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COVID-19 and Coagulopathy: ISTH Issues Guidance on Diagnosis and Management

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date

SUMMARY:

The ISTH released guidance on the recognition and management of coagulopathy in the setting of COVID-19. The ISTH emphasizes the term ‘interim’ as the medical community continues to learn more about the clinical course of those infected with SARS-CoV-2. The stated goal of this guidance is

…to provide a risk stratification at admission for a COVID‐19 patient and management of coagulopathy which may develop in some of these patients, based on easily available laboratory parameters

Recommended Labs at Admission (decreasing order of importance)

D-dimers

  • Consider hospital admission for patients with markedly raised D-dimers even in absence of other severity symptoms
    • “Arbitrarily defined as three-four fold increase”
    • High levels indicate increased thrombin generation

Note: This guidance does not address pregnancy specifically | D-dimer is elevated in normal pregnancy (see ‘Learn More – Primary Sources’ below)

Prothrombin time (PT)

  • Current literature is demonstrating mild prolongation of PT at admission in ICU vs non-ICU cohorts (e.g., 12·2 s vs 10·7 s; Huang et al. Lancet, 2020)
  • Caution: Such “subtle changes” will not be as readily identified if PT is reported as INR

Thrombocytopenia

  • Unlike typical sepsis, thrombocytopenia at admission for COVID-19 was not as strong an indicator of sepsis mortality
  • The authors state that “thrombocytopenia at presentation may be but not consistent prognosticator”

Monitoring Coagulation Markers

  • Monitor D-dimers, platelet count, PT and fibrinogen to identify worsening coagulopathy
    • Worsening parameters: “More aggressive critical care support is warranted” including consideration of ‘experimental’ therapies and blood product support
    • Stable or improving parameters: Provides “added confidence for stepdown of treatment if corroborating with the clinical condition”

DIC

  • Importance of regular laboratory monitoring
    • Day 4: In one study (Tang et al. J Thromb Haemost, 2020), DIC was much more likely to develop on day 4 among nonsurvivors vs survivors (71.4% vs 0.6%)
  • Days 10 and 14: Statistically significant increase in D-dimer levels, and PT, and decrease in fibrinogen levels were likewise seen in nonsurvivors

KEY POINTS:

Management Points

  • Inhibition of thrombin generation may reduce risk for multi-organ failure in the setting of sepsis

Prophylactic LMWH

  • “Should be considered in ALL patients (including non-critically ill) who require hospital admission for COVID-19 infection, in the absence of any contraindications (active bleeding and platelet count less than 25 x 109 /L)”
  • Monitor closely if severe renal impairment is present
  • “Abnormal PT or APTT is not a contraindication”
  • Additional benefits of LMWH include
    • VTE prevention
    • Anti-inflammatory properties

Parameter Thresholds

  • Non-bleeding patients: Maintain
    • Platelet count >20 x 109/L
    • Fibrinogen >2.0 g/L
  • Bleeding patients (rare in setting of COVID-19): Maintain
    • Platelet count >50 x 109/L
    • Fibrinogen >2.0 g/L
    • PT ratio <1.5 (note: not the same as INR)

Other therapies to manage coagulopathy

  • Should be considered experimental, for example
    • Antithrombin supplementation | Recombinant thrombomodulin | Hydroxychloroquine

Lancet Haematology – Expert Opinion

Hospitalized Patients (Severe COVID-19)

  • Closely monitor patient for coagulopathy: Repeat every 2–3 days
    • D-dimer
    • PT
    • Platelet counts
  • Administer subcutaneous LMWH for all hospitalized patients
    • Evidence to support this practice in severe COVID-19 | “In view of the hypercoagulable state of patients with severe COVID-19, and the potential increased risk of thrombosis, we suggest that all patients with COVID-19 that are admitted to hospital should receive this prophylactic treatment in the absence of medical contraindications”
  • Be on alert for VTE
    • Consider VTE in the setting of rapid respiratory deterioration and/or high D-dimer concentrations
    • CT angiography or ultrasound of the venous system of the lower extremities

Note: If diagnostic testing is not possible and there are no bleeding risk factors, consider therapeutic anticoagulation | Experimental therapies such as plasma exchange, or administration of other anticoagulants or anti-inflammatory drugs should only be undertaken via clinical trials

Learn More – Primary Sources:

ISTH interim guidance on recognition and management of coagulopathy in COVID‐19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China (Huang et al. Lancet 2020)

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia (Tang et al. J Thromb Haemost, 2020)

D-dimer During Pregnancy: Establishing Trimester-Specific Reference Intervals

Coagulation abnormalities and thrombosis in patients with COVID-19 (Lancet Haematology Expert Comment)

Critical Care Medicine: Coagulopathy of Coronavirus Disease 2019

COVID-19, ACE Inhibitors and ARBs: Professional Guidance and Evidence Update

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date

SUMMARY:

Coronavirus disease 2019 (COVID-19) is an infection caused by the SARS-CoV-2 virus. The virus is known to target the angiotensin converting enzyme 2 (ACE-2) co-receptor. Therefore, concern has been raised whether the use of common medications that impact ACE and the renin angiotensin system may also result in increased COVID-19 infection risk. Papers have now been published demonstrating no increased risk with use of ACE inhibitors or angiotensin receptor blockers (ARBs).

High Risk Groups for COVID-19 infection

  • Patients at higher risk for significant morbidity and mortality from COVID-19 infection include older patients, especially those with chronic medical conditions such as the following
    • Pulmonary disease
    • Cardiac disease
    • Kidney disease
    • Diabetes
    • Hypertension
  • It is unclear whether the above associations are independently related to pathogenesis, other associated comorbidities, or even treatment
    • These disorders themselves are not necessarily independent and often appear together in patients, particularly in the context of the metabolic syndrome
  • ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19

Angiotensin Converting Enzymes

  • ACE-1 and ACE-2 are two major enzymes found in the renin-angiotensin system
    • ACE enzymes play a critical role in the balance of peptides in the angiotensin family
    • ACE-2 is found on
      • Epithelial cells in both respiratory and GI tracts
      • Cardiac and kidney cells

ACE Inhibitors and ARBs

  • ACE inhibitors and ARBs
    • Strongly influence angiotensin peptides
    • Increase ACE-2 activity in cardiac tissue

What We Currently Know about SARS-CoV-2 Infectivity

  • SARS-CoV-2 is covered with crown-like glycoprotein spikes (hence ‘corona’) comprised of 2 subunits
    • Subunit S1: Binds to ACE-2 on the cell surface
    • Subunit S2: Fuses with the cell membrane
    • TMPRSS2 (host enzyme): Promotes cellular entry of the virus

Do ACE Inhibitors and ARBs Increase Risk for COVID-19?

  • ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19
  • Theoretical risk raised
    • Because ACE inhibitors and ARBs ‘may’ increase expression of ACE-2 leading to greater risk for virus to enter and infect cells, could these medication lead to increased risk for COVID-19 morbidity and/or mortality?
  • Possible benefit
    • Study from China showed that while hypertension is a risk factor for COVID-19 mortality, patients on ACE inhibitors and ARBs did better (see review in ‘Learn More – Primary Sources’ below)
    • Underlying mechanism is unclear, but there may be a biphasic pattern: (1) In phase 1, these medications could increase infectivity (2) In phase 2, ACE-2 downregulation by the virus may be the “hallmark” of COVID-19 progression and therefore medications that upregulate in the second phase may be of benefit
    • In addition, there is a hypothesis that ACE-2 also stimulates one of the angiotensin peptides (angiotensin-(1-7)) that has positive anti-inflammatory effects | Therefore, medications that stimulate ACE-2 could have a beneficial effect

Current Evidence

  • Zhang et al. (Circ Res, 2020)
    • Retrospective, multi-centered study | 1128 hospitalized patients with COVID-19 | ACE Inhibitors/ARB group: 188
    • After adjustment, detected risk for all-cause mortality was lower in the ACE Inhibitors/ARB group compared to the non-ACE Inhibitors/ARB group
    • Adjusted hazard ratio: 0.42 (95% CI, 0.19 to 0.92; p = 0.03)
    • These medications may be associated with a lower risk of all-cause mortality in the setting of COVID-19 compared to non-users
  • Reynolds et al. (NEJM, 2020)
    • 12,594 tested | 5894 patients positive for COVID-19 | Severe in 17%
    • Hypertension history: 34.6% of tested patients | 59.1% were COVID-19 positive had a positive test | Severe in 24.6%
    • Authors conclude that there was no association with likelihood of a positive test or severity of illness
  • Mancia et al. (NEJM, 2020)
    • Population-based case–control study | 6272 patients with confirmed SARS-CoV-2 infection
    • Use of ARBs or ACE inhibitors did not show any association with Covid-19 overall or those with severe or fatal disease
  • Editorial (Jarcho et al. NEJM, 2020)
    • The accompanying editorial recognizes limitations inherent in observational data
    • However, these studies support professional guidance that recommend against altering these medications when indicated
    • Furthermore, the editorial authors state

Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe Covid-19 among those infected, or the risk of in-hospital death among those with a positive test. 

KEY POINTS:

Recommendations

  • Guidance is based on the current lack of evidence that ACE inhibitors or ARBs increase risk of infection or result in a more severe course of COVID-19 disease
    • It is acknowledged that new data may result in a future update to these guidelines
  • Professional recommendations do not support stopping or changing medications for patients who are currently being treated with ACE inhibitors or ARBs
  • In addition, cessation is associated potential for significant harms including
    • Medical risk: Exacerbation of underlying medical conditions
    • Infection risk: Due to increased pharmacy encounters, visits for blood work etc.
  • The HFSA/ACC/AHA recommends

…continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease

In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation

Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice

Learn More – Primary Sources:

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19 (Vaduganathan et al., NEJM)

Drugs and the renin-angiotensin system in covid-19 (BMJ)

HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19

COVID-19: An ACP Physician’s Guide and Resources

European Medicines Agency: EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic

British Society for Heart Failure (BHF) and British Cardiology Society (BCS): Statement on ACI Inhibitors and ARBs in COVID-19

Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19 (Zhang et al. Circ Res, 2020)

Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19 (Reynolds et al. NEJM, 2020)

Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19 (Mancia et al. NEJM, 2020)

Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19 (Editorial. NEJM 2020)

COVID-19 Testing: CDC Guidance on Virus and Antibody Testing

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date.

SUMMARY:

The CDC has provided guidance on both viral testing for SARS-CoV-2 as well as the role of antibody testing. Testing for the presence of the virus during the pandemic remains the current diagnostic standard. While antibody testing can play a role for public health teams to understand the spread of the disease, currently its use as a diagnostic test for individuals remains limited. A COVID-19 vaccine will not affect the results of SARS-CoV-2 viral tests.

Viral Testing

Specimen Collection

  • Obtain an upper respiratory specimen for initial diagnostic testing
    • A nasopharyngeal (NP) specimen collected by a healthcare professional  or
    • An oropharyngeal (OP) specimen collected by a healthcare professional  or
    • A nasal mid-turbinate swab collected by a healthcare professional or by a supervised onsite self-collection (using a flocked tapered swab)  or
    • An anterior nares (nasal swab) specimen collected by a healthcare professional or by onsite or home self-collection (using a flocked or spun polyester swab)  or
    • Nasopharyngeal wash/aspirate or nasal wash/aspirate (NW) specimen collected by a healthcare professional
  • Lower respiratory tract specimens
    • Collect and test sputum in patients who develop a productive cough | Induction of sputum is not recommended
    • Under certain clinical circumstances (e.g., those receiving invasive mechanical ventilation), a lower respiratory tract aspirate or bronchoalveolar lavage sample should be collected and tested as a lower respiratory tract specimen

How is SARS-CoV-2 RNA Testing Performed?

RT-PCR

  • Usually performed using real-time reverse transcription polymerase chain reaction (RT-PCR)
    • Qualitative detection of RNA
  • Multiple tests on the market that can target various genes
    • Envelope (env) | Nucleocapsid (N) | Spike (S) | RNA-dependent RNA polymerase (RdRp) | ORF1
  • A positive test can only determine presence of SARS-CoV-2 RNA and not whether the virus is intact and capable of infecting others

Antigen

  • Antigen tests can quickly detect fragments of proteins found on or within the virus by testing samples collected from the nasal cavity using swabs
  • The benefit of antigen testing is speed, with results potentially available within minutes
  • However, antigen tests, while very specific for the virus, are not as sensitive as molecular PCR tests
    • Positive antigen results: Highly accurate but higher chance of false negatives | Negative antigen results may still need PCR confirmation prior to treatment decisions or to prevent inadvertent spread of SARS-CoV-2

Note: Prior receipt of a COVID-19 vaccine should not affect the results of SARS-CoV-2 viral tests (NAAT or antigen)

Breath Sample Analysis

  • FDA has issued an emergency use authorization (EUA) for a diagnostic test that detects chemical compounds in breath samples associated with a SARS-CoV-2 infection
  • Test is performed by a qualified, trained operator under the supervision of a health care provider licensed or authorized by state law to prescribe tests
  • Results available in <3 minutes

Diagnostic Testing

Signs or Symptoms of COVID-19

  • Positive test
    • NAAT: Indicates infection regardless of vaccine status
    • Positive antigen test result may need confirmatory testing if the person has a low likelihood of SARS-CoV-2 infection (e.g., no known exposure to a person with COVID-19 within the last 14 days or is fully vaccinated or has had a SARS-CoV-2 infection in the last 3 months)
    • Isolate if positive test: Discontinue isolation 5 days after symptom onset and at least 24 hours after the resolution of any fever (without the use of fever-reducing medications) | Continue to wear mask around others for 5 additional days
      • Some individuals may require extended isolation and precautions (e.g., severely immunocompromised)
      • Testing is not recommended to determine when infection has resolved
      • Loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation​
  • Negative test
    • If symptoms are consistent with COVID-19, may be a false negative | Isolation and further discussion with healthcare professional recommended

Testing to determine resolution of infection

  • May be appropriate for severe illness or immunocompromise
  • “For all others, a test-based strategy is no longer recommended except to discontinue isolation or precautions earlier than would occur under the symptom-based strategy”

Screening Testing

No Symptoms and No Close Contact with Someone Known to Have a COVID-19 Infection

  • Asymptomatic or presymptomatic infection contribute to community SARS-CoV-2 transmission
    • May help with re-opening of businesses, communities, and schools
  • Point-of-care tests (e.g., antigen tests) can be particularly helpful due to short turn-around times
  • Quarantine not required while results are pending
  • Examples of screening programs
    • Testing employees in a workplace setting
    • Testing students, faculty, and staff in a school or university setting
    • Testing a person before or after travel

How Early Will a Test Be Positive and How Long Until Negative?

  • In patient with COVID-19 infection who tested positive using a nasopharyngeal swab
    • Earliest detection: Day 1 of symptoms
    • Peak levels highest within week 1 and therefore probability of detection will be highest during that time
    • Viral load declines by week 3 and therefore virus more likely to be undetectable in to week 4
    • Infection severity: More virus may be present in patients with severe disease and therefore it may take longer to obtain a negative test result vs someone with a mild COVID-19 infection

Performance of RT-PCR Viral Tests

  • RT-PCR specificities are close to 100% because they target specific RNA sequences of the SARS-CoV-2 virus
  • False negative results may be due to
    • Inappropriate timing of collection vs symptom onset
    • Poor sampling technique (need to sample at the back of the nose)
  • False positive results may occur due to lab error or contamination
  • However, even with good analytic performance, PPV and NPV are related to prevalence and therefore can differ between geographic regions
    • In a setting with high COVID-19 prevalence, a negative test does not necessarily rule out the possibility that an individual is infected with SARS-CoV-2

Antibody Testing

General CDC Antibody Guidance

  • According to the CDC

Antibody testing does not replace virologic testing and should not be used to establish the presence or absence of acute SARS-CoV-2 infection

Antibody testing is not currently recommended to assess for immunity to SARS-CoV-2 following COVID-19 vaccination, to assess the need for vaccination in an unvaccinated person, or to determine the need to quarantine after a close contact with someone who has COVID-19

Some antibody tests will not detect the antibodies generated by COVID-19 vaccines

Because these vaccines induce antibodies to specific viral protein targets, post-vaccination antibody test results will be negative in persons without history of previous infection, if the test used does not detect antibodies induced by the vaccine

  • In general, antibodies will be detectable 7 to 14 days after illness onset and will be present in most people by 3 weeks
    • Infectiousness likely decreased by that time
    • Evidence suggests some degree of immunity will have developed
  • IgM and IgG can appear together, usually within 1 to 3 weeks
    • IgG antibodies appear to persist for at least several months
    • Some individuals may be infected but will not develop antibodies
  • Neutralizing antibodies can also be identified and are associated with immunity
  • FDA requires companies providing antibody testing to obtain an EUA

What Are the Different Types of Antibody Tests?

  • Antigenic Targets
    • Spike glycoprotein (S): Present on viral surface and facilitates virus entry
    • Nucleocapsid phosphoprotein (N): Immunodominant and interacts with RNA
    • Protein targeting is important to reduce cross-reactivity (cause of false positives which may occur with other coronaviruses like the common cold) and improve specificity
  • Types of Antibody Testing
    • Binding antibody detection that use purified SARS-CoV-2 (not live virus)
      • Point-of-care (POC) tests
      • Laboratory tests that usually require skilled personnel and specialized equipment
    • Neutralizing antibody detection (none currently FDA authorized)
      • Serum or plasma is incubated with live virus followed by infection and incubation of cells
      • Can take up to 5 days to complete the study

When Can Antibody Testing be Helpful?

Antibody testing may be helpful in the following situations

  • Seroconversion: In a patient who did not receive a positive viral test
    • A positive antibody test at least 7 days following acute illness onset but a previous negative antibody test may indicate new onset SARS-CoV-2 infection
  • To support a diagnosis in the presence of a complex clinical situation, such as patients who present with COVID-19 complications (e.g., multisystem inflammatory syndrome and other post-acute sequelae of COVID-19)
    • Note: Due to antibody persistence, a single positive antibody test result may reflect previous SARS-CoV-2 infection and not a recent illness
  • Clinical, occupational health, and public health purposes, such as serologic surveys

Vaccination and Test Interpretation

  • In a person never vaccinated
    • testing positive for antibody against either N, S, or RBD indicates prior natural infection
  • In a vaccinated person
    • Testing positive for antibody against the vaccine antigen target, such as the S protein, and negative for other antigen: Suggests vaccine-induced antibody and not SARS-CoV-2 infection
    • Testing positive for any antibody other than the vaccine-induced antibody, such as the N protein: Indicates resolving or resolved SARS-CoV-2 infection that could have occurred before or after vaccination
  • The CDC states that

SARS-CoV-2 antibodies, particularly IgG antibodies, might persist for months and possibly years

Therefore, when antibody tests are used to support diagnosis of recent COVID-19, a single positive antibody test result could reflect previous SARS-CoV-2 infection or vaccination rather than the most recent illness

Learn More – Primary Sources:

CDC: Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19)

Interim Guidelines for COVID-19 Antibody Testing in Clinical and Public Health Settings

CDC: Overview of Testing for SARS-CoV-2

Interpreting SARS-CoV-2 Test Results

The Promise and Peril of Antibody Testing for COVID-19

EUA Authorized Serology Test Performance

Remdesivir Emergency Authorization: FDA Update and Summary of Preliminary NIH Study Data

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date

SUMMARY:

The FDA has issued an emergency use authorization (EUA) for the investigational antiviral drug remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. The approval is based on the NIH’s clinical trial showing “promising results.”

  • An EUA is different than a full FDA approval
    • An EUA is based on an FDA evaluation of evidence and risks vs potential or known benefits of of “unproven” products during an emergency
  • The FDA states

The emergency use authorization allows for remdesivir to be distributed in the U.S. and administered intravenously by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease

Severe disease is defined as patients with low blood oxygen levels or needing oxygen therapy or more intensive breathing support such as a mechanical ventilator

It was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use

KEY POINTS:

NIH Remdesivir Trial

  • RCT involving 1063 patients:
    • Adaptive COVID-19 Treatment Trial (ACTT)
    • Sponsored by the National Institute of Allergy and Infectious Diseases (NIAID)
    • Multicentered (including US, UK, and Singapore)
    • Started in February 2020
    • Current primary endpoint: Being well enough for hospital discharge or returning to normal activity level

Preliminary Data

  • Time to recovery
    • Median time to recovery: 11 days for remdesivir group vs 15 days for placebo group
    • 31% faster time to recovery in remdesivir group vs placebo (p<0.001)
  • Mortality Rate
    • 8.0% in remdesivir group vs 11.6% for the placebo group (p=0.059)
    • “Suggests benefit” but not statistically significant
  • Second (next) stage of trial
    • Remdesivir in combination with another agent | Likely to be a janus kinase inhibitor
  • One of the investigators (UK team) stated (April 30, 2020)

As far as the results are concerned, it’s cautious optimism

There is some effect but it is not a wonder effect

We have to find out when is the best time to give this drug, who benefits more

There is still a lot of data to come out of this trial

Learn More – Primary Sources:

Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment

NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19

Covid-19: Remdesivir is helpful but not a wonder drug, say researchers (BMJ)

COVID-19: Category Definitions, Symptoms and Those at Increased Risk

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date. This summary has been updated with the latest CDC guidelines on when to end quarantine.

SUMMARY:

The novel coronavirus, named SARS-CoV-2, is the pathogen underlying the pandemic (a global outbreak of disease). The disease associated with this virus has been officially named COVID-19. Coronaviruses represent a large family of viruses. They can cause human illness, but many are found in animals and, rarely, animal coronaviruses can evolve and infect people as was the case in previous infectious outbreaks such as MERS and SARS.



COVID-19 Categories (NIH Panel)

  • Asymptomatic or pre-symptomatic infection
    • Test positive for SARS-CoV-2 using a virologic test (i.e., a nucleic acid amplification test [NAAT] or an antigen test)
    • No symptoms that are consistent with COVID-19
  • Mild illness
    • Have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell)
    • No shortness of breath, dyspnea, or abnormal chest imaging
  • Moderate illness
    • Evidence of lower respiratory disease during clinical assessment or imaging and oxygen saturation (SpO2) ≥94% on room air at sea level
  • Severe illness
    • SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%
  • Critical illness
    • Respiratory failure, septic shock, and/or multiple organ dysfunction

Note: SpO2 is a key parameter for defining the illness categories listed above | Pulse oximetry has important limitations (e.g., skin pigmentation, thickness or temperature) | Clinicians who use SpO2 when assessing a patient must be aware of those limitations and conduct the assessment in the context of that patient’s clinical status

Pregnancy: Oxygen supplementation in pregnancy generally used when SpO2 <95% on room air at sea level to accommodate the physiologic needs of mother and fetus

Symptoms

  • Incubation period
    • Time from exposure to development of symptoms: 2 to 14 days
      • Delta variant studies: Mean incubation period of 4.3 days (see ‘Learn More – Primary Sources Below) which was shorter than initial variants (5.0 days)
      • Omicron variant studies: Median incubation period of 3 to 4 days
  • Signs and Symptoms
    • Fever or chills
    • Cough
    • Shortness of breath or difficulty breathing
    • Fatigue
    • Muscle or body aches
    • Headache
    • New loss of taste or smell
    • Sore throat
    • Congestion or runny nose
    • Nausea or vomiting
    • Diarrhea
  • Additional points regarding presentation
    • Older adults: Especially those with comorbidities may have delayed presentation of fever and respiratory symptoms
    • Fatigue, headache, and muscle aches (myalgia) are among the most commonly reported symptoms in people who are not hospitalized
    • Sore throat and nasal congestion or runny nose (rhinorrhea) also may be prominent symptoms
    • GI symptoms may be relatively common
      • Nausea, vomiting or diarrhea may occur prior to fever and lower respiratory tract signs and symptoms
    • Loss of smell (anosmia) or taste (ageusia) has been commonly reported, especially among women and younger or middle-aged patients

Those at Risk Based on Evidence (CDC)

  • Age

Age is the strongest risk factor for severe COVID-19 outcomes. Approximately 54.1 million people aged 65 years or older reside in the United States; in 2020 this age group accounted for 81% of U.S. COVID-19 related deaths, and as of September 2021 the mortality rate in this group was more than 80 times the rate of those aged 18-29

Higher Risk: Meta-analysis or systematic review demonstrates good or strong evidence

  • Asthma
  • Cancer
  • Cerebrovascular disease
  • Chronic kidney disease*
  • Chronic lung diseases limited to
    • Interstitial lung disease
    • Pulmonary embolism
    • Pulmonary hypertension
    • Bronchiectasis
    • COPD (chronic obstructive pulmonary disease)
  • Chronic liver diseases limited to
    • Cirrhosis
    • Non-alcoholic fatty liver disease
    • Alcoholic liver disease
    • Autoimmune hepatitis
  • Cystic fibrosis
  • Diabetes mellitus, type 1 and type 2*‡
  • Disabilities‡
    • Attention-Deficit/Hyperactivity Disorder (ADHD)
    • Cerebral Palsy
    • Congenital Malformations (Birth Defects)
    • Down syndrome
    • Limitations with self-care or activities of daily living
    • Learning Disabilities
    • Spinal Cord Injuries
    • See ‘Learn More – Primary Care’ CDC reference that includes extensive list for included disabilities
  • Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies)
  • HIV (human immunodeficiency virus)
  • Mental health disorders limited to
    • Mood disorders, including depression
    • Schizophrenia spectrum disorders
  • Neurologic conditions limited to dementia‡
  • Obesity (BMI ≥30 kg/m2 or ≥95th percentile in children)*‡
  • Primary Immunodeficiencies
  • Pregnancy and recent pregnancy
  • Physical inactivity
  • Smoking, current and former
  • Solid organ or hematopoietic cell transplantation
  • Tuberculosis
  • Use of corticosteroids or other immunosuppressive medications

Suggestive Higher Risk: Underlying medical condition or risk factor that neither has a published meta-analysis or systematic review nor completed the CDC systematic review process

  • Children with certain underlying conditions
  • Overweight (BMI ≥25 kg/m2, but <30 kg/m2)
  • Sickle cell disease
  • Substance use disorders

Comorbidities with mostly case series, case reports, or, if other study design, the sample size is small 

  • Overweight (BMI ≥25 kg/m2, but <30 kg/m2)
  • Sickle cell disease
  • Substance use disorders
  • Thalassemia

Mixed Evidence: Meta-analysis or systematic review is inconclusive, either because the aggregated data on the association between an underlying condition and severe COVID-19 outcomes are inconsistent in direction or there are insufficient data

  • Alpha 1 antitrypsin deficiency
  • Bronchopulmonary dysplasia
  • Hepatitis B
  • Hepatitis C
  • Hypertension*
  • Thallassemia

Footnotes:

* indicates underlying conditions for which there is evidence for pregnant and non-pregnant people

‡ underlying conditions for which there is evidence in pediatric patients

Learn More – Primary Sources:

Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare Providers

Impact of SARS-CoV-2 Delta variant on incubation, transmission settings and vaccine effectiveness: Results from a nationwide case-control study in France (Lancet Regional Health, 2022)

CDC: Clinical Presentation | Clinical Care Considerations

CDC Coronavirus Disease 2019: Overview of Testing for SARS-CoV-2

Clinical Questions about COVID-19: Questions and Answers

WHO: Novel coronavirus Information Page

JAMA: Coronavirus Disease 2019

FDA: Coronavirus Disease 2019

BMJ: Coronavirus Updates

NEJM: 2019 Novel Coronavirus

Annals of Internal Medicine: Content Related to Coronavirus in Annals of Internal Medicine

JAMA: What Is a Pandemic?

COVID-19: Category Definitions, Symptoms and Those at Increased Risk

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date. This summary has been updated with the latest CDC guidelines on when to end quarantine.

SUMMARY:

The novel coronavirus, named SARS-CoV-2, is the pathogen underlying the pandemic (a global outbreak of disease). The disease associated with this virus has been officially named COVID-19. Coronaviruses represent a large family of viruses. They can cause human illness, but many are found in animals and, rarely, animal coronaviruses can evolve and infect people as was the case in previous infectious outbreaks such as MERS and SARS.



COVID-19 Categories (NIH Panel)

  • Asymptomatic or pre-symptomatic infection
    • Test positive for SARS-CoV-2 using a virologic test (i.e., a nucleic acid amplification test [NAAT] or an antigen test)
    • No symptoms that are consistent with COVID-19
  • Mild illness
    • Have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell)
    • No shortness of breath, dyspnea, or abnormal chest imaging
  • Moderate illness
    • Evidence of lower respiratory disease during clinical assessment or imaging and oxygen saturation (SpO2) ≥94% on room air at sea level
  • Severe illness
    • SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%
  • Critical illness
    • Respiratory failure, septic shock, and/or multiple organ dysfunction

Note: SpO2 is a key parameter for defining the illness categories listed above | Pulse oximetry has important limitations (e.g., skin pigmentation, thickness or temperature) | Clinicians who use SpO2 when assessing a patient must be aware of those limitations and conduct the assessment in the context of that patient’s clinical status

Pregnancy: Oxygen supplementation in pregnancy generally used when SpO2 <95% on room air at sea level to accommodate the physiologic needs of mother and fetus

Symptoms

  • Incubation period
    • Time from exposure to development of symptoms: 2 to 14 days
      • Delta variant studies: Mean incubation period of 4.3 days (see ‘Learn More – Primary Sources Below) which was shorter than initial variants (5.0 days)
      • Omicron variant studies: Median incubation period of 3 to 4 days
  • Signs and Symptoms
    • Fever or chills
    • Cough
    • Shortness of breath or difficulty breathing
    • Fatigue
    • Muscle or body aches
    • Headache
    • New loss of taste or smell
    • Sore throat
    • Congestion or runny nose
    • Nausea or vomiting
    • Diarrhea
  • Additional points regarding presentation
    • Older adults: Especially those with comorbidities may have delayed presentation of fever and respiratory symptoms
    • Fatigue, headache, and muscle aches (myalgia) are among the most commonly reported symptoms in people who are not hospitalized
    • Sore throat and nasal congestion or runny nose (rhinorrhea) also may be prominent symptoms
    • GI symptoms may be relatively common
      • Nausea, vomiting or diarrhea may occur prior to fever and lower respiratory tract signs and symptoms
    • Loss of smell (anosmia) or taste (ageusia) has been commonly reported, especially among women and younger or middle-aged patients

Those at Risk Based on Evidence (CDC)

  • Age

Age is the strongest risk factor for severe COVID-19 outcomes. Approximately 54.1 million people aged 65 years or older reside in the United States; in 2020 this age group accounted for 81% of U.S. COVID-19 related deaths, and as of September 2021 the mortality rate in this group was more than 80 times the rate of those aged 18-29

Higher Risk: Meta-analysis or systematic review demonstrates good or strong evidence

  • Asthma
  • Cancer
  • Cerebrovascular disease
  • Chronic kidney disease*
  • Chronic lung diseases limited to
    • Interstitial lung disease
    • Pulmonary embolism
    • Pulmonary hypertension
    • Bronchiectasis
    • COPD (chronic obstructive pulmonary disease)
  • Chronic liver diseases limited to
    • Cirrhosis
    • Non-alcoholic fatty liver disease
    • Alcoholic liver disease
    • Autoimmune hepatitis
  • Cystic fibrosis
  • Diabetes mellitus, type 1 and type 2*‡
  • Disabilities‡
    • Attention-Deficit/Hyperactivity Disorder (ADHD)
    • Cerebral Palsy
    • Congenital Malformations (Birth Defects)
    • Limitations with self-care or activities of daily living
    • Intellectual and Developmental Disabilities
    • Learning Disabilities
    • Spinal Cord Injuries
  • Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies)
  • HIV (human immunodeficiency virus)
  • Mental health disorders limited to
    • Mood disorders, including depression
    • Schizophrenia spectrum disorders
  • Neurologic conditions limited to dementia‡
  • Obesity (BMI ≥30 kg/m2 or ≥95th percentile in children)*‡
  • Primary Immunodeficiencies
  • Pregnancy and recent pregnancy
  • Physical inactivity
  • Smoking, current and former
  • Solid organ or hematopoietic cell transplantation
  • Tuberculosis
  • Use of corticosteroids or other immunosuppressive medications

Suggestive Higher Risk: Underlying medical condition or risk factor that neither has a published meta-analysis or systematic review nor completed the CDC systematic review process

  • Children with certain underlying conditions
  • Down syndrome
  • HIV (human immunodeficiency virus)
  • Neurologic conditions, including dementia
  • Overweight (BMI ≥25 kg/m2, but <30 kg/m2)
  • Sickle cell disease
  • Solid organ or blood stem cell transplantation
  • Substance use disorders
  • Use of corticosteroids or other immunosuppressive medications

Comorbidities with mostly case series, case reports, or, if other study design, the sample size is small 

  • Overweight (BMI ≥25 kg/m2, but <30 kg/m2)
  • Sickle cell disease
  • Substance use disorders
  • Thalassemia

Mixed Evidence: Meta-analysis or systematic review is inconclusive, either because the aggregated data on the association between an underlying condition and severe COVID-19 outcomes are inconsistent in direction or there are insufficient data

  • Alpha 1 antitrypsin deficiency
  • Bronchopulmonary dysplasia
  • Hepatitis B
  • Hepatitis C
  • Hypertension*

Footnotes:

* indicates underlying conditions for which there is evidence for pregnant and non-pregnant people

‡ underlying conditions for which there is evidence in pediatric patients

Learn More – Primary Sources:

Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare Providers

NIH: Clinical Spectrum | COVID-19 Treatment Guidelines

Impact of SARS-CoV-2 Delta variant on incubation, transmission settings and vaccine effectiveness: Results from a nationwide case-control study in France (Lancet Regional Health, 2022)

CDC: Clinical Presentation | Clinical Care Considerations

CDC Coronavirus Disease 2019: Overview of Testing for SARS-CoV-2

Clinical Questions about COVID-19: Questions and Answers

WHO: Novel coronavirus Information Page

JAMA: Coronavirus Disease 2019

FDA: Coronavirus Disease 2019

BMJ: Coronavirus Updates

Lancet: Coronavirus Hub

NEJM: 2019 Novel Coronavirus

Annals of Internal Medicine: Content Related to Coronavirus in Annals of Internal Medicine

JAMA: What Is a Pandemic?