Diagnosis: COVID-19 (COrona VIrus Disease)
Etiologic agent: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Transmission: Primary transmission person-to-person by respiratory droplet. Transmission via aerosol is also likely and airborne precautions are recommended if a procedure is done that may generate an aerosol. There is concern for viral transmission from coming into contact with contaminated vector surfaces, though this is not though to be the primary source of transmission. The virus has been found in stool, though this is of uncertain clinical significance.
COVID-19 can be detected for at least 3 hours in an aerosol, 72 hours on plastic, 48 hours on stainless steel, 24 hours on cardboard and 4 hours on copper. Note that this does not necessarily indicate infectivity for these durations.
Virus has persisted up to 39 days in the sputum and 13 days in the feces after a negative pharyngeal swab. What this means for transmission isn’t know. (Ann Intern Med. 2020. DOI: 10.7326/M20-0991)
Incubation: The mean incubation period is 5.5 days with the great majority symptomatic by 11.5 days. Only 1 per 10,000 will turn positive greater than 14 days after exposure. (Ann Intern Med 2020 Mar 10; [e-pub]. (https://doi.org/10.7326/M20-0504))
Spectrum of disease: 81% will have mild illness, 14% will require admission and 6% are severe with 5% needing ICU admission or ventilation. The case fatality rate is variable depending on the country and is overall likely about 2%.
A calculator to help determine disease progression and outcome can be found here. (JAMA Intern Med. Published online May 12, 2020. doi:10.1001/jamainternmed.2020.2033)
Mortality is about 2%-3% with deaths the result of respiratory failure, sepsis and myocarditis, found in 50% of those who die and 33% of those admitted to an ICU (JAMA 2020 Mar 19 DOI: 10.1001/jama.2020.4326 ).
- Fever, 44% on admission and 89% during hospitalization in China. Of 24 patients in Seattle with confirmed COVID-19, only 50% were febrile on admission (NEJM March 30, 2020 DOI: 10.1056/NEJMoa2004500)
- Fatigue 70%
- Cough 68%-82% (generally non-productive)
- Myalgias 17%-35%
- Other symptoms include dyspnea, sputum production and diarrhea in 3.8%.
- Encephalopathy is being increasingly recognized.
- Symptoms added to by the CDC include headache, repeated shaking chills, myalgias, sore throat and anosmia.
- A Guillian-Barre-like syndrome has been reported in some patients with COVID-19. N Engl J Med 2020 Apr 17; [e-pub]. (https://doi.org/10.1056/NEJMc2009191)
- Pharyngeal erythema-46%
- Fever-42% (>39C in 9%)
- Vomiting, rhinorrhea, congestion
- 16% were asymptomatic but this number is likely higher since individuals with symptoms are more likely to get tested.
- A Kawasaki-like syndrome, teremed Multisystem Inflammatory Syndrome in Children (MIS-C). has been increasingly reported in children.
The CDC has advised being on the lookout for the increasingly reported Any such cases should be reported to the CDC. The case definition (verbatim from the CDC) is as follows:
- An individual aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
- No alternative plausible diagnoses; AND
- Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms
- Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
- Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin
Additional Considerations (per CDC)
Some individuals may fulfill full or partial criteria for Kawasaki Disease, but should be reported if they meet the case definition for MIS-C.
Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection
Additional information can be found here: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19)
The CDC reports that the medium time to dyspnea ranged from 5-8 days in those patients who developed severe disease. For those that developed critical disease, the medium time to development of ARDS ranged from 8-12 days.
Symptoms of severe disease mediated by cytokine storm include SIRS with hypotension, capillary leak syndrome, renal failure, ARDS, myocarditis with heart failure, etc. A markedly elevated serum ferritin is an early marker of cytokine storm.
It is now clear from multiple studies that 10-43% of patients with COVID-19, especially those who are critically ill, are hypercoagulable. The exact number is not well elucidated. Studies differed with variations in severity of illness presentation among patients.
Twenty-percent of 200 severe patients had an elevated aPTT with 91% of these patients being positive for a lupus-anticoagulant. Anticoagulants and thrombolytics should not be withheld on the basis of an elevated aPTT. (NEJM May 5, 2020 DOI: 10.1056/NEJMc2013656).
This hypercoagulability results in both arterial and venous thromboses. It has been known almost from the start of the epidemic that an elevated d-dimer in COVID-19 patients is a marker for poor outcomes since the d-dimer is a marker for ongoing thrombosis. The thrombotic complications seen in COVID-19 include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, acute coronary syndrome (ACS)/myocardial infarction (MI), limb ischemia and gastrointestinal (GI) ischemia. There are also reports of cardiac valve clots.
Patients with COVID-19 associated coagulopathy generally have normal clotting studies (aPTT, PT/INR) but may have an elevated aPTT reflecting an anticardiolipin antibody/lupus-like anticoagulant (90% in one series of those with an elevated aPTT). Unlike in disseminated intravascular coagulation (DIC), hypercoagulable COVID-19 patients often have normal or slightly high platelet counts and high fibrinogen. These patients are hypercoagulable despite the elevated aPTT and should be anticoagulated as per standard of care.
NEJM May 5, 2020 DOI: 10.1056/NEJMc2013656
Abdominal Visceral Infarction in 3 Patients with COVID-19 https://wwwnc.cdc.gov/eid/article/26/8/20-1161_article?deliveryName=USCDC_333-DM28184
Journal of Thrombosis and Heamostasis, https://onlinelibrary.wiley.com/doi/10.1111/jth.14888
See also: Spiezia, L. et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thrombosis and Hemostasis 21 April 2020 DOI https://doi.org/10.1055/s-0040-1710018
The possible list of differential diagnoses for COVID-19 is broad. Note that absolute prevalence of this disease will vary depending on your country and type of medical practice:
Infectious: Respiratory pathogens including (those tested on a respiratory pathogen panel noted with an *):
- Coronavirus* (Coronavirus detected on RPP is NOT COVID-19)
- Chlamydia pneumoniae*
- Human metapneumovirus (HmPV)*
- Human rhinovirus/enterovirus*
- Legionella pneumophilia
- Mycoplasma pneumoniae*
- Pneumocystis jirovecii (in immunocompromised hosts)
- Respiratory syncytial virus (RSV)*
- Rhinovirus (common cold)
- Streptococcus pneumoniae
- Infectious mononucleosis
- Acute HIV
- Primary viral or bacterial pneumonia
- Fungal pneumonia
- Aspiration pneumonia
- Pulmonary: Pulmonary edema, Pulmonary embolism, COPD exacerbation, asthma, Pulmonary hypertension/Cor pulmonale, ARDS, pneumonitis
- Cardiac: Acute Coronary syndrome, CHF, valvular disease
Other: Tumor, Acute Chest Syndrome (from Sickle Cell Disease)
- Less Common: Electronic cigarette (e-cigarette), or vaping, product use–associated lung injury” (EVALI), hypersensitivity pneumonitis, pulmonary infiltrates with eosinophilia, Loefler’s syndrome, polyangiitis with granulomatosis,
Pregnancy: Information on COVID-19 in pregnancy can be found here.
Inpatient obstetrics: Information on handling inpatient obstetrics can be found here
- Pediatrics: Information on COVID-19 in children can be found here.
Testing: Additional Testing information including criteria for testing can be found here.
PCR testing for COVID-19 (2019-nCoV rRT-PCR):
Sensitivity: Based on limited data, reverse-transcriptase PCR is positive in those with active disease 93% of the time using a BAL specimen, 72% of the time for sputum and 63% for nasal swabs. (JAMA 2020 Mar 11; [e-pub]. https://doi.org/10.1001/jama.2020.3786) There are many tests on the market and their clinical characteristics will vary.
- A rapid test is now available from Abbott labs using isothermal nucleic acid amplification. Sensitivity is as low as 85% in a post-market study done at the Cleveland Clinic. No doubt more information will be forthcoming.
- A nasopharyngeal specimen is preferred over just an anterior nasal swab.
The CDC has issued guidelines for antibody testing. Among the recommendations are:
- Using an FDA reviewed test.
- Using a test with a specificity of 99.5% or greater, as screening will likely result in a high level of false positives.
- Focusing on high risk individuals is more likely to be useful than mass screening because of the lower positive predictive value in low risk populaitons.
- Being aware that testing for neutralizing antibodies has not yet been approved in the US.
- Being similarly aware that IgA testing is not recommended at this time (IgG and IgM testing are both available).
- Avoiding use of serologic test results to make decisions about who can return to work.
- Avoiding use of serologic tests “to make decisions about grouping persons residing in or being admitted to congregate settings, such as schools, dormitories, or correctional facilities.”
Non-specific laboratory findings may include lymphopenia (82%) and less commonly a leukocytosis. Additional findings include and elevated LDH (98%), elevated CRP (85%), elevated D-dimer, elevated Interleukin-6 (IL-6) and elevated transaminases. The ferritin is “always” elevated in severe patients with cytokine release syndrome (cytokine storm).
An elevated D-dimer, severe lymphopenia and coagulation abnormalities are associated with a worse outcome.
An elevated troponin suggests COVID-19 related myocarditis. However, this can also been seen in patients with an NSTEMI associated with demand in sepsis or heart failure exacerbations.
Procalcitonin is generally normal but if elevated portends a worse course.
Pitfalls: Eighteen to 50% of test positive patients may be asymptomatic at the time of testing complicating control efforts. (Euro surveill. 2020;25(10):pii=2000180. https://doi.org/10.2807/1560-7917.ES.2020.25.10.2000180)\
- New guidelines for discontinuing patients from home isolation can be found here.
- Guidelines for the discontinuation of transmission-based precautions for hospitalized patients are with COVID-19 are here.
- New breast feeding guidelines can be found here.
Return to work criteria for critical infrastructure workers have changed. The new criteria can be found here. These workers include:
- Federal, state, & local law enforcement
- 911 call center employees
- Fusion Center employees
- Hazardous material responders from government and the private sector
- Janitorial staff and other custodial staff
- Workers – including contracted vendors – in food and agriculture, critical manufacturing, informational technology, transportation, energy and government facilities
- Home Care for a patient with COVID-19 or who have a known exposure to COVID-19 a can be found here.
- Steps a patient should take if they are homebound and have COVID-19 or are a person under investigation are here.
- Personal protective equipment for health care personnel including a list of aerosol-producing procedures can be found here.
Apple has a CDC approved website and app to help people decide whether
or not they need isolation, testing, etc. It can be found at: https://www.apple.com/covid19/ and in the iOS app store by the name of Apple COVID-19.
Radiograph: Chest x-ray may show a “viral” pneumonia with an abnormal chest CT in 85% (63% in children). The most common pattern is bilateral “ground glass” appearance (56%, 33% in children) and bilateral patchy infiltrates (52%, 12% in children) with 18% of children having unilateral patchy infiltrates.
Rapidly Progressive Phase
8 March 2020. Licensed under Creative Commons Attribution 4.0
Jin, Y., Cai, L., Cheng, Z. et al.
Ultrasound: There are very preliminary studies using ultrasound for diagnosis from which we can’t draw conclusions. Ultrasound findings in these small studies include B-lines, pleural thickening and subpleural consolidations.
Potential Aerosol Generating Procedures (per University of Iowa):
- Nebulized medication administration (consider MDI with space instead).
- Manual ventilation before intubation
- Endotracheal intubation
- High-frequency oscillating ventilation
- Open suctioning
- Sputum induction
- *Note that high-flow nasal cannula is not considered high risk
Treatment: For more information, please refer to the body of World Health Organization articles about COVID-19 to date.
Patients with COVID-19 who demonstrate very mild illness may not require hospitalization (refer here for criteria on which patients should be screened for COVID-19). Determining which patients may be screened and treated as outpatients as opposed to which patients should present for in-person screening is individualized, but those who are elderly or have chronic, underlying lung disease are part of a higher risk population group.
COVID-19 has been associated with profound cytokine storm leading to a hyperinflammatory state. A component of immune dysregulation is also suspected, and the virus may have a potential for attacking specifically T lymphocytes. In the most severe cases, this can progress to fulminant ARDS, multisystem organ failure, and fatal dysrhythmias. While much is to be learned about this disease, interleukin-6 (IL6) is at least one of the mediators of cytokine storm-related organ dysfunction. Additional clinical manifestations of this cytokine storm syndrome include capillary leak syndrome, hypotension, renal disease, myocarditis with heart failure, and renal failure. A markedly elevated serum ferritin is an early marker of cytokine storm. Cytokine storm related myocarditis and heart failure is the cause of at least some COVID-19 related mortality.
The treatments for COVID-19 are largely supportive and include management complications such as hypoxia and shock.
The SCCM guidelines recommend that high flow nasal cannula (HFNC) be used over conventional oxygen therapy for management of hypoxia in patients with COVID-19. Some data suggests that patients may be less likely to require intubation as compared to those managed with traditional oxygen therapy. The SCCM reports data is lacking for the concern that HFNC increases the risk for aerosolization of COVID-19. The SCCM further recommends that HFNC be used over non-invasive positive pressure ventilation (NIPPV) for the management of hypoxic respiratory failure in patients with COVID-19 as NIPPV is showing a high failure rate in COVID-19 and also a much higher risk of transmitting the virus to health-care providers due to aerosolization of particles. The SCCM guidelines note certain situations in which NIPPV may be beneficial, and also note that patients on either HFNC or NIPPV should be monitored carefully as they are at risk for very rapid decline and early intubation should be considered.
Ventilation Strategies: In contrast to viral pneumonia, which is often complicated by superimposed bacterial pneumonia, some severely ill patients are progressing directly to acute respiratory distress syndrome (ARDS). For those patients that require intubation, the SCCM guidelines recommend ARDS volume ventilation strategies, with low tidal volume, high PEEP, lung protective ventilation with target plateau pressures of <30 cm H20. They also recommend recruitment maneuvers if patients experience hypoxia despite optimizing mechanical ventilation. They recommend against the utilization of staircase recruitment maneuvers. The SCCM guidelines recommend proning strategies in patients with moderate to severe ARDS with neuromuscular blockage for up to 28 hours. New data suggests that "self proning" can improve oxygenation in hypoxic paitents although it isn't clerar if it reduces the rate of intubation.
Nitric Oxide: While the routine use of nitric oxide is not recommended, a trial of an inhaled pulmonary vasodilator can be used per the SCCM guidelines in those patients with severe ARDS. If no improvement is seen, it should be tapered off.
ECMO: While there are no clinical trials that have reported data on the outcomes of venovenous ECMO in patients with COVID-19, the SCCM guidelines do recommend this as a rescue therapy for patients who experience refractory hypoxia despite proning, paralysis and maximum optimization via mechanical ventilation.
Steroids: The SCCM guidelines do not recommend steroids for treatment of mechanically ventilated patients without ARDS. They do recommend systemic corticosteroids in patients with COVID-19 and ARDS, though issued a statement that this is a weak recommendation with low quality evidence and not all board members agreed, that some wished not to issue a recommendation without further evidence.
Fluids and Pressors: The SCCM Guidelines recommends for adults with COVID-19 and shock, that crystalloids be used as fluid resuscitation of choice. They recommend that norepinephrine be the first line pressor, with vasopressin be added as the second line vasopressor. If norepinephrine is not available, vasopressin or epinephrine should be used as the first line vasopressor agent to target a MAP goal of 60-65 mm Hg. The SCCM recommends that dobutamine be added if there is evidence of continued cardiac dysfunction with hypoperfusion despite adequate fluid resuscitation despite norepinephrine.
Steroids in refractory shock: For patients with refractory shock, the SCCM guidelines recommend low-dose corticosteroid therapy as opposed to high-dose corticosteroid therapy (200mg hydrocortisone/day) typically utilized in septic shock used to combat acute, secondary adrenal insufficiency.
Antibiotics: The SCCM guidelines recommend empiric antimicrobial therapy for mechanically ventilated patients with COVID-19 with daily reassessment of need and potential for de-escalation.
Fever Control: The SCCM guidelines recommend the use of acetaminophen for fever control, noting that it may increase patient comfort and does not increase the rate of mortality. They note that enough evidence is not available to recommend the use of non-steroidal anti-inflammatory drugs.
Anticoagulation: There is consensus that “all” patients admitted to the hospital should be treated with prophylactic-dose heparin (e.g. enoxaparin or others) and should have a low threshold for evaluation of blood clot (e.g. chest CT, extremity doppler, etc.). If a patient is deteriorating and CT for PE will be delayed, it is reasonable to start full anticoagulation while awaiting study results, balancing treatment with consideration of bleeding risk.
Some institutions are starting full-dose anticoagulation on critically ill patients without known clot, which remains controversial.
Lopinavir/ritonavir: The SCCM guidelines recommends against routine use of lopinavir/ritonavir for management of patients with COVID-19 and says there is insufficient evidence to provide a recommendation on any other antivirals for treatment of patients with COVID-19 at this time. Lopinavir/Ritonavir has been shown to be ineffective in the treatment of COVID-19 in a 199 person randomized trial. All patients were hospitalized and had a PO2 of <94%. There was no difference in time to clinical improvement. There was no difference in 28-day mortality (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7) or detectable viral RNA. (NEJM. https://www.nejm.org/doi/full/...) DOI: 10.1056/NEJMoa2001282
The Infectious Disease Society of America (IDSA) recommends that lopinavir/ritonavir be used in the treatment of COVID-19 only in the context of a clinical trial.
The results of the long-awaited remdesivir trial have been released; remdesivir seems to reduce the duration of illness in those hospitalized patients with mild illness. There was no mortality benefit observed in this study.
1063 patients with COVID-19 were randomized to either placebo or up to 10 days of remdesivir. The principle outcome was time to recovery, defined by either by discharge from the hospital or clinical recovery with continued hospitalization for isolation purposes only. The recovery time was 11 days in those getting remdesivir versus 15 days those getting placebo (p<0.001).
Unfortunately, there was no difference in mortality (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Additionally, the benefit was only seen in patients who were receiving low flow oxygen. Intubated patients, those requiring high flow oxygen and/or non-invasive ventilation and those not requiring oxygen did not benefit. Early treatment seems to be key in the use of remdesivir. The FDA has given emergency approval for the use of remedesivir in hosptialized patients.
NEJM May 22, 2020 DOI: 10.1056/NEJMoa2007764
Tocilizumab (anti-IL 6) is a humanized immunoglobulin that blocks receptor binding to IL-6. Randomized controlled trials are underway exploring the use of in efforts to suppress the hyperinflammatory syndrome associated with COVID-19. Secondary hemophagocytic lymphohistiocytosis (sHLH) has been seen to develop in this patient population and is characterized by fulminant and fatal hypercytokinaemia with multiorgan failure. This mechanism is also an important component by which patients are developing fulminant myocarditis, an often fatal consequence of COVID-19 in very severe cases. SCCM guidelines state that there is insufficient data to issue a recommendation for or against use of tocilizumab (anti-IL 6) in the treatment of COVID-19 in critically ill adults. The Infectious Disease Society of America (IDSA) recommends that tocilizumab be used in the treatment of COVID-19 only in the context of a clinical trial.
Interferon beta-1a showed no benefit in a well done randomized, controlled trial of ARDS (not specific to COVID-19) (JAMA. 2020;323(8):725-733. doi:10.1001/jama.2019.22525). The SCCM guidelines state that there is insufficient data to issue a recommendation for or against use of interferon in the treatment of COVID-19 in critically ill adults.
Hydroxychloroquine and Chloroquine have been suggested as a treatment for COVID-19. The great majority of the data so far argues for no benefit and a likely harm.
We now have a retrospective analysisof 96,032 patients who were treated with chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide. Attempts were made to control for factors such as cardiovascular disease, diabetes mellitus, age, lung disease and baseline severity. Of the patients, 1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide. The other 81,144 patients were in the control group.
The bottom line is that there was no benefit to drug treatment and an increase in mortality with treatment (control group 9·3% vs 16.4% in the chloroquine group and up to 24% mortality with hydroxychloroquine plus a macrolide).
WHO has stopped ongoing studies of these drugs based on this data. Until there is a controlled trial, these drugs should not be used for inpatient treatment as there is likely significant harm. It should be noted, however, that this was not a controlled trial and adjustment for comorbidities is always imprecise.
The Lancet. May 22, 2020DOI:https://doi.org/10.1016/S0140-6736(20)31180-6
ACE-I and Angiotensin-II receptor antagonists (ARBs): The primary route of virus entry into cells seems to be ACE2 receptors which are blocked by ARBs. However, ARBs upregulate the ACE2 receptor. There is no data suggesting that ARBS or ACE-I worsen outcomes in COVID-19 and they may be beneficial.
Mehra MR et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19 May 1, 2020 DOI: 10.1056/NEJMoa2007621
Convalescent serum: A study of five patients with severe disease showed improvement after the use of convalescent serum. (JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783. An additional uncontrolled trial of 10 patients also suggests benefit (This shows promise but data is still very limited. It is being used on protocol at some hospitals.
NSAIDS: There is no evidence that NSAIDS worsen the course or outcome of COVID-19.
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