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Coronavirus Disease 2019 (COVID-19)

Frank J. Domino, MD, Robert Baldor, Kathleen Barry, Jeremy Golding, MD and Mark B. Stephens, MD Reviewed 08/2020
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Subject: Coronavirus Disease 2019 (COVID-19)

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BASICS

DESCRIPTION

  • Coronavirus Disease 2019 (COVID-19) is a severe acute multi-system respiratory syndrome which was first detected in Wuhan City, Hubei Province, China.

  • The disease results from a novel virus, named coronavirus 2 (SARS-CoV-2).

  • The syndrome leads to multisystem complications including respiratory failure and death, particularly in elderly and immune-compromised individuals.

EPIDEMIOLOGY

Incidence

ALERT

A multisystem inflammatory syndrome (MIS-C) related to COVID-19, similar to Kawasaki disease (toxic shock syndrome), is reported in children. It is a "post-infectious immune response," associated with a positive test either for SARS-CoV-2 or for antibodies to the virus (2). https://emergency.cdc.gov/han/2020/han00432.asp

  • Common findings in MIS-C include the need for respiratory support, cardiovascular and clotting problems as well as gastrointestinal symptoms and skin rashes. Children with MIS-C often require intensive care (3).

 
  • Racial disparities are evident in the U.S., with African Americans being disproportionately impacted. Age-adjusted hospitalizations are highest among non-Hispanic, American Indian, Alaska Native and Black persons, followed by Hispanic or Latino individuals (4).

  • Prevalence: A Centers for Disease Control (CDC) study evaluated ~16,000 serum samples collected for non-COVID-19 reasons from 10 sites around the U.S. from Marc 23 to May 12. The seroprevalence of SARS-CoV-2 antibodies ranged from 1% in San Francisco to 7% in New York City. The authors estimate in Missouri, 24 times more people may have been infected than what was reported, and at other sites, estimates were 10 times higher than was reported (5).

ETIOLOGY AND PATHOPHYSIOLOGY

  • A novel (new) coronavirus (SARS-CoV-2) causes the coronavirus disease COVID-19.

  • SARS-CoV-2 is related to bat coronaviruses and to other Severe Acute Respiratory Syndrome (SARS) coronaviruses.

  • It is believed to evolve in animals including camels, cats, and bats.

  • Virology: SARS-CoV-2 is a positive-sense single stranded RNA virus (+ssRNA), a beta-coronavirus belonging to the same subgenus as the virus responsible for the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). The SARS-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE-2) receptor for cellular entry.

  • Initial spreading for this novel coronavirus appears to have come from a bat reservoir (6).

  • For over 95% of infected persons, symptoms appear within 11.5 days. Median incubation time to is about was 5.5 days (7).

  • Based upon data from the cruise ship Diamond Princess of 96 asymptomatic, infected people, just 11 developed COVID-19 symptoms at a median of 4 days after first PCR result. For patients who never developed symptoms, median time between first positive PCR and the first negative result was 9 days. By day 15 after the first positive result, 90% of the patients had resolved infection (defined as two negative PCR results), but the resolution took longer among older patients (8).

  • Retrospective cohort study found the median duration of viral shedding to be up to 20 days, with some cases as long as 37 days.

  • Symptoms develop because of viral effects on pulmonary tissue, and the associated immune response ("cytokine storm").

  • The virus affects the pulmonary and systemic vasculature, resulting in venous and arterial thrombosis including stroke, pulmonary embolism, and myocardial infarction, even in younger patients not normally considered to be at high risk for these problems.

  • Severe COVID-19 is associated with "hyperferritinemic syndrome" which includes: magrophage activation syndrome (MAS), adult-onset Still's disease (AOSD), catastrophic antiphospholipid syndrome (CAPS) and septic shock. This systemic reaction is characterized by high serum ferritin and a life-threatening hyper-inflammation sustained by a cytokines storm which eventually leads to multi-organ failure (9).

  • Presymptomatic is defined as being infected but not yet expressing symptoms. Asymptomatic COVID-19 infection is actually relatively rare, as most patients who are infected do develop some symptoms, but these are often minor and discounted by the patient.

  • A systematic review of 50,155 patients from 41 studies with confirmed COVID-19 found the rate of asymptomatic infection was 15.6% (95% CI: 10.1%-23.0%). Ten of the included studies identified rate of presymptomatic patients (were asymptomatic at screening and developed symptoms during follow-up) to be 48.9% (95% CI: 31.6%-66.2%). The pediatric rate of asymptomatic infection was found to be 27.7% (95% CI: 16.4%-42.7%), which is much higher than adult patients (10).

RISK FACTORS

  • Travel from countries of the world or specific regions that are experiencing outbreaks

  • The U.S. State Department issues travel bans and/or advisories as conditions change around the world, and advice can be found at https://travel.state.gov.

  • Spread primarily via respiratory droplets produced when an infected person coughs or sneezes

  • Risk factors for severe COVID infection include age over 65 or older, chronic kidney chronic obstructive pulmonary disease, obesity (BMI ≥ 30, risk of death: (OR = 1.71; 95% CI, 0.8-3.64) for BMI ≥ 35, risk of death: OR of 12.1 (95% CI, 3.25-45.1) (11), serious heart conditions (e.g. heart failure, coronary artery disease, cardiomyopathies), sickle cell disease, type 2 diabetes, and being immunocompromised after a solid organ transplant. The more of these conditions people have, the higher their risk. For pediatric patients, the CDC states: "Children who are medically complex, who have neurologic, genetic, metabolic conditions, or who have congenital heart disease are at higher risk for severe illness from COVID-19 than other children" (12).

  • Clinical risk factors for severe disease include chest radiography abnormality, age, hemoptysis, dyspnea, unconsciousness, number of comorbidities, cancer history, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and direct bilirubin; these can be evaluated using a web-based risk calculator (13).

  • Proton pump inhibitor (PPI) use was found to increase COVID-19 risk; an online survey in the U.S. of 53,130 adults found 6.4% reporting a positive COVID-19 test was 2.15 for once-daily PPIs and an odds ratio of 3.67 for twice-daily use. No such relationship was found with histamine-2 receptor antagonist use (14).

  • Blood group A: study comparing the genomes of ~1600 people with severe COVID-19 in Italy and Spain with controls found blood group A was associated with a 45% increased risk for COVID-19 respiratory failure, while blood group O was associated with a 35% lower risk (15).

  • Factors independently associated with an increased risk of in-hospital death were:

    • Age greater than 65 years (mortality of 10.0%, vs. 4.9% among those <65 years of age; odds ratio, 1.93; 95% confidence interval [CI], 1.60 to 2.41)

    • Coronary artery disease (10.2%, vs. 5.2% among those without disease; odds ratio, 2.70; 95% CI, 2.08 to 3.51)

    • Heart failure (15.3%, vs. 5.6% among those without heart failure; odds ratio, 2.48; 95% CI, 1.62 to 3.79)

    • Cardiac arrhythmia (11.5%, vs. 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33 to 2.86)

    • Chronic obstructive pulmonary disease (14.2%, vs. 5.6% among those without disease; odds ratio, 2.96; 95% CI, 2.00 to 4.40)

    • Current smoking (9.4%, vs. 5.6% among former smokers or nonsmokers; odds ratio, 1.79; 95% CI, 1.29 to 22.47)

ALERT

Pregnancy increases risk of ICU admission (1.5%) vs. non-pregnant (0.9%), and risk for mechanical ventilation 0.5% vs. 0.3%. Mortality rates are not different (16).

 
  • Pregnancy and breastfeeding do not increase vertical transmission. Researchers compared data on ~80 neonates whose mothers were SARS-CoV-2 positive. About 80% of these children roomed with their mother. Mothers wore surgical masks when near their infant and used good hand and breast hygiene. At 14 days, none of the neonates tested positive (17). A systematic review of pregnancy-related SARS-CoV-2 infection found the risk of maternal intensive care unit admission was 3.0% (critical disease diagnosis [defined as respiratory failure, septic shock, and multiorgan dysfunction or failure] was 1.4%), with no deaths reported. Rate of preterm birth was 20.1% (~10%-11% in non-infected births worldwide); the cesarean section rate was 84.7% (almost triple the baseline rate in the three included countries). Vertical transmission did not occur; rates of neonatal death was found to be 0.3% (18).

GENERAL PREVENTION

  • Population health:

    • Containment efforts (quarantine, universal testing, rapid identification of illness, contact tracing) are effective. When disease increases faster than containment can control (as in the U.S., Spain, Italy), mitigation strategies are initiated (hand hygiene, travel restrictions, school closures, and social distancing).

  • Hand washing, avoid others if ill, avoid touching face

    • Hand washing for 20 seconds with soap lowers viral carriage and lowers risk of transmission.

  • Social distancing:

    • Keeping six feet apart from others, closing of schools, workplaces, meetings, social and religious gatherings, and sporting events.

    • Data from Germany suggests that minimizing contact with others and closure of nonessential business is most effective at stopping the exponential spread of the virus (19).

    • Additional data using cell phone tracking in the U.S. found decreases in mobility were strongly associated with decreases in COVID-19 case growth. Social distancing is an "effective way to mitigate COVID-19 transmission in the USA. Until a COVID-19 vaccine is widely available, social distancing will remain one of the primary measures to combat disease spread" (20).

    • Transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 m (n=10 736, pooled adjusted odds ratio [aOR] 0·18, 95% CI 0·09 to 0·38; risk difference [RD] –11·5 to –7·5; moderate certainty).

    • Protection was increased as distance was lengthened (change in relative risk [RR] 2·02 per m; pinteraction=0·041; moderate certainty).

  • Wearing masks in public reduces risk of transmission to others (21,22).

    • Convert a medical mask to higher efficiency with 3 rubber bands to approximate the protection from an N95 mask: https://www.fixthemask.com/make-it#3-rubber-bands.

    • A mathematical modeling study found universal use of face masks decreases the effective reproduction number. Re can be decreased below 1 (meaning each infected person will infect less than one person), mitigating spread (23). The most effective method to prevent transmission is face mask use in public. Face masks are beneficial in preventing an ill individual from spreading the infection and in preventing well individuals from inhaling infectious particles and becoming ill.

    • Face mask use could result in a large reduction in risk of infection (n=2647; aOR 0·15, 95% CI 0·07 to 0·34, RD –14·3%, –15·9 to –10·7; low certainty), with stronger associations with N95 or similar respirators compared with disposable surgical masks or similar (e.g. reusable 12–16-layer cotton masks; pinteraction=0·090; posterior probability >95%, low certainty) (24).

    • Anecdotal report of two hair stylists who, while tested positive for SARS-CoV-2, but before their results came back, saw 139 customers while symptomatic. Of the 100 clients who were interviewed, 98% were also wearing face coverings. No clients developed symptoms (25).

    • Face masks plus social distancing, quarantine, and contact tracing are current efforts to fight the COVID-19 pandemic (26).

    • Researchers in Australia used high-speed cameras to evaluate respiratory droplets expelled during speaking, coughing, and sneezing. A 3-layer surgical mask was the most effective at limiting droplet spread, a 2-layer cloth cotton mask was more effective during coughing and sneezing than one made from a single layer, but even a single-layer mask was better than no mask (27).

  • Social isolation and quarantine:

    • Self-quarantine for all with symptoms of fever or new cough until symptoms resolve

    • Quarantine if exposed to confirmed COVID-19 infections reduces infections and deaths compared to no quarantine.

    • Quarantine of returning international travelers from high risk countries to prevent transmission and death has small benefit.

    • Combination of quarantine and prevention methods (sheltering, school and business closures, social distancing) had a greater effect on disease transmission, use of critical care and deaths compared to quarantine alone.

  • Use of gloves is not recommended for the general population as it may decrease patient hand hygiene and increase carelessness.

  • Exposure to a contaminated surface "is not thought to be the main way the virus spreads" (28).

  • Exposure risk: Children age 10-19 years have been found to spread SARS-CoV-2 to household members more readily than adults. Data from South Korea of ~60,000 contacts of 5700 COVID-19 index patients. Overall, 12% of household contacts were infected, versus 2% of non-household contacts. When the index patient was aged 10–19 years, 19% of household contacts were infected; when the index patient was 30–49, 12% of household members were infected; and when the index patient was 0–9 years, 5% of household contacts were infected (29).

ALERT

Close schools: National data on the rates of COVID-19 incidence and mortality across the USA after primary and secondary schools were closed in March 2020 found school closures were associated with a 62% decline in the incidence of COVID-19 per week (vs. a 265% per week before closures). The absolute reduction in COVID-19 incidence associated with school closures was estimated at 424 cases per 100,000 people during days 17–42 after closures. Regarding COVID-19-related mortality, school closures were associated with a decline of 58% per week after school closures. The absolute reduction was estimated at 13 deaths per 100,000 during days 27–42 after closures (30).

 
  • Vaccine data:

    • While multiple trials are underway, a vaccine is not currently available.

    • Strategies include nucleic-acid based vaccines and traditional recombinant technologies (31).

DIAGNOSIS

Office-based triage 
  • Screen all patients prior to facility entry (https://www.ama-assn.org/practice-management/sustainability/use-covid-19-screening-script-when-reopening-your-practice).

  • Establish Telemedicine protocol.

    • Telemedicine billing guidelines are available (https://www.ama-assn.org/practice-management/digital/ama-telehealth-quick-guide).

  • For those who come to the office:

    • Instruct patients who arrive to wear a surgical mask.

    • Maintain strict social distancing.

    • Remind parents who wish to have a child seen not to bring other family members into the office, and only bring in one child.

  • In general, patients with COVID-19 can be grouped into the following illness categories:

    • Asymptomatic or presymptomatic infection: individuals who test positive for SARS-CoV-2 but have no symptoms

    • Mild illness: individuals who have any of various signs and symptoms (e.g. fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnea, or abnormal imaging

    • Moderate illness: individuals who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SaO2) >93% on room air at sea level

    • Severe illness: individuals who have respiratory frequency >30 breaths per minute, SaO2 <93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50%

    • Critical illness: individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction

HISTORY

  • Many patients with COVID-19 have mild illness or no symptoms; some "asymptomatic test-positive cases" have been found to be pre-symptomatic, testing positive before onset of symptoms.

  • Of patients who develop symptoms, 95% will have symptoms appear within 11.5 days of exposure.

  • Common symptoms include: fever, shortness of breath/difficulty breathing, cough, shaking/chills, muscle pain, headache, sore throat, abdominal pain/diarrhea, and new loss (or alteration) of taste and smell (32).

  • Gastrointestinal symptoms (i.e. anorexia and diarrhea), loss of smell, taste, and fever were 99% specific for COVID-19 (a highly specific test, when positive) (33).

  • Most symptomatic cases mount a fever >38°C/100.4°F.

  • Some patients with severe COVID-19 disease who presented initially with milder illness and seeming improvement in the first week, went on to develop an abrupt pulmonary and systemic decompression theorized to be due to "cytokine storm."

  • Activate EMS if any of the following are present:

    • Extreme difficulty breathing (cannot talk without gasping for air)

    • Blue-colored lips or face

    • Severe or persistent pain or pressure in the chest

    • Severe constant dizziness or lightheadedness

    • Acting confused or unable to wake up

    • Slurred speech (new or worsening)

    • New onset seizure or seizures that will not stop

    • Painful red or purple lesions on fingers or toes in the winter (anecdotal)

ALERT

Risk factors for progression to acute respiratory distress syndrome (ARDS):

  • Age >65 years, neutrophilia, and organ or coagulation dysfunction (34)

  • Chronic lung disease, immunocompromise, obesity (35)

  • Hypertension and diabetes (36)

 

PHYSICAL EXAM

  • Mild-to-severe respiratory illness with fever, cough, dyspnea, and chest discomfort

  • Wheeze and rales are not typically found

  • Hypoxia. Pulse oximetry may reveal dramatic, relatively asymptomatic hypoxemia. Hypoxemia may be an early diagnostic clue of COVID-19 (37).

DIFFERENTIAL DIAGNOSIS

Influenza, other virally-mediated respiratory illness 

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

  • Priorities for testing include:

    • PRIORITY 1: Healthcare facility workers with symptoms

    • PRIORITY 2: Patients in long-term care facilities with symptoms, patients 65 years of age and older with symptoms, patients with underlying conditions with symptoms, first responders with symptoms

    • PRIORITY 3 as resources allow: critical infrastructure workers, individuals who do not meet any of the above categories with symptoms, healthcare facility workers and first responders, individuals with mild symptoms in communities experiencing high numbers of COVID-19 hospitalizations (38).

  • Testing options: molecular tests detect the SARS-CoV-2 viral RNA from nasopharyngeal and other respiratory specimens. Serological tests detect the presence of antibodies (IgG;IgM) produced by the immune system in response to the infection.

    • Molecular test: CDC 2019-Novel Coronavirus (2019-nCoV) RT-PCR diagnostic panel (specimens refrigerated at 2-8ºC)

      • Intended for use with upper and lower respiratory specimens collected only from persons who meet CDC criteria for COVID-19 testing

      • Nasopharyngeal swab AND oropharyngeal swab (use only synthetic fiber swabs with plastic shafts with a viral transport media), or oral swabbing AND nasal swabbing on a single swab

      • Systematic review of RT-PCR testing finds false negative rates of between 2% and 29% (sensitivity of 71% and specificity of 95%) for nasopharyngeal swab. As this test is highly specific, when positive, it rules IN disease. However, when negative, repeat testing should be obtained as it does not rule out disease (39).

        • The Abbott ID NOW point-of-care test for SARS-CoV-2 has been recently called into question, as it may have a high false-negative result; if positive, it can be assumed to be a true positive, but if negative, consider further testing (40).

    • Serologic testing for an immune response is best used to determine who has been exposed. Serologic tests are not designed to be diagnostic of infection, but rather as evidence of exposure.

      • The U.S. Food & Drug Administration (FDA) has stated that these tests should only be used by institutions collecting convalescent sera and not for diagnostic purposes (41).

      • Based upon a Cochrane Systematic Review, testing for IgG and IgM antibodies against SARS-CoV-2 found a sensitivity of just 30% during the first week of symptoms, increasing to 91% by the third week. Specificity was above 98%, a high rate of false negatives, but a positive is highly likely to be a true positive (42).

  • PCR tests are more accurate (have a higher sensitivity) but take longer. Antigen tests have a lower sensitivity but a high specificity (43).

  • Pooled testing: the FDA has issued an emergency use authorization for the Quest Diagnostics RT-PCR test for SARS-CoV-2 to be used with swab specimens pooled from up to four patients. The rationale for pooled testing is if the pool tests negative, all patients are considered negative; if it's positive, each individual sample needs to be retested, saving time and supplies (44).

  • Obtain coagulation studies and d-dimer on admission and closely monitor for signs consistent with deep vein thrombosis. Venous thrombosis has been found in over 70% of critically ill patients within 48 hours of hospitalization, despite being on anti-thrombosis prophylaxis since admission (45).

  • Deep vein thrombosis almost tripled mortality (46).

Follow-Up Tests & Special Considerations

ALERT
  • For worsening symptoms: chest X-ray, confirmatory CT scan. Early CT findings include peripheral ground glass opacities (GGO) which can progress to bilateral or multifocal pneumonia

  • Consider LDH, hsCRP and d-dimer as a baseline.

  • For patients whose symptoms progress from mild to moderate, severe or critical, consider obtaining and monitoring d-dimer, prothrombin time, platelet counts, fibrinogen.

    • Increased d-dimers are reported in patients with severe illness and may predict mortality.

    • A tripling of the d-dimer may predict worsening clinical course.

    • Fibrinogen should be monitored to predict disseminated intravascular coagulation (DIC); nonsurvivors with severe illness have developed DIC around day 4; significant worsening in those parameters at days 10 and 14 was also reported.

    • Prophylactic low-molecular weight heparin (unless there is active bleeding or a platelet count of <25x109/L) is suggested with the hope of lowering the impact of the septic-like coagulopathy and protecting against venous thromboembolism.

 

TREATMENT

GENERAL MEASURES

  • Resources for healthcare providers from the U.S. CDC can be found at: https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index/html.

  • Current data on critical care can be found at: https://journals.lww.com/ccmjournal/Fulltext/2020/06000/Surviving_Sepsis_Campaign__Guidelines_on_the.29.aspx.

  • Continuously updated guidelines from NIH based on severity of illness: https://www.covid19treatmentguidelines.nih.gov/whats-new/

  • Hospital infection prevention and control measures include use of personal protective equipment (PPE) for aerosol, droplet, and contact precautions (e.g. masks, face shields, gloves, gowns), including eye protection (e.g. face shields or goggles) and single-patient dedicated medical equipment (e.g. stethoscopes, blood pressure cuffs, thermometers). Limit the number of individuals and providers entering the room of a patient with COVID-19.

  • If necessary, hospitalized patients with confirmed COVID-19 may be cohorted in the same room. Airborne infection isolation rooms (AIIRs) should be used for patients who will be undergoing any aerosol-generating procedures. During the procedures, all staff should wear N95 respirators or powered, air-purifying respirators (PAPRs).

  • Respiratory/ventilatory support (recommendations of NIH updated June 2020):

    • For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel recommends high-flow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV).

    • For patients with persistent hypoxemia despite increasing supplemental oxygen requirements in whom endotracheal intubation is not otherwise indicated, the Panel recommends considering a trial of awake prone positioning to improve oxygenation.

    • The Panel recommends against using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation in patients who otherwise require intubation and mechanical ventilation.

    • For mechanically ventilated adults with COVID-19 and ARDS, the Panel recommends using low tidal volume (VT) ventilation (VT 4-8 mL/kg of predicted body weight) over higher tidal volumes (VT >8 mL/kg) (AI).

    • For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone ventilation.

ALERT
  • Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience a range of clinical manifestations, from no symptoms to critical illness. Currently, no FDA-approved drugs exist to specifically treat patients with COVID-19.

  • Treatment is not recommended for patients who are asymptomatic or presymptomatic. The proportion of infected individuals who remain asymptomatic or minimally symptomatic is high, and likely significantly exceeds the proportion of symptomatic patients.

  • Asymptomatic persons testing positive for SARS-CoV-2 should self-isolate. If they remain asymptomatic, they can discontinue isolation 10 days after the date of their first positive SARS-CoV-2 test. Individuals who become symptomatic should contact their healthcare provider for further guidance. Healthcare workers who test positive and are asymptomatic may obtain additional guidance from their occupational health service. See the CDC COVID-19 website for detailed information. No additional laboratory testing is currently recommended.

  • Mild illness

    • Mild illness can be defined by various signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath or dyspnea or abnormal imaging. Most mildly ill patients can be managed at home through telemedicine or remote visits.

    • Closely monitor all patients with symptomatic COVID-19 and risk factors for severe disease as some may rapidly progress.

    • No specific laboratory evaluations are indicated in otherwise healthy patients with mild COVID-19 disease.

    • There are insufficient data to recommend any specific medication or immunomodulatory therapies for patients with COVID-19 with mild illness.

  • Moderate illness

    • Moderate COVID-19 illness is defined by evidence of lower respiratory disease by clinical assessment, imaging with SpO2 >93% on room air at sea level. Given that pulmonary disease can rapidly progress, patients with moderate COVID-19 should be admitted for close observation. If bacterial pneumonia or sepsis is suspected, administer empiric antibiotic treatment for community-acquired pneumonia, reevaluate regularly. Deescalate or stop antibiotics when there is no evidence of bacterial infection.

    • There are insufficient data to recommend any antiviral or immunomodulatory therapy in patients with moderate COVID-19 illness.

  • Severe illness

    • Patients with COVID-19 are considered to have severe illness if they have SpO2 ≤93% on room air at sea level, respiratory rate >30, PaO2/FiO2 <300, or lung infiltrates in over 50% of lung fields. These patients may experience rapid clinical deterioration and will likely need to undergo aerosol-generating procedures. They should be admitted to the hospital and placed in AIIRs, if available. Administer oxygen therapy immediately using nasal cannula or high-flow oxygen.

    • If secondary bacterial pneumonia or sepsis is suspected, administer empiric antibiotics, reevaluate regularly, and if there is no evidence of bacterial infection, deescalate or stop antibiotics.

  • Critical illness

    • COVID-19 is primarily a pulmonary disease. Severe cases may be associated with ARDS, septic shock that may represent virus-induced distributive shock, cardiac dysfunction, elevations in multiple inflammatory cytokines that provoke a cytokine storm, and/or exacerbation of underlying comorbidities. In addition to pulmonary disease, patients with COVID-19 may also experience cardiac, hepatic, renal, and central nervous system disease.

    • Since patients with critical illness are likely to undergo aerosol-generating procedures, they should be placed in AIIRs when available.

    • Most of the recommendations for the management of critically ill patients with COVID-19 are extrapolated from experience with other life-threatening infections. Currently, there is limited information to suggest that the critical care management of patients with COVID-19 should differ substantially from the management of other critically ill patients, although special precautions to prevent environmental contamination by SARS-CoV-2 is warranted.

    • As with any patient in the intensive care unit (ICU), successful clinical management of a patient with COVID-19 depends on attention to the primary process leading to the ICU admission, but also to other comorbidities and nosocomial complications.

    • Proning is useful to reduce need for intubation and in intubated patients to reduce O2 requirement, as noted above.

ALERT

Patients with critical (requiring ventilation) COVID-19 illness and those requiring supplemental oxygen (severe disease) should receive dexamethasone as below (http://www.covid19treatmentguidelines.nih.gov/immune-based-therapy-immunomodulators).

 

MEDICATION

  • Oxygen

  • Hydration

  • Acetaminophen (max is 1,000 mg every 6 hours in patient without liver disease) given around the clock to address fever

  • Hospitalized adults with COVID-19 should receive VTE prophylaxis per the standard of care for other hospitalized adults (unless there is active bleeding or a platelet count of <25x109/L) is suggested with the hope of lowering the impact of the septic-like coagulopathy and protecting against venous thromboembolism (https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy-antithrombotic-therapy).

  • Those who develop thromboembolism should be managed with therapeutic doses of anticoagulant therapy as per the standard of care for patients without COVID-19.

  • Use of NSAIDs in addition to acetaminophen is controversial; there is no data showing they are problematic, but a theoretical rationale should make their use only if acetaminophen is inadequate to maintain fever control.

ALERT

Use of chloroquine or hydroxychloroquine, either alone or with azithromycin, should NOT be prescribed for outpatients. Experimental protocols with sicker inpatients are underway. Use in outpatients may well cause harm and decrease availability of medication for patients with known need (e.g., rheumatoid arthritis, systemic lupus erythematosus).

 
ALERT

Patients who have worsening symptoms with declining function should be admitted to the hospital for observation for further deterioration.

 

First Line

  • Antibiotics: for severely and critically ill patients, some start empiric broad-spectrum antimicrobial therapy for COVID-19 patients; for patients in shock, empiric broad-spectrum antimicrobial therapy is the standard of care. Antibiotic stewardship is critical to avoid reflexive or continued courses of antibiotics (https://www.covid19treatmentguidelines.nih.gov/critical-care/general-considerations/).

  • Dexamethasone: dexamethasone (at a dose of 6 mg per day for up to 10 days) for the treatment of COVID-19 in patients who are mechanically ventilated (AI) and in patients who require supplemental oxygen but who are not mechanically ventilated (NIH Guideline). Dexamethasone improves 28-day mortality compared to placebo in patients requiring IMV (NNT=8.5) and those patients requiring oxygen therapy (NNT=29). Dexamethasone is not recommended for milder disease and may be harmful.

  • Remdesivir: the NIH Panel recommends administering the investigational antiviral agent remdesivir for 5 days for the treatment of COVID-19 in hospitalized patients with SpO2 ≤94% on room air (at sea level) or those who require supplemental oxygen, and for patients who are on mechanical ventilation or ECMO. Recovery is shortened with remdesivir but no mortality benefit has been shown (47).

  • A large number of medications remain under investigation: antivirals, immunomodulatory medications, cytokine inhibitors, and other classes. The following medications are among the better-known examples of medications under investigation:

    • Lopinavir-Ritonavir (not likely to prove effective)

    • Hydroxychloroquine /chloroquine (not likely to prove effective in prophylaxis or in treatment) with or without azithromycin, and maybe harmful (prolonged QT and increased death)

      • Systematic review of hydroxychloroquine treatment of hospitalized COVID-19 patients did not reduce risk of death or illness vs. standard care. High dose regimens or when combined with macrolides may be associated with harm. Postexposure prophylaxis may not reduce the rate of infection, but the quality of evidence is low (48).

      • In outpatients with ≤4 days of COVID-19 symptoms (with either laboratory-confirmed SARS-CoV-2 infection or epidemiological link to a confirmed COVID-19 case), a randomized clinical trial studied 5 days of hydroxychloroquine or placebo. The treatment and placebo group outcomes were found to not differ in symptom-severity change, hospitalizations, or deaths. But, the hydroxychloroquine recipients had significantly more adverse effects (mostly GI) compared to placebo recipients (43% vs. 22%; number needed to harm, 5) (49).

    • Interferons

    • Monoclonal antibodies

    • Convalescent plasma (sera): promising benefit in terms of mortality and speed of recovery, but still preliminary. FDA has granted emergency authorization for use in patients critically ill with COVID-19. As of July 2020, NIH considers data to be insufficient to recommend for or against convalescent plasma.

ALERT

If you have a patient who has recovered from COVID-19, and is interested in donating plasma, go to https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma.

 

ISSUES FOR REFERRAL

For any patient meeting criteria for evaluation for COVID-19, clinicians are encouraged to contact and collaborate with their state or local health department. 

SURGERY/OTHER PROCEDURES

Depending on local case rates, elective procedures and surgeries may be postponed. COVID-19 testing is required pre-operatively for elective and emergent procedures. 

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

  • Review NIH Guidelines as above.

  • Any patient who has had a potential exposure and is ill should NOT enter an ambulatory healthcare facility; remain at home to allow quarantine. Maintain contact via telephone or telemedicine methods.

  • CDC recommends for patients aged ≥2 years to call 911 if any of the following are present:

    • Extreme difficulty breathing (cannot talk without gasping for air)

    • Blue-colored lips or face

    • Severe or persistent pain or pressure in the chest

    • Severe constant dizziness or lightheadedness

    • Acting confused or unable to wake up

    • Slurred speech (new or worsening)

    • New onset seizure or seizures that will not stop

ONGOING CARE

  • Anxiety of patients infected with coronavirus and their close contacts, along with the general population, remains high. Reassure those who test positive to monitor their symptoms and to contact you if they worsen.

  • CDC services include phone and text consultations for these issues at:

  • For the general population, offer support and tele-counseling sessions; some therapists are offering this service without charge.

  • Limit anxiolytics as they can compromise symptom recognition in patients who may become ill from any severe illness or infection.

FOLLOW-UP RECOMMENDATIONS

  • General population: On May 22, 2020, the CDC issued new guidelines on management of COVID-19 patients.

    • People with COVID-19 who experienced symptoms and isolated at home can leave home under the following conditions:

      • If there has not been a test to determine persistent infection, people can leave home after these three things have happened:

        • Afebrile for at least 72 hours (that is three full days of no fever without the use of medicine that reduces fevers) AND

        • Other symptoms have improved (for example, when your cough or shortness of breath have improved) AND

        • At least 10 days have passed since symptoms first appeared

      • If there has been a test to determine persistent infection people can leave home after these three things have happened:

        • Afebrile (without the use of medicine that reduces fevers) AND

        • Other symptoms have improved (for example, when cough or shortness of breath have improved) AND

        • There have been two negative tests in a row, at least 24 hours apart.

    • People who DID NOT have COVID-19 symptoms, but tested positive and have isolated at home can leave home under the following conditions:

      • If there has not been a test to determine persistent infection, people can leave home after these two things have happened:

        • At least 10 days have passed since the date of the first positive test AND

        • Symptoms have not appeared (no cough or shortness of breath) since the test

      • If there has been a test to determine persistent infection, people can leave home after:

        • There have been two negative tests in a row, at least 24 hours apart.

    • Note: if you develop symptoms, follow guidance above for people with COVID-19 symptoms (50).

  • Healthcare workers: On April 30, 2020, the CDC offered the following Return to Work guidelines, "Return to Work Criteria for HCP with Suspected or Confirmed COVID-19."

    • Symptomatic HCP with suspected or confirmed COVID-19

      • Either strategy is acceptable depending on local circumstances

        • Symptom-based strategy. Exclude from work until:

          • At least 3 days (72 hours) have passed since recovery defined as resolution of fever without the use of fever-reducing medications and improvement in respiratory symptoms (e.g., cough, shortness of breath); and,

          • At least 10 days have passed since symptoms first appeared

        • Test-based strategy. Exclude from work until:

          • Resolution of fever without the use of fever-reducing medications, and

          • Improvement in respiratory symptoms (e.g., cough, shortness of breath), and

          • Negative results of an FDA Emergency Use Authorized COVID-19 molecular assay for detection of SARS-CoV-2 RNA from at least two consecutive respiratory specimens collected ≥24 hours apart (total of two negative specimens). See Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for 2019 Novel Coronavirus (2019-nCoV). Of note, there have been reports of prolonged detection of RNA without direct correlation to recovery of live, infectious virus from viral culture.

    • HCP with laboratory-confirmed COVID-19 who have not had any symptoms

      • Either strategy is acceptable depending on local circumstances

        • Time-based strategy. Exclude from work until:

          • 10 days have passed since the date of their first positive COVID-19 test assuming they have not developed symptoms since their positive test. If they develop symptoms, then the symptom-based or test-based strategy should be used. Note, because symptoms cannot be used to gauge where these individuals are in the course of their illness, it is possible that the duration of viral shedding could be longer or shorter than 10 days after their first positive test.

        • Test-based strategy. Exclude from work until:

          • Negative results of an FDA Emergency Use Authorized COVID-19 molecular assay for detection of SARS-CoV-2 RNA from at least two consecutive respiratory specimens collected ≥24 hours apart (total of two negative specimens). Note, because of the absence of symptoms, it is not possible to gauge where these individuals are in the course of their illness. There have been reports of prolonged detection of RNA without direct correlation to viral culture.

    • Note that detecting viral RNA via PCR does not necessarily mean that infectious virus is present.

    • Consider consulting with local infectious disease experts when making return to work decisions for individuals who might remain infectious longer than 10 days (e.g., severely immunocompromised).

    • If HCP had COVID-19 ruled out and have an alternate diagnosis (e.g., tested positive for influenza), criteria for return to work should be based on that diagnosis.

Patient Monitoring

Encourage those who test positive to monitor their breathing, and if they develop dyspnea with activity or at rest, to contact their PCP or be seen in an emergency department. 

PATIENT EDUCATION

  • Frequently clean hands by using alcohol-based hand rub or soap and water.

  • When coughing and sneezing, cover mouth and nose with flexed elbow or tissue. Throw tissue away immediately and wash hands.

  • Avoid close contact with anyone who has fever and cough.

  • If you have fever, cough, and difficulty breathing, seek medical care early.

  • Wear a face mask when in public and unable to remain at least 6 feet from others.

  • Urge patients NOT to ingest disinfectants and "light" therapies for prevention or treatment of COVID-19.

  • Medications and other therapies written for the general public can be found at https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html.

  • Urge patients NOT to seek out hydroxychloroquine for prevention or treatment of COVID-19.

  • Patients with COVID-19 should continue taking their angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs).

    • A statement from the American Heart Association, the Heart Failure Society of America, and the American College of Cardiology (51) initially supported this position and 3 recent studies have found no worsening of outcomes of COVID-19 infections based upon anti-hypertensive agent being taken (52). A recent single-center case of 362 patients hospitalized with COVID-19 infection found no difference in severity of the disease, complications, and risk of death in those who were taking ACEIs/ARBs compared with those not on these medications (53).

  • Patients with mild illness should self-isolate/quarantine until symptoms have completely resolved for 72 hours minimum.

  • Patient resource on home care: https://www.cdc.gov/coronavirus/2019-ncov/downloads/10Things.pdf

  • All should try to get 30 minutes of exercise per day. A survey study of ~370 adults' health and wellbeing after one month of confinement due to COVID-19 in China found those who stopped working reported worse mental and physical health conditions. This was mitigated by exercise for ≤30 minutes per day (54).

PROGNOSIS

  • 80% of patients have mild, self-resolving illness requiring no intervention.

  • Duration of immunity from infection is unknown. While reinfection has occurred with other coronaviruses, they typically occur months to years after the initial infection (55).

  • Immunity persistence is unclear; from a study of 82 confirmed and 58 probably cases of COVID-19 from China, the median duration of IgM detection was 5 days (interquartile range, 3-6), while IgG was detected at a median of 14 days (interquartile 10-18) after symptom onset (56).

  • A small US study followed antibody levels after mild COVID-19 in 34 patients with mild COVID-19 using serial anti-SARS-CoV-2 receptor binding domain IgG levels. The estimated mean IgG half-life was 36 days (57).

  • U.S. cohort data tracked estimated excess deaths in the U.S. between March 1 and May 30, 2020, and compared it to data from January 5, 2015 through January 25, 2020. During these three months in 2020, there were 780,975 total deaths; 122,300 more deaths than expected from previous years, with COVID-19 accounting for 78% of these deaths, implying significant under-reporting (58).

  • Laboratory findings that correlate with an increased mortality include leukocytosis with lymphopenia, and highly-elevated LFTs, creatinine, lactate dehydrogenase, troponin, N-terminal-pro-brain natriuretic peptide, and d-dimer compared to those who recovered.

  • Morbidities that correlate with death include acute respiratory distress syndrome, sepsis, acute cardiac injury, heart failure, acute kidney injury, and encephalopathy (59).

  • UK cohort data of neurologic outcomes of COVID infection included cerebrovascular events and mental status changes (encephalopathy, encephalitis) (60).

  • Postinfection neuropsychiatric disorders were studied in a systematic review and meta-analysis of 65 studies and 7 preprints from multiple countries.

    • From the 25 studies of SARS and MERS:

      • Insomnia (41% of patients), anxiety (36%), concentration impairment (38%), memory difficulties (34%), depression (33%), and confusion (27%)

      • After the infection (60 days to 12 years), 40 studies found traumatic memories (30%), emotional lability (24%), memory impairment (19%), fatigue (19%), irritability (13%), anxiety (12%), insomnia (12%), pressured speech (12%), euphoria (11%), and depression (10%) with a prevalence of 15% for depression and for anxiety, and 32% for post-traumatic stress disorder (PTSD).

    • Of the 12 COVID-19 studies:

      • Findings included acute-phase delirium, agitation, and alterations in consciousness, with some cognitive dysfunction after hospitalization (61).

  • An Italian cohort study of 143 patients hospitalized for COVID-19 evaluated symptoms at a mean of 60 days after symptom onset and 36 days after hospital discharge. Mean age of 56.5 years, 37% were women, and the mean length of hospitalization was 13.5 days. During hospitalization, 73% had interstitial pneumonia, 15% required noninvasive ventilation, and 5% received mechanical ventilation. Participants were virus-free by PCR. Only 13% of participants reported being symptom-free but 55% had 3 or more symptoms. The most common persistent symptoms were fatigue 53%, dyspnea 43%, joint pain 27%, and chest pain 22%. Compared to pre-COVID-19 infection, 44% reported their quality of life was ≥10 points lower on a scale of 0 (worst health) to 100 (best health) (62).

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ADDITIONAL READING

SEE ALSO

CODES

CLINICAL PEARLS

  • Coronavirus Disease 2019 (COVID-19) is a severe acute respiratory syndrome which originated in China and has spread world-wide, causing a pandemic.

  • The disease results from a novel virus, newly named coronavirus 2 (SARS-CoV-2).

  • The syndrome may lead to death, particularly in elderly and immune-compromised individuals.

  • PCR test sensitivity is low, so consider pre-test probability, especially in evaluating negative results, and recommend self-quarantine for those with a high-risk exposure and/or symptoms.

  • For any meeting criteria for evaluation of COVID-19, clinicians are encouraged to contact and collaborate with their state or local health department.

 
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