Surviving Sepsis Campaign Guidelines.
  • Monitor patients for signs of clinical deterioration and sepsis. Monitor hematologic parameters and biochemistries as needed to monitor for complications such as acute hepatic or renal injury, shock, or acute cardiac complications. (WHO interim guidance 3/13/2020)
  • Avoid fluid overload by using conservative fluid management in patients with SARI but no evidence of shock. (WHO interim guidance 3/13/2020)
  • For acute management of shock, assess fluid responsiveness by measuring dynamic parameters, and use a conservative fluid strategy with balanced crystalloids over colloids or unbalanced crystalloids. Norepinephrine is recommended as the first-line vasopressor, with vasopressin or epinephrine as second line if norepinephrine is not available. (Surviving Sepsis Campaign Guidelines, March 26, 2020)
  • For patients with severe pneumonia complicated by sepsis, even if suspected of having COVID-19, appropriate empiric antimicrobials should be given promptly.
  • See WHO interim guidance for details regarding management of ARDS in the ventilated patient, including prone ventilation if severe ARDS and using lower tidal volumes (4 to 8 ml/kg predicted body weight) and lower inspiratory pressures (plateau pressure less than 30 cm H20).
  • The Surviving Sepsis Guidelines generally agree with the WHO interim guidance regarding management of ARDS in ventilated patients, noting that a higher PEEP is recommended over lower PEEP strategy. If severe ARDS and continued hypoxemia, a trial of an inhaled pulmonary vasodilator can be considered, as well as referral to an ECMO center if available.
  • Test of cure
  • For outpatients: When ample testing supplies are available, patients may be considered cured using a test-based strategy: clinically recovered (no fever without use of antipyretics and no cough or dyspnea) plus two negative PCR tests 24 hours apart. A symptom-based strategy omits PCR testing but recommends that isolation be maintained for at least 10 days after illness onset and at least 3 days (72 hours) after recovery. The CDC defines recovery as resolution of fever without the use of fever-reducing medications with progressive improvement or resolution of other symptoms. (CDC interim guidance)
  • For hospitalized patients: A test-based strategy as described above is recommended, with recovery from fever without antipyretics, recovery from respiratory symptoms, and two negative PCR tests at least 24 hours apart. (CDC interim guidance)
  • A briefing paper from the National Academies of Medicine and Sciences suggested two sequential negative PCR tests be used to indicate that virus is no longer being shed.

Prognosis

Bottom Line

  • Overall prognosis
  • Approximately 85% experience a mild illness, while 15% experience a severe disease requiring hospitalization, including 5% who require ICU admission.54 22
  • In a report of the initial 41 confirmed cases of COVID-19 in Wuhan, China, days from illness onset to dyspnea in 21 patients was 8 days (5.0-13.0) and to ARDS, occurring in 11 patients, was 9 days (8.0-14.0).41
  • Viral shedding persisted a median of 20 days in hospitalized patients who recovered, and as long as 37 days.18
  • In a retrospective cohort study of 191 adults hospitalized in Wuhan, China with confirmed COVID-19 infections who had been discharged or had died by January 31, 2020, 72% were discharged and 28% died as inpatients.18
  • Based on modeling by the COVID-19 research unit at Imperial College in London, the infected fatality ratio is estimated to be 0.9% overall (95% credible interval 0.4% to 1.4%). It is lowest in children (0.002%), and is higher with increasing age (0.08% for 30 to 39, 0.60% for 50 to 59, 2.2% for 60 to 69, 5.1% for 70 to 79 and 9.3% for 80 and older). Mortality is also higher in those with comorbidities such as hypertension, diabetes and chronic cardiopulmonary conditions. It is important to note that any estimates of fatality ratios during a pandemic will be in accurate and should be considered preliminary.
  • The same group published a more detailed and updated report on March 30. They provide updated estimates of the infection fatality ratio (IFR, deaths/all infections including mild and asymptomatic) and the case fatality ratio (CFR, deaths/symptomatic or confirmed infections). They estimate a mean duration from symptom onset to death of 18 days, and for survivors the time from symptom onset to hospital discharge of 25 days. They do a good job of trying to adjust for biases in the data due to oversampling of severe cases early in a pandemic, failure to adjust for age, and the lag between case identification and death. The overall IFR is estimated to be 0.66%, and the overall CFR 1.38%. The CFR increases from 0.06% for those in their 20’s to 0.15% in their 30’s, 0.30% in their 40’s, 1.3% in their 50’s, 4.0% in their 60’s, 8.6% in their 70’s, and 13.4% for those 80 and older. The proportion hospitalized increased from 1% for patients in their 20’s to 4% in their 40’s to 12% in their 60’s.65
  • These estimates are likely to change as the epidemic evolves, as there is currently incomplete case ascertainment, especially in the US, and likely underreporting of deaths as well. Data from Italy and China found similar case-fatality rates when stratified by age, with the exception of a higher rate in Italy for those 80 years and older. Since data were not reported for those 90 and older in China, this could still represent an effect of greater age in Italy within this group.
  • Based on data from the 10 influenza pandemics over the past 250 years, a report from the National Academies of Sciences concludes that a second peak wave occurred approximately 6 months after emergence of the virus in the human population regardless of when it first emerged in the northern hemisphere.
  • In the UK, standardized mortality rates were less than 1.0 in whites and were higher in persons of Black African (SMR 3.2), Black Caribbean (2.2), Pakistani (3.3), Indian (1.7), and Bangladeshi (2.4) origin.103
  • A study comparing mortality rates for Black and White patients in Louisiana found that after adjusting for severity at presentation, age, comorbidities and socioeconomic factors there was no difference in case fatality ratios.107 A second larger study in a US 92 hospital system similarly found no difference in mortality after adjusting for age, sex, insurance status, comorbidity, neighborhood deprivation, and site of care (HR for Black vs White 0.93, 95% CI 0.83-1.09).164
  • A study of 800 patients with active cancer, of whom one third were not receiving active treatment, found no association between active therapy and mortality. As in other populations, age and comorbidities increased the risk of death.106
  • The CDC summarized over 1.7 million cases and over 100,000 deaths due to COVID-19 from January 22 through May 30, 2020 in the MMWR. The CDC had sufficient information on 287,320 individuals regarding chronic diseases. Cardiovascular disease was present in 32% of cases, diabetes in 30% and chronic lung disease in 18%. Of all 1.7 million patients reported to the CDC during this time period, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an ICU and 71,116 (5%) died. The hospitalization rate was six times higher among patients with a chronic disease (45.4% vs. 7.6%) and the death rate was twelve times higher (19.5% vs. 1.6%).
  • Persistence of symptoms
  • In an Italian study, patients who had been hospitalized for COVID-19 but now met criteria for discontinuing quarantine were invited to attend a COVID-19 follow-up clinic. Of 179 eligible patients, 143 agreed to participate and were still PCR negative. Patients were a mean of 60 days post symptom onset, and 32% reported 1 or 2 symptoms and 55% reported 3 or more persistent symptoms; fully 44% reported a clinically significant decline in a quality-of-life scale compared to their pre-COVID-19 state. The most common post-COVID-19 symptoms at follow-up were fatigue (53%), dyspnea (43%), joint pain (28%), chest pain (22%), cough (17%), and anosmia (16%). 144
  • Reinfection
  • The first known case of re-infection was reported in August 2020 of a 33-year-old man who became ill with COVID-19 4½ months after his initial infection; this second illness was milder. Viral sequencing of the two viruses did not match.
  • Biomarkers and risk factors
  • Laboratory tests that are risk factors for severe disease or death in COVID-19 include elevated c-reactive protein, lactate dehydrogenase, procalcitonin, d-dimer and neutrophils, and decreased leukocyte count.
  • A clinical prediction rules developed and validated in China incorporates 10 predictor variables to predict critical illness in hospitalized COVID-19 patients. The area under the ROC curve was 0.88 in both derivation and validation groups. An online version is available.94
  • A risk score from an English consortium studying hospitalized patients includes age, sex, comorbidities, respiratory rate, O2 saturation, Glasgow Coma Scale, BUN, and CRP to place patients into 4 risk groups with increasing mortality: 1.2%, 9.9%, 31.4%, and 61.5%.176
  • Based on early data from Wuhan City, China, adverse risk factors for mortality include increasing age (OR 1.1 per year, 95% CI 1.03-1.17), a higher SOFA score, d-dimer greater than 1 mcg/L on admission, and comorbidities including hypertension, diabetes, and cardiopulmonary disease.18 A second series of 201 patients from Wuhan City found that neutrophilia, lymphopenia, elevated LCH, increasing age, elevated c-reactive protein, and low albumin were risk factors for progression to ARDS.20
  • Among 5700 consecutive hospitalized patients with COVID-19 in New York, the median age was 63 years, 60% were men, 34% had diabetes, and 42% were obese. At the time of admission, only 28% were receiving supplemental oxygen and only 31% were febrile. At the end of the study period, 21% had died, 14% required ICU care, of 12% mechanical ventilation (of whom 88% died).66
  • A systematic review warned that many of the prognostic modeling studies are of poor methodologic quality. They concluded that increasing age, male sex, CRP, LDH, and lymphopenia are the most widely reported risk factors for poor prognosis.53
  • Complications
  • ARDS is the most important complications of infection with SARS-CoV-2.
  • A study in Lombardy region of Italy compared rates of out of hospital cardiac arrest from 2/21/20 to 3/31/20 with the same period in 2019. There were 362 cases in 2020 compared with only 229 in 2019, a 58% increase.93
  • Cardiovascular complications
  • Stroke complicated COVID-19 in 5.9% of patients in Wuhan, China. These patients were older, had more cardiovascular co-morbidities, and more severe pneumonia. In the US, stroke accompanying COVID-19 infection is now being reported in young and middle-aged patients, many of whom were otherwise healthy.
  • A case series reported findings regarding 5 persons with SARS-CoV-2 infection who presented during a 2-week period with a large vessel stroke (7 times the usual rate of stroke in persons under age 50 years). Their ages ranged from 33 to 49 years; 2 were healthy, one had hypertension and hyperlipidemia, one had undiagnosed diabetes, and one had diabetes and a history of mild stroke. The vessels involved include the middle cerebral artery in three, posterior cerebral artery in one, and internal carotid artery in one. All were treated with antiplatelet therapy, one with TPA, and 4 with clot retrieval. All but one experienced at least some improvement in their symptoms, and 3 had been discharged at the time the article was written. D-dimer levels were significantly elevated in three patients.67
  • A retrospective cohort study in New York compared the incidence of ischemic stroke in influenza patients between 2016 and 2018 (0.2%) with that in COVID-19 patients (1.6%), with an adjusted odds ratio of 7.6 (95% CI 2.3 - 25.2).136
  • In a study at Ohio State University, all athletes with COVID-19 were referred for cardiac MRI, echocardiogram, ECG, and troponin, and 27 agreed to participate. Twelve (46%) had mild symptoms and the remainder were asymptomatic. None had ECG evidence of myocarditis or elevated troponin I levels, and none had echocardiographic or MRI evidence of abnormal ventricular enlargement or dysfunction. Four athletes (15%), all male, however, had MRI evidence of myocarditis. Additionally, 12 athletes (46%) had late gadolinium enhancement, indicative of past myocardial injury or perhaps part of the athlete's heart syndrome.174
  • Thrombotic complications
  • Investigators studied the incidence of thrombotic complications of all 184 ICU patients with COVID-19 pneumonia hospitalized at 3 Dutch academic medical centers. 31% of the patients had thrombotic complications, including 27% with venous thromboembolism and 3.7% with arterial thrombotic events. Pulmonary embolism was the most frequent complication (25% of all patients). The investigators recommend that all patients with COVID-19 admitted to the ICU receive thrombosis prophylaxis. This is consistent with the observation that high levels of d-dimer are associated with a worse prognosis.69
  • A consecutive series of 3334 patients with COVID-19 hospitalized between March 1 and April 17, 2020 at NYU Langone Health Center was studied, of whom 829 were in the ICU and 2505 were not in the ICU. During this period most patients received thromboprophylaxis. Rates of PE were 6.2% in the ICU and 2.2% on the ward; for deep vein thrombosis rates were 9.4% in the ICU and 2.0% on the ward. Rates of stroke were 3.7% in the ICU and 0.9% on the ward, and for myocardial infarction were 13.9% in the ICU and 7.3% on the ward. These rates appear to be higher than with other respiratory infections.167
  • An observational study compared survival for 2773 in patients with COVID-19 who did and did not receive anticoagulation while hospitalized, adjusting for age, comorbidities including atrial fibrillation, and several other potential confounders. Overall 28% received systemic anticoagulation. They found no difference between groups with regards to mortality, but they did find that those who received anticoagulation were more likely to receive mechanical ventilation, but also were more likely to survive it. This study likely suffers from extensive unmeasured confounding and confounding by indication; a clinical trial is needed.88
  • A second study of 449 patients in Wuhan, China with severe COVID-19 found no difference in overall 28-day mortality. However, they did find an association between anticoagulant use and lower mortality in those with an elevated sepsis induced coagulopathy score (40% vs. 64%, p = 0.03, NNT = 4).
  • A case series from Bergamo, Italy reported an outbreak of Kawasaki-like disease in children. They compared 19 children diagnosed prior to 2/17/20 with 10 diagnosed since that time. The monthly incidence since 2/17/20 was 30x higher than previously, and children were older (mean 7.5 vs. 3.0 years) and sicker (more with shock, cardiac involvement, and need for adjunctive corticosteroids).92

Management of Special Populations

Pregnancy

  • To date, studies have found no evidence of the virus in breastmilk or amniotic fluid samples.2524
  • Two case series of 10 and 38 births respectively found no evidence of infection by PCR in the infants. Vertical transmission of infection therefore seems unlikely.3938
  • WHO interim guidance recommends that mother and infant be allowed to remain together and have skin to skin contact, regardless of whether they or their infant have COVID-19 infection.
  • A study 215 pregnant women who delivered in New York in late March or early April 2020 found that 13.5% were SARS-CoV2-positive but asymptomatic, and 1.9% were SARS-CoV2 positive and symptomatic.60
  • A study in a single UK hospital compared rates of stillbirth, preterm birth, cesarean delivery, or NICU admissions during the pandemic and during the same period one year before. Rates of stillbirth were significantly higher during the pandemic (6.98 vs.1.19 per 1000 births, p <0.05). The cause is not known, but the authors hypothesized it could be due to asymptomatic COVID-19 infection, worse prenatal care, or thrombotic complications affecting the placenta. The other outcomes did not increase during the pandemic.160
  • A systematic review concluded that pregnant women less likely to manifest COVID-19 symptoms but more likely to need intensive care than non-pregnant women.173

Infants and Children

  • Infants and children generally have milder illness and a milder clinical presentation. In one series of 171 children with confirmed infection with COVID-19, 41% had fever, and 16% had no signs or symptoms. Only 3 required ICU support, all of whom had serious comorbidities (hydronephrosis, leukemia, and intussusception).29
  • In an Italian case series of 100 childhood cases presenting to pediatric emergency departments, only 54% presented with fever, 44% with cough and 11% with shortness of breath. Mortality ranged from 0% to 0.6% in the Italian study and 4 other studies summarized by the authors. 81
  • A case series from China Table 1 identified 2,143 cases, of which 731 (34.2%) were laboratory confirmation cases and 1,412 (65.8%) suspected cases. Cases were initially identified based on clinical signs and symptoms and exposure history. The median age was 7 years. More cases were boys (56.6%) than girls (43.4%). Of the confirmed cases, 12.9% were asymptomatic, 43.1% mild, 41% moderate, 2.5% severe and 0.4% critical. Severe and critical cases were more prevalent in those under 1 year of age. On average, children were less severely ill compared to adult cases.73
  • A CDC report in MMWR of pediatric hospitalizations in 14 states from 3/1/20 to 7/25/20 found a rate of 8 hospitalizations/100,000 children. Highest rate was <2 years (25/100,000) and was much higher for Hispanic and Black children (16.4 and 10.5 per 100,000, respectively, compared to non-Hispanic White children (2.1 per 100,000). One in 3 hospitalized children required intensive care.
  • In a study of 91 children with COVID-19 identified by contact tracing in South Korea, 2% remained asymptomatic, 60% had respiratory symptoms, and 55% had non-specific systemic symptoms. Viral shedding was 14 to 20 days, longer in those who were more symptomatic.170
  • Multisystem inflammatory syndrome
  • A case series from Bergamo, Italy reported an outbreak of an inflammatory disorder in children that is similar to Kawasaki disease. They compared 19 children diagnosed prior to 2/17/20 with 10 diagnosed since that time. The monthly incidence since 2/17/20 was 30x higher than previously, and children were older (mean 7.5 vs. 3.0 years) and sicker (more with shock, cardiac involvement, and need for adjunctive corticosteroids).92
  • This syndrome is now referred to as multisystem inflammatory syndrome. Five case series describe the characteristics of children with this syndrome. Overall, 381 children were included in these studies, 115 (30%) were black, 276 (72%) had lab-confirmed COVID-19, and 143 (38%) also met criteria for Kawasaki Disease. Overall, 88% had gastrointestinal symptoms, 53% had nausea or vomiting and 58% had abdominal pain. Rash occurred in 60% of the children and desquamation, only reported in two studies, occurred in 7 of 28 (25%). Two-hundred twelve (56%) 36% had redness or swelling of the lips or mucous membranes. Coronary artery dilation occurred in 11% of the children, myocardial dysfunction in 32% and shock in 34%. Only three of the studies reported chest radiograph data; 101 of the 224 (45%) were abnormal.124125123

References and Additional Resources

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