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Subject: Coronavirus Disease 2019 (COVID-19)
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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.
Anthony Fauci, MD gave an outstanding Medicine Grand Rounds at Harvard Medical School on September 10, 2020, covering all aspects of this virus and illness. It can be viewed at https://player.vimeo.com/video/456649458.
On January 31, 2020, the United States Secretary of Health and Human Services declared the SARS-CoV-2 virus a U.S. public health emergency.
Infection and mortality statistics are reported daily by the World Health Organization (WHO) at https://www.who.int/emergencies/diseases/novel-coronavirus-2019, and more information on the world pandemic can be tracked at https://www.who.int/.
Johns Hopkins University Global COVID-19 cases by country: https://coronavirus.jhu.edu/map.html
U.S. cases: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html
U.S. projections: https://covid19.healthdata.org/united-states-of-america
State-by-state seroprevalence rates vary widely: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/commercial-lab-surveys.html
Pediatric cases of COVID-19 typically are milder than adults. Pediatric symptoms include: 73% fever, cough, or shortness of breath. In adults, 93% will have this symptom complex. Hospitalizations in pediatric populations are less common than in adults (1).
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: An ongoing seroprevalence study from the Centers for Disease Control (CDC) shows estimates from ten sites around the United States ranging from 1–7% (5).
Children represent ~10% of COVID cases (6).
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.
A less virulent form of the virus may explain why some patients get severely ill while others do not. A retrospective analysis in Singapore compared outcomes of those infected with the SARS-CoV-2 variant with a 382-nucleotide deletion (Δ382) only vs. infected with wild-type only vs. those infected with both types. Hypoxia requiring supplemental oxygen occurred in no patients infected with Δ382 virus alone but in ~30% of those in the other two groups. After multivariable adjustment, Δ382 virus was associated with a ~90% reduction in the odds of hypoxia requiring oxygen. Patients with the 382-nucleotide deletion variant had lower levels of inflammatory markers (7).
Initial spreading for this novel coronavirus appears to have come from a bat reservoir (8).
For over 95% of infected persons, symptoms appear within 11.5 days. Median incubation time to is about was 5.5 days (9).
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 (10).
Retrospective cohort study found the median duration of viral shedding to be up to 20 days, with some cases as long as 37 days.
The estimated median incubation time is 7–76 days (90th percentile is 14–28 days; 10% of patients will have an incubation period longer than 14 days (11).
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: macrophage 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 (12).
Presymptomatic COVID-19 infection is defined as being infected but not yet expressing symptoms. Asymptomatic COVID-19 infection is relatively rare, as most patients who are infected do develop some symptoms, but these symptoms 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 (13).
Coagulopathy associated with COVID-19 infection includes includes illness ranging from mild thrombocytopenia and rare prolongations of prothrombin time (PT) or partial thromboplastin time (PTT) resulting in increased risk for thrombosis and bleeding. Venous thromboembolism (VTE) was radiologically confirmed in, on average, 4.8% of patients, ranging from 7.6% in those critically ill and 3.1% in non–critically ill patients. The rate of arterial thromboembolism was 2.8% overall, with 5.6% in critically ill patients and 1.2% in non–critically ill patients. Bleeding was found in 4.8% of patients, ranging from 7.6% in critically ill patients to 3.1% in non–critically ill patients; the rate of major bleeding was 2.3% overall, but as high as 5.6% in critically ill patients.
Researchers compared the neutrophil activation state from severe COVID-19 cases to patients with less severe disease (requiring only supplemental oxygen) and found those with severe infections had neutrophil activation marker CD177 highly upregulated, had highly activated platelets, and had dysregulated thrombosis cascades compared with less severe infections (14).
Thrombosis was predicted by increased by D-dimer level at admission (>2500 ng/mL; odds ratio, 6.79), elevated platelet count, C-reactive protein, and erythrocyte sedimentation rate.
Bleeding was predicted by elevated D-dimer level at admission (>2500 ng/mL; OR, 3.56) and by excess thrombocytopenia (15).
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) (16), 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" (17).
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 (18).
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 (19).
Vitamni D deficiency:
A retrospective cohort study of 489 COVID-19 patients found after multivariate analysis that testing positive for COVID-19 was associated with age up to 50 years (RR=1.06; 95% CI 101–1.09; not being white (RR=2.54; 95% CI 1.26–5.12); and having vitamin D deficiency (RR=1.77; 95% CI 1.12–2.81) compared to sufficient vitamin D levels (20).
A pilot trial of early 25-hydroxyvitamin D treatment in hospitalized COVID-19 patients reduced ICU admissions (2% in the treated group vs. 50% in placebo group) and concerning discharge, 0% of the vitamin D group died and all were discharged to home, while in the placebo group, ~8% died, with the rest discharged to home (21).
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 (22).
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)
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 (23).
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 (24). 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% (25).
A study of SARS-CoV-2 positive women who submitted breast milk samples evaluated by reverse transcriptase–polymerase chain reaction found no viral particles, implying breastfeeding when infected with the virus is not likely to transmit infection (26).
In the U.S., 40% adults report at least one adverse mental or behavioral health problem: 31% reported symptoms of anxiety or depression, 26% had symptoms of trauma- and stressor-related disorder linked to the pandemic, 13% began or increased substance use; ~11% said they had seriously considered suicide in the prior 30 days. Those at greatest risk of mental health issues include: young adults, Hispanic and African Americans, essential workers, unpaid caregivers for adults, and those with preexisting psychiatric conditions (27).
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).
Physical distancing of at least 1 meter (preferably 2 meters) reduces viral transmission; use of face masks reduces the risk of infection as does proper use of eye protection (28).
Keeping six feet apart from others, closing of schools, workplaces, meetings, social and religious gatherings, and sporting events
Minimizing contact with others and closure of nonessential business is effective at stopping the exponential spread of the virus (29).
Cell phone tracking in the U.S. found decreases in mobility were strongly associated with decreases in COVID-19 case growth. Until a COVID-19 vaccine is widely available, physical distancing is one of the primary measures to combat disease spread (30).
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 increases as distance is lengthened (change in relative risk [RR] 2·02 per m; pinteraction=0·041; moderate certainty).
Social distancing resulted in decreased rate of childhood infection disease (acute otitis media, bronchiolitis, common cold, croup, gastroenteritis, influenza, nonstreptococcal pharyngitis, pneumonia, sinusitis, skin and soft tissue infections, streptococcal pharyngitis, and urinary tract infection (UTI) based upon observational cohort study from a large pediatric primary care network in Massachusetts. Rates of influenza, croup, and bronchiolitis went to <1 case per 100,000 (31).
Wearing masks in public reduces risk of transmission to others (32,33).
N95 confer the greatest protection (28).
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.
Health care workers who added a face shield to a face mask reduced their personal infection rate almost 100% in an observational study from India (34).
Universal use of face masks decreases the effective reproduction number. Re below 1 (meaning each infected person will infect less than one person) mitigates spread (35). 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. "My mask protects you; your mask protects me."
Face mask reduces 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) (28).
Face masks, physical distancing, social isolation, and contact tracing are current efforts to contain the COVID-19 pandemic (36).
High-speed camera evaluation of respiratory droplets expelled during speaking, coughing, and sneezing suggests that 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 (37).
Theoretical data finds N95 masks most efficacious, followed by surgical masks, polypropylene masks and handmade cotton face coverings. Gaiter-type fleece coverings converted larger respiratory droplets into numerous smaller droplets which can travel further and were considered “counterproductive” (38).
Increasing data shows aerosol transmission (with particles able to travel and infect in areas with recirculated air) is likely to occur (39).
Hand washing, avoid others if ill, avoid touching face
Hand washing for 20 seconds with soap lowers viral carriage and lowers risk of transmission.
Humidity: A summary of 10 international studies investigated the influence of humidity on viral (corona viruses SARS-CoV-1, MERS and SARS-CoV-2) spread and survival found air humidity >40% lowers the potential for the virus to be spread through aerosol transmission (40).
Social isolation and quarantine:
Self-quarantine recommended for all with symptoms of fever or new cough until symptoms resolve
Quarantine is recommended if exposed to confirmed COVID-19 infections to reduce infections and deaths.
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" (41).
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 (42).
Household exposure to SARS-CoV-2 appears to be the most common risk factor for transmission based upon contact tracing, cell phone data and public transportation use. Ten percent of household contacts to index cases became infected vs. 1% from healthcare settings and 0.1% from public transportation. Risk for transmission increased as severity of index case symptoms increased (43).
School closures: 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 (44).
American Academy of Pediatrics (AAP) released guidelines regarding children and COVID-19 which include cloth face masks being recommended for nearly all children aged ≥ 2 years and guidance on when to test children: having COVID-19 symptoms, having a close contact with a confirmed case, and prior to elective procedures (45).
Multiple trials are underway (46).
Reports indicate a vaccine has been made available in Russia (no phase 3 trial data available).
Strategies include nucleic-acid based vaccines and traditional recombinant technologies (47).
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 to wear a surgical mask.
Maintain strict physical 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
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 12 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 (48).
Modeling data to discern influenza from COVID-19 found influenza initially presents as cough. COVID-19 often begins with fever, followed by URI symptoms, then upper GI and finally lower GI symptoms (49).
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) (50).
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 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)
Risk factors for progression to acute respiratory distress syndrome (ARDS):
Age >65 years, neutrophilia, and organ or coagulation dysfunction (51)
Chronic lung disease, immunocompromise, obesity (52)
Hypertension and diabetes (53)
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 (54).
Livedoid and necrotic skin eruptions (55)
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 (56).
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 (57).
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 (58).
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 (59).
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 (60).
PCR tests are more accurate (have a higher sensitivity) but take longer. Antigen tests have a lower sensitivity but a high specificity (61).
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 (62).
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 (63).
Deep vein thrombosis almost tripled mortality (64).
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.
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.
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 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 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.
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.
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.
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).
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.
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).
Patients who have worsening symptoms with declining function should be admitted to the hospital for observation for further deterioration.
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 (65).
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. Initial data finds recovery is shortened with remdesivir but no mortality benefit has been shown (66). In late August 2020, the US FDA gave emergency authorization despite the drug's limited data or mortality benefit
A study of 600 patients with COVID-19 who did not require oxygen randomized to either a 5- or 10-day course of remdesivir or standard care. At day 11, 5 days of remdesivir improved vs. standard care. There was no difference for the 10-day group, but by day 14, both treatment groups were significantly better than standard care (67).
A recent industry sponsored trial of 584 patients with moderate COVID-19 (defined as hospitalized with evidence of COVID-19 pneumonia but no hypoxia) were randomized to 10 days of RDV, 5 days of RDV, or standard care with outcomes measured at “Day 11” on a 7-point ordinal scale. Those in the 5 day arm had significantly better scores than those in the 10 day arm or control groups, but in all groups there was no significant difference in time to recovery, time to improvement in clinical status, or death at 28 days (67).
ECMO: Venovenous extracorporeal membrane oxygenation (ECMO) has some potential for COVID-19 patients with severe respiratory failure despite receiving invasive mechanical ventilation (68).
Famotidine: A retrospective, propensity matched trial of ~900 SAR-CoV-2 patients admitted to the hospital found treatment with famotidine decreased in-hospital mortality (OR = 0.37; CI 0.16 – 0.86, p = 0.021); combined death or intubation (OR = 0.47; CI 0.23 – 0.96, p = 0.040) and lower serum markers of inflammation (69).
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 (70).
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) (71).
Convalescent plasma (sera): Promising benefit has been reported in critically ill patients, but there is still very limited data on its benefit (72).
FDA has granted emergency authorization for use in patients critically ill with COVID-19. This is based on data from the Mayo Clinic of 35,000 patients hospitalized with COVID-19. Outcomes found the 7-day mortality was 8.7% in those transfused within 3 days of diagnosis vs. 11.9% if transfused 4 or more days later. At 30-days, mortality was 21.6% vs. 26.7%, p<0.0001. It also found transfusions with higher IgG levels (18.45 S/Co) vs. low IgG plasma had lower mortality at 7 and 30 days. Pooled relative risk of mortality with high antibody levels was 0.65 [0.47-0.92] at 7 days and 0.77 [0.63-0.94] at 30 days. This study did not contain a placebo arm and was published without peer review (73).
In late August 2020, the NIH cautioned against emergency approval, saying that the data were not strong enough. NIH considers data to be insufficient to recommend for or against convalescent plasma.
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.
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:
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.
The CDC offers a range of options for those experiencing anxiety, depression and who are at risk from self-harm or domestic violence: https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/managing-stress-anxiety.html
CDC services include phone and text consultations for these issues at:
Disaster Distress Helpline: call 1-800-985-5990, or text TalkWithUs to 66746
National Domestic Violence Hotline: call 1-800-799-7233 and TTY 1-800-787-3224
Depression prevalence in the U.S. has tripled during the pandemic compared to 2017–2018 data. Approximately 1,400 adults surveyed about depressive symptoms in spring of 2020 were compared to ~5,000 adults from the National Health and Nutrition Examination Survey in 2017–2018. In the pre-pandemic cohort, 9% had depressive symptoms vs. 28% during the pandemic; this included a 7-fold increase in risk of severe depression. Populations currently at greatest risk are those with the lowest incomes, where almost 50% had reported depressive symptoms during the pandemic (74).
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.
Consider cardiac magnetic resonance imaging (MRI) in college athletes before returning to play. A small study of 26 college athletes who tested COVID-19 positive (45% without symptoms) were screened for cardiac manifestations by cardiac MRI after recovery. All had normal electrocardiograms, echocardiograms, and troponin levels. Fifteen percent (all male) had findings consistent with myocarditis with mild (slight shortness of breath) or no symptoms (75).
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:
Note: if you develop symptoms, follow guidance above for people with COVID-19 symptoms (76).
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,
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
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.
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.
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.
For patients on PPIs, consider switching to an H2RA (famotidine 20 mg BID or nizatidine 150 mg BID).
As vitamin D deficiency increases risk of COVID-19 infection and severity of disease, consider recommending to patients to take 2–4,000 IU vitamin D per day. While not proven to be protective, vitamin d deficiency is common, and there is little risk at this dose.
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 (77) 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 (78). 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 (79).
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 (80).
80% of patients have mild, self-resolving illness requiring no intervention.
Observational data from Indiana found the infection fatality ratio of 0.26% of those not institutionalized aged 12 and older. Higher infection fatality ratios were seen in those aged 60 and older (1.71%) (this does not include those in nursing homes, rehabilitation centers, etc.) and among non-whites (0.59%). The infection fatality ratio of those aged 65 and older for the seasonal influenza is ~0.8% (81).
Duration of immunity from infection is unknown. While reinfection has occurred with other coronaviruses, they typically occur months to years after the initial infection (82).
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 (83).
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 (84).
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 (85).
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 (86).
UK cohort data of neurologic outcomes of COVID infection included cerebrovascular events and mental status changes (encephalopathy, encephalitis) (87).
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 (88).
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) (89).
Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) FAQs.
https://www.cdc.gov/coronavirus/2019-ncov/faq.html. Accessed March 25, 2020.
Centers for Disease Control and Prevention. COVID-19 Situation Summary.
https://www.cdc.gov/coronavirus/2019-nCoV/summary.html. Accessed March 25, 2020.
World Health Organization. Coronavirus disease (COVID-2019) situation reports.
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/. Accessed March 25, 2020.
Telemedicine & COVID-19
Algorithm: COVID-19 Outpatient Testing
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 patients meeting criteria for evaluation of COVID-19, contact and collaborate with state or local health department.