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Subject: Coronavirus Disease 2019 (COVID-19)
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Coronavirus Disease 2019 (COVID-19) is a severe acute respiratory syndrome which was first detected in Wuhan City, Hubei Province, China.
The disease results from a novel virus, newly named coronavirus 2 (SARS-CoV-2).
The syndrome may lead to respiratory failure and death, particularly in elderly and immune-compromised individuals.
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.
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/cases-updates/cases-in-US.html
Worldwide crude mortality rate is approximately 4.7%.
Pediatric cases of COVID-19 have had milder disease course 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 ~5% vs. ~10% in adults (1).
A multisystem inflammatory syndrome related to COVID-19, similar to Kawasaki disease (toxic shock syndrome), is being reported in children. It is described as a "post-infectious immune response." It is associated with a positive test either for SARS-CoV-2 or for antibodies to the virus. This condition has often required cardiac or respiratory support with at least 3 deaths to date (2). More information can be found at: https://emergency.cdc.gov/han/2020/han00432.asp.
A systematic review of data published between December 1, 2019 and March 3, 2020 evaluated the clinical course of children ≤19 years with confirmed SARS-CoV-2 infection (17 studies from China and 1 from Singapore) included 1065 cases. Findings included all but one child had a mild clinical presentation. Common symptoms included fever, dry cough, fatigue, and nasal congestion/rhinorrhea; infants also had gastrointestinal symptoms. Only one patient required respiratory support and only one death was reported (3).
Racial disparities are appearing in the U.S. population based upon data from Chicago and Louisiana, where African Americans account for 70% of the deaths, but only comprise 30% of the population. In Michigan, African Americans comprise 14% of the population but account for ~40% of the deaths, with many of the cases occurring in Detroit where 80% of the population is black.
A novel (new) coronavirus (originally named "2019-nCoV," now officially coronavirus 2 [SARS-CoV-2]) caused the coronavirus disease COVID-19.
Related to bat coronaviruses and to other Severe Acute Respiratory Syndrome (SARS) coronaviruses
Believed to evolve in animals; some strains of coronaviruses cause illness in people and others primarily infect animals, including camels, cats, and bats
Virology: SARS-CoV-2 is a positive-sense single stranded RNA virus (+ssRNA), a betacoronavirus belonging to the same subgenus as the virus responsible for the severe acute respiratory syndrome (SARS) and the virus causing 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 may have been from animal to man via exposure to a large seafood and animal market.
For over 95% of infected persons, symptoms appear within 11.5 days. Median incubation time to is about was 5.5 days (4).
Retrospective cohort study from Wuhan found the median duration of viral shedding to be 20 days, with the longest shedding at 37 days.
Symptoms develop because of viral effects on pulmonary tissue, and the associated immune response ("cytokine storm").
The virus also seems to affect 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 (5).
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.
Can be spread through community contact
Spread via respiratory droplets produced when an infected person coughs or sneezes
Risk factors for adverse outcomes include age over 70 years, tobacco abuse, cardiovascular disease, cerebrovascular disease, hypertension, diabetes, and chronic pulmonary disease.
Critical illness risk factors 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 (6).
Observational study covering international patients found 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)
No increased risk of in-hospital death was found to be associated with the use of ACE inhibitors (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74) (7).
Population health: containment efforts (quarantine, universal testing, rapid identification of illness, contact tracing) have been found to be successful in other parts of the world. 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
Social distancing: a public health intervention that keeps people and communities at a distance from others so those infected with an illness are less likely to pass it on to others. Includes keeping six feet apart from others, closing of schools, workplaces, meetings, social and religious gatherings, and sporting events.
Using data from Germany's social distancing methods, these authors evaluated which intervention (cancelling large events, school closures, and, lastly, contact banning and closure of nonessential stores) would reduce the exponential growth of infection; while all 3 reduced transmission, only banning contact with others and closure of nonessential stores stopped the exponential growth of the epidemic (8).
Wearing medical (surgical) masks in public may reduce risk of transmission to others. Experimental data has found surgical and cotton masks allow the SARS-CoV-2 virus to pass through after cough, with the virus concentrated on the outer surface, but there is conflicting data on if masks lower or prevent others from contagion (9,10). N95 respirators were not tested.
Use of gloves is not recommended for the general population as it may decrease patient hand hygiene and increase carelessness. On May 22, 2020, the CDC revised their recommendations on infection from touching contaminated surfaces, saying, "COVID-19 spreads from person to person contact...the virus does not spread easily in other ways." Exposure to a contaminated surface "is not thought to be the main way the virus spreads, but we are still learning more about this virus" (11).
A Cochrane recent review found:
Hand washing for 20 seconds with soap lowers viral carriage and lowers risk of transmission.
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.
Vaccine is not available.
In lab evaluation, comparing SARS Corona Virus to COVID-19 found: COVID-19 virus was detectable 72 hours after application to plastic and after 48 hours on stainless steel: on cardboard was less than 24 hours (12).
From China of 108 participants randomized to low dose (n=36), middle dose (n=36), or high dose (n=36) of a vaccine
Although a high rate of adverse events were reported by 7 days, all were mild (injection site pain, fever, fatigue, headache, and muscle pain). No serious adverse events were reported within 28 days post-vaccination. An antibody response was found in 97% of the low-dose group, 95% of the middle-dose group, and 100% of the high-dose group (13).
This phase 1 trial of an Ad5 vectored COVID-19 vaccine from Wuhan, China evaluated of 108 adults randomized to low dose (n=36), middle dose (n=36), or high dose (n=36) of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein. Adverse events were found between 75-83% of participants, with almost all mild to moderate. The vaccine was able to induce antibodies by day 14 and peaked at day 28. Efficacy of vaccine will be part of Phase II (13).
Protocols include reschedule all in-person health maintenance visits and follow-up visits unless acute needs are present.
See patients with non-COVID-19 symptoms in office only if absolutely necessary.
Establish Telemedicine protocol and provide follow-up visits and patient questions by phone.
Telemedicine is able to be billed for most types of visits (including new and established E/M, prenatal, behavioral health, pre-op visit, advanced care planning, occupational therapy and speech therapy), Medicare Annual Wellness Visit (both first visit [0G0438] and subsequent [0G0439]), and well child visits. Adult patient "physicals" and "Welcome to Medicare" visits are not covered (14).
For those who come to the office:
Instruct patients who arrive to wear a surgical mask.
Move all members of the party to an isolated room.
Remind parents who wish to have a child seen not to bring other family members into the office, and only bring in one child.
80% of those 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.
Although afebrile in the initial pre-symptomatic phase, most symptomatic cases mount a fever >38°C/100.4°F. 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 (15).
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."
Centers for Disease Control and Prevention (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
Painful red or purple lesions on fingers or toes in the winter (anecdotal)
Any ill patient with the following criteria should don a surgical mask immediately and be placed in isolation (ideally, negative air pressure) with staff wearing an N-95 respirator:
Fever OR symptoms of lower respiratory illness (e.g. cough, shortness of breath, etc.) and in the last 14 days before symptom onset, has a:
History of travel to a country with a high prevalence of COVID-19, OR
Close contact with a COVID-19 patient or a person under investigation (PUI) for the COVID-19 virus infection, OR
Travel on a cruise ship in past 14 days
Some states are now recommending those who have close contact to COVID-19 patients must have real-time reverse transcriptase (RT-PCR) testing.
Risk factors for progression to acute respiratory distress syndrome (ARDS), based upon Wuhan data:
Age >65 years, neutrophilia, and organ or coagulation dysfunction (16)
Chronic lung disease, immunocompromise, obesity (17)
Hypertension and diabetes (18)
Mild-to-severe respiratory illness with fever, cough, dyspnea, and chest discomfort
Wheeze and rales are not typically found
Pulse oximetry may reveal dramatic, relatively asymptomatic hypoxemia. Hypoxemia may be an early diagnostic clue of COVID-19.
CDC encourages clinical judgement to determine if signs and symptoms are compatible with COVID-19 and whether the patient should be tested. 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 (19)
Testing options: there are currently molecular tests (RNA) and serologic (IgG, IgM) tests. Molecular tests detect the SARS-CoV-2 viral RNA from nasopharyngeal and other respiratory specimens. Serological tests are blood tests that are used to detect the presence of antibodies 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 (20).
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 (21).
Serologic testing for an immune response is best used to determine who has been exposed.
Some have theorized that if SARS-CoV-2 IgG is present, safe return to work activities may be considered on the assumption they are protected from re-infection. This has yet to be proven. Serologic tests are not designed to be diagnostic of infection, but rather a marker for public health decisions.
The U.S. Food & Drug Administration has stated that these tests should only be used by institutions collecting convalescent sera and not for diagnostic purposes (22).
Antigen testing: The FDA has issued Emergency Use Authorization for an antigen test which can provide rapid detection (within 15 minutes) of COVID-19. PCR tests are more accurate (have a higher sensitivity) but take longer. Antigen tests have a lower sensitivity but a high specificity, meaning a positive test means they likely have an infection, but a negative test may be a false negative, and decisions on repeat or other testing should be made on clinical circumstance (23).
Sensitivity: Over 90% theoretically, but only ~70% in routine clinical use due to swab sampling inconsistencies; consider the possibility of a false negative in patients for whom you have a high degree of clinical suspicion; treat and quarantine.
For worsening symptoms: chest X-ray, confirmatory CAT scan; showing bilateral or multifocal pneumonia
For patients who are positive, consider obtained LDH, hsCRP and D-dimer as a baseline should they progress to significant dyspnea.
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. Centers for Disease Control can be found at: https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index/html.
For providers who may find themselves having to provide critical care, this guideline is available: https://journals.lww.com/ccmjournal/Abstract/onlinefirst/Surviving_Sepsis_Campaign_Guidelines_on_the.9 5707.aspx
The National Institutes of Health (NIH) Guidelines are based upon severity of illness (24):
Management of persons with COVID-19
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. This section discusses the clinical management of patients according to the severity of their illness. Currently, no Food & Drug Administration (FDA) approved drugs exist to specifically treat patients with COVID-19. Chloroquine and hydroxychloroquine, which are not FDA-approved for COVID-19, are available from the Strategic National Stockpile for hospitalized adults and adolescents (weighing ≥50 kg) under an Emergency Use Authorization. An array of drugs approved for other indications, as well as multiple investigational agents, are being studied for the treatment of COVID-19 in several hundred clinical trials around the globe. Some drugs can be accessed through expanded access or compassionate-use mechanisms. No drug has been proven to be safe and effective for the treatment of COVID-19.
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
Asymptomatic or Presymptomatic Infection
Asymptomatic infection can occur, although the percentage of patients who remain truly asymptomatic for the course of their infection is unknown. It is unclear at present what percentage of individuals who present with asymptomatic infection may progress to clinical disease. Some asymptomatic individuals have been reported to have objective radiographic findings consistent with COVID-19 pneumonia. Eventually, the availability of widespread testing for SARS-CoV-2 and the development of serologic assays for antibodies to the virus will help determine the true prevalence of asymptomatic and presymptomatic infections.
Persons who test positive for SARS-CoV-2 and who are asymptomatic 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 Centers for Disease Control and Prevention COVID-19 website for detailed information.
The Panel recommends no additional laboratory testing and no specific treatment for persons with suspected or confirmed asymptomatic or presymptomatic SARS-CoV-2 infection.
Patients may have mild illness defined by any of 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 in an ambulatory setting or at home through telemedicine or remote visits.
All patients with symptomatic COVID-19 and risk factors for severe disease should be closely monitored. In some patients, the clinical course may rapidly progress.
No specific laboratory evaluations are indicated in otherwise healthy patients with mild COVID-19 disease.
There are insufficient data to recommend either for or against any antiviral or immunomodulatory therapy in patients with COVID-19 with mild illness.
Moderate COVID-19 illness is defined as evidence of lower respiratory disease by clinical assessment or imaging with SpO2 >93% on room air at sea level. Given that pulmonary disease can rapidly progress in patients with COVID-19, patients with moderate COVID-19 should be admitted to a healthcare facility for close observation. If bacterial pneumonia or sepsis is strongly suspected, administer empiric antibiotic treatment for community-acquired pneumonia, reevaluate daily, and if there is no evidence of bacterial infection, deescalate or stop antibiotics.
Most patients with moderate-to-severe illness will require hospitalization. Hospital infection prevention and control measures include use of personal protective equipment (PPE) for 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). The number of individuals and providers entering the room of a patient with COVID-19 should be limited. If necessary, confirmed COVID-19 patients may be cohorted in the same room. If available, airborne-infection isolation rooms (AIIRs) should be used for patients who will be undergoing any aerosol-generating procedures. During these procedures, all staff should wear N95 respirators or powered, air-purifying respirators (PAPRs) rather than a surgical mask.
The optimal pulmonary imaging technique for people with COVID-19 is yet to be defined. Initial evaluation may include chest x-ray, ultrasound, or if indicated, computed tomography (CT). Electrocardiogram (ECG) should be performed if indicated. Laboratory testing includes a complete blood count (CBC) with differential and a metabolic profile, including lever and renal function tests. Measurements of inflammatory markers such as C-reactive protein (CRP), D-dimer, and ferritin, while not part of the standard care, may have prognostic value.
There are insufficient data for the Panel to recommend either for or against any antiviral or immunomodulatory therapy in patients with COVID-19 with moderate 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 >50%. These patients may experience rapid clinical deterioration and will likely need to undergo aerosol-generating procedures. They should be 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 daily, and if there is no evidence of bacterial infection, deescalate or stop antibiotics.
Evaluation should include pulmonary imaging (chest x-ray, ultrasound, or if indicated, CT), and ECG, if indicated. Laboratory evaluation includes CBC with differential and metabolic profile, including liver and renal function tests. Measurements of inflammatory markers such as CRP, D-dimer, and ferritin, while not part of standard care, may have prognostic value.
There are insufficient data for the Panel to recommend either for or against any antiviral or immunomodulatory therapy in patients with COVID-19 with severe illness.
COVID-19 is primarily a pulmonary disease. Severe cases may be associated with acute respiratory distress syndrome (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.
The Surviving Sepsis Campaign (SSC), an initiative supported by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, issued Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) in March 2020. The Panel relied heavily on the SSC guidelines in making the recommendations in these Treatment Guidelines.
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.
There are insufficient data for the Panel to recommend either for or against any antiviral or immunomodulatory therapy in critically ill patients with COVID-19.
Acetaminophen (max is 1,000 mg every 6 hours in patient without liver disease) given around the clock to address fever
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.
Treat as if bacterial pneumonia if consistent with history and physical examination.
Medications under investigation:
An open-label randomized study in Wuhan, China. Fourteen days of lopinavir-ritonavir therapy did not differ from standard case regarding clinical improvement or decrease in viral RNA load (25).
From Hong Kong, 86 patients were randomized to 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million IU of interferon beta-1b on alternate days (combination group), or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group), and found a decrease in viral shedding in the combination group: (7 days [IQR-11]) vs. (12 days [8-15]); hazard ratio 4·37 ([95% CI 1·86–10·24], p=0·0010) (26).
A small open label study of 36 hospitalized patients with proven COVID-19 found hydroxychloroquine lowered "viral carriage" at day 6. A subset of these patients was treated with both hydroxychloroquine and azithromycin, and at day 6 also showed a reduced viral load compared to hydroxychloroquine alone or no mediation. No further outcome data was included in the study, and this was published without peer review (27).
A French researcher issued a video suggesting hydroxychloroquine may be effective at reducing the infectivity of the virus within 6 days, but this has not been published and has not been replicated.
Hydroxychloroquine and azithromycin: a small observational trial failed to show any morbidity or mortality benefit (27). A subsequent trial of this combination found no such benefit (28).
A prepublication open-label trial of hydroxychloroquine in 150 patients in China found no benefit at 28 days of the intervention (29).
Hydroxychloroquine, alone or with azithromycin, should NOT be used in the outpatient setting for the prevention of or treatment of COVID-19 infections.
On April 24, 2020, the U.S. FDA issued the following warning: chloroquine and hydroxychloroquine should not be taken for COVID-19 outside a hospital or clinical trial setting, as the drugs confer potentially life-threatening cardiac risks (30).
On April 24, 2020, the journal Nature Medicine published a cohort study of 84 COVID-19 patients given the combination of hydroxychloroquine plus azithromycin inducing an average QTc interval increase from 435 ms at baseline to a maximal average value of 463 ms with ~11% having a QTc interval above 500 ms, "a known marker of high risk of malignant arrhythmia and sudden cardiac death" (31). A study from Boston and one from France recently confirmed this drug combination lengthened the QTc (32,33).
A systematic review of use of chloroquine or hydroxychloroquine concluded "there is a dearth of evidence to support the efficacy of CQ or HCQ in preventing COVID-19. Considering potential safety issues and the likelihood of imparting a false sense of security, prophylaxis with CQ or HCQ against COVID-19 needs to be thoroughly evaluated in observational studies or high-quality randomized controlled studies" (34).
Data from a multinational registry found the use of hydroxychloroquine or chloroquine, with or without a macrolide, double the risk of mortality; mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·233—1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368—1·531), chloroquine (16·4%; 1·365, 1·218—1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273—1·469); each were independently associated with an increased risk of in-hospital mortality. Also was found, when compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935—2·900), hydroxychloroquine with a macrolide (8·1%, 5·106, 4·106—5·983), chloroquine (4·3%; 3·561, 2·760—4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344—4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia (35).
An observational study of ~15,000 hospitalized COVID-19 patients who were treated with hydroxychloroquine or chloroquine, with or without a macrolide, were compared to ~81,000 who were not treated with these drugs. The hydroxychloroquine and chloroquine groups had higher in-hospital mortality (>16-24%) rates than the control groups (9%). Ventricular arrhythmia during hospitalization were also higher (4-8%) than controls (0.3%) (35).
World Health Organization announced that it has halted a hydroxychloroquine trial due to demonstrated adverse event rates and lack of benefit.
Ivermectin: an antiparasitic agent has been found to be an in vitro inhibitor of the SARS-CoV (36)
Remdesivir (a broad-spectrum antiviral agent): in-vitro studies of remdesivir found it can inhibit coronaviruses such as SARS-CoV and MERS-CoV replication; this is currently being studied in SARS-CoV2 (the coronavirus causing COVID-19) (37).
A small uncontrolled trial of remdesivir by the drug's manufacturer (Gilead) of 53 patients found: at baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. At the end of the study, 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. It is unclear if this differs from baseline without a control group (38).
A recent NIH "interim report of preliminary findings" of a randomized, placebo-controlled trial of intravenous remdesivir in ~1100 hospitalized patients with COVID-19 with lung involvement (including those requiring supplemental oxygen or mechanical ventilation) found the median time to recovery (no longer requiring oxygen or hospitalization) faster with remdesivir than placebo (11 vs. 15 days). RRR = 31%. The mortality rate was 8.0% with remdesivir and 11.6% with placebo (p=0.059), a non-statistically significant difference.
An underpowered randomized trial of remdesivir from China in adults who were within 12 days of symptom onset with severe COVID-19 were randomized to intravenous remdesivir or placebo for 10 days. The primary endpoint of time to clinical improvement within 28 days after randomization did not differ significantly between the remdesivir and placebo groups (median: 21 and 23 days, respectively). The researchers stated they "could not exclude clinically meaningful differences and saw numerical reductions in some clinical parameters" due to it being underpowered.
An industry-sponsored, open-label trial evaluated 5-day and 10-day dosing remdesivir in hospitalized patients with severe COVID-19 disease. The study demonstrated that patients receiving a 10-day treatment course of remdesivir achieved similar improvement in clinical status compared with those taking a 5-day treatment course (odds ratio: 0.75 [95% CI 0.51 – 1.12] on day 14). What is unknown is the clinical course of similar patients who did not receive remdesivir (39).
Based upon this and other data, the FDA issued an "Emergency Use Authorization" approval, noting the drug has not been proven safe and effective.
1059 hospitalized patients who were initially on oxygen but NOT mechanical ventilation with COVID-19 were randomized to either 10 days of remdesivir or placebo; outcomes found the median recovery time (defined as no longer requiring hospitalization, or hospitalization no longer requiring supplmental oxygen or ongoing medical care) was 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19). At 14 days, a non-statistically significant mortality difference was 7.1% in the remdesivir group and 11.9% in the placebo group (40).
Methylprednisolone: a small study from Wuhan found that in those with COVID-19-induced ARDS, had a significantly better outcome: 23 of 50 (46%) methylprednisolone recipients died compared with 21 of 34 (61.8%) nonrecipients (hazard ratio 0.38).
A meta-analysis based upon primarily observational data on the safety and efficacy of corticosteroids in SARS-CoV-2, SARS-CoV, and MERS-CoV infections found corticosteroid use on in-patients was associated with delayed virus clearing, prolonged hospitalizations, and increased need for mechanical ventilation with no reduction in mortality (41).
Tocilizumab, a monoclonal antibody blocking used in the treatment of rheumatoid arthritis, inhibits the receptor for the interleukin-6 cytokine. This class of drug has been investigated to help prevent the cytokine storm theorized to increase the risk of respiratory failure and death in COVID-19 patients. An unpublished, multicenter open-label randomized controlled trial was conducted using tocilizumab on patients hospitalized for moderate-to-severe COVID-19 pneumonia that did not require intensive care at admission. The primary outcome was need for ventilation (non-invasive or mechanical) or death at day 14. A significantly lower proportion of patients reached the primary outcome in the tocilizumab arm (https://www.aphp.fr/contenu/tocilizumab-improves-significantly-clinical-outcomes-patients-moderate-or-severe-covid-19).
The U.S. FDA has approved the use of plasma from recovered patients to treat people who are critically ill with COVID-19. The decision is based upon past experience with other respiratory infections (2009-2019 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic).
Convalescent serum from those recovered from COVID-19 (2 infusions of plasma [total volume, 400 mL] from donors) was used on 5 critically ill patients in China who were mechanically ventilated. They also received intravenous corticosteroids and at least 2 of the following: lopinavir /ritonavir, interferon alpha-1b, favipiravir, arbidol, and darunavir. Outcomes reported include body temperature returned to normal in 4 of 5 patients within 3 days and ARDS resolved in 4 patients at 12 days after transfusion, with 3 of the patients weaned from mechanical ventilation within 2 weeks of treatment. Coronavirus viral loads became negative within 12 days after the transfusion (42).
A systematic review of observational data on convalescent plasma in patients with COVID-19 found:
Convalescent plasma may reduce mortality in critically ill patients,
Increase in neutralizing antibody titers and disappearance of SARS-CoV-2 RNA was observed in almost all the patients after convalescent plasma therapy, and
Beneficial effect of clinical symptoms after convalescent plasma (43).
Proning: some data exists that placing COVID-19 patients with severe hypoxia in the prone position may prevent need for mechanical ventilation. A recent observational study from New York City measured the change in oxygen saturation 5 minutes after self-proning in 50 patients with hypoxia and subsequently confirmed COVID-19 infection. Initial median oxygen saturation was 80% that increased to 84% after patients were placed on supplemental oxygen. After 5 minutes of being in the prone position while still using oxygen, median oxygen saturation increased to 94% (44). Two small studies from Europe found ideally 3 hours of proning of hospitalized patients with hypoxemia on oxygen but not intubated had improved oxygenation and respiratory rates (but unclear outcomes regarding intubation or mortality) (45,46).
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 with infection with coronavirus and their close contacts, along with the general population, remains high. Reassure those who test positive to monitor their breathing and shortness of breath and to contact you for any worsening.
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
For the general population, offer support and tele-counseling sessions; many 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.
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 stay home (home isolated) can leave home under the following conditions:
If you have not had a test to determine if you are still contagious, you can leave home after these three things have happened:
You have had no fever 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 your symptoms first appeared
If you have had a test to determine if you are still contagious, you can leave home after these three things have happened:
You no longer have a fever (without the use of medicine that reduces fevers) AND
You received two negative tests in a row, at least 24 hours apart. Your doctor will follow CDC guidelines.
People who DID NOT have COVID-19 symptoms, but tested positive and have stayed home (home isolated) can leave home under the following conditions:
If you have not had a test to determine if you are still contagious, you can leave hoe after these two things have happened:
At least 10 days have passed since the date of your first positive test AND
You continue to have no symptoms (no cough or shortness of breath (since the test)
If you have had a test to determine if you are still contagious, you can leave home after:
Note: if you develop symptoms, follow guidance above for people with COVID-19 symptoms (47).
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 Used 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 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 diagnostic test assuming they have not subsequently 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 patients go out to the store or have the potential to inadvertently come in close contact to others.
Urge patients to NOT ingest disinfectants and "light" therapies to prevent or treat 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 (48) 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 (7,49). 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 takin ACEIs/ARBs compared with those not on these medications (50).
Patients with mild illness should self-isolate/quarantine until symptoms have completely resolved for 48 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 (51).
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 (52).
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 (53).
Data on those severely ill from COVID-19 from Wuhan data (16):
Median hospital stay was 12 days, 33% required mechanical ventilation, and median time from admission to ARDS was 2 days.
Abnormal laboratory findings include elevated lactate dehydrogenase in 194 (98%), elevated high-sensitivity C-reactive protein in 166 (85.6%), elevated interleukin-6 in 60 (48.8%), and elevated D-dimer in 44 (23.3%).
Age >65 years, neutrophilia, and organ or coagulation dysfunction were associated with ARDS and death.
Characteristics of severely ill patients that correlate with death include: age 68 vs. 51, being male, having a history of hypertension and cardiovascular disease.
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 (54).
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 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.