NOTE: The FDA has addressed the use of bebtelovimab among nonhospitalized patients in light of an increase in subvariants. Due to resistance, bebtelovimab is not currently authorized for emergency use in any US region. Information and guidelines may change rapidly. Check in with listed reference in ‘Learn More – Primary Sources’ to best keep up to date.
SUMMARY:
NIH has released guidance on the diagnosis, management and treatment of COVID-19. A Panel was convened to develop recommendations, with the understanding that there is still much that is unknown and the guidelines will be updated as additional data become available
Infection Control When Caring for Patients with COVID-19
Aerosol-generating procedures
Use fit-tested respirators (N-95 respirators) or powered air-purifying respirators rather than surgical masks
The above masks should be used in addition to other PPE (gloves, gown, and eye protection such as a face shield or safety goggles)
Endotracheal intubation
Should be done by healthcare professionals “with extensive airway management experience, if possible”
Intubation should be done with video laryngoscopy, if possible
Hemodynamic Support
First-choice vasopressor: Norepinephrine
To assess fluid responsiveness
Use dynamic parameters, skin temperature, capillary refilling time, and/or lactate levels vs static parameters
Acute resuscitation of adults with COVID-19 and shock
Use buffered/balanced crystalloids over unbalanced crystalloids
Panel recommends against initial use of albumin
Septic shock and steroids
IV hydrocortisone 200 mg per day administered either as an infusion or in intermittent doses
Duration of hydrocortisone is typically a clinical decision
Patients who are receiving corticosteroids for COVID-19 are receiving sufficient replacement therapy such that they do not require additional hydrocortisone
Ventilatory Support for Patients with COVID-19
Oxygen saturation (SpO2) target
Optimal goal is uncertain
A target SpO2 of 92% to 96% “seems logical”
Experience suggests that SpO2 <92% or >96% may be harmful
Prone position
Appropriate candidate for awake prone positioning: Patients who can adjust their own position independently and tolerate lying prone
Awake proning should not be used as a substitute for intubation and invasive mechanical ventilation in patients with refractory hypoxemia who otherwise meet the indications for these interventions
Pregnancy: Acceptable and can be done in left lateral decubitus or fully prone
Refractory hypoxemia in patients who otherwise require intubation and mechanical ventilation
Panel recommends against using awake prone positioning as a rescue therapy to avoid intubation
Options for providing enhanced respiratory support include high-flow nasal cannula (HFNC), NIPPV, intubation and invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)
Use HFNC oxygen rather than noninvasive positive pressure ventilation (NIPPV)
If HFNC is unavailable and there is no indication of intubation: Use a closely monitored trial of NIPPV
For patients on supplemental oxygen
Monitor closely for worsening of respiratory status
If respiratory status worsens, the Panel recommends early intubation by an experienced practitioner in a controlled setting
For patients mechanically ventilated with ARDS
Use low tidal volume (VT) ventilation (VT 4 to 8 mL/kg of predicted body weight) vs higher tidal volumes (VT >8 mL/kg)
If refractory hypoxemia despite optimized ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone ventilation
In the setting of hypoxemia and severe ARDS despite optimized ventilation and other rescue strategies, a trial of inhaled pulmonary vasodilators is recommended as a rescue therapy| Taper if there is no rapid improvement in oxygenation
Inpatient Pharmacologic Management
Note: For patients who are hospitalized for reasons other than COVID-19 and who are found to have mild to moderate COVID-19 and a high risk of disease progression, the Panel recommends following its recommendations for treating nonhospitalized patients with COVID-19 (section below)
The following applies to individuals admitted for the treatment of COVID-19
Therapeutic Management of Hospitalized Adults With COVID-19 Based on Disease Severity
Remdesivir
Recommended for use in hospitalized patients who require supplemental oxygen
200 mg IV once, then RDV 100 mg IV once daily for 4 days or until hospital discharge
If the patient progresses to more severe illness, complete course
Dexamethasone
Found to improve survival in hospitalized patients who require supplemental oxygen
Greatest effect observed in patients who require mechanical ventilation
The Panel recommends against using dexamethasone among patients who do not require supplemental oxygen
Dose
6 mg IV or PO once daily for up to 10 days or until hospital discharge
If dexamethasone is not available, an equivalent dose of another corticosteroid may be used
Tocilizumab
Humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)
FDA approved to treat inflammatory diseases
Dose
8 mg/kg actual body weight (up to 800 mg) administered as a single IV dose
In clinical trials, a third of the participants received a second dose of tocilizumab 8 hours after the first dose if no clinical improvement was observed
Avoid tocilizumab for the following
Significant immunosuppression | Alanine transaminase >5 times the upper limit of normal | High risk for gastrointestinal perforation | Uncontrolled, serious bacterial, fungal, or non-SARS-CoV-2 viral infection | Absolute neutrophil count <500 cells/µL | Platelet count <50,000 cells/µL
Baricitinib
Oral Janus kinase (JAK) inhibitor that is selective for JAK1 and JAK2
FDA approved to treat rheumatoid arthritis
Dose
Baricitinib dose is dependent on eGFR; duration of therapy is up to 14 days or until hospital discharge
eGFR ≥60 mL/min/1.73 m2: Baricitinib 4 mg PO once daily
eGFR 30 to <60 mL/min/1.73 m2: Baricitinib 2 mg PO once daily
eGFR 15 to <30 mL/min/1.73 m2: Baricitinib 1 mg PO once daily
eGFR <15 mL/min/1.73 m2: Baricitinib is not recommended
Tofacitinib
Oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis
Dose
10 mg PO twice daily for up to 14 days or until hospital discharge
Use as an alternative immunomodulatory drug if baricitinib is not available or not feasible to use (BIIa)
eGFR <60 mL/min/1.73 m2: Tofacitinib 5 mg PO twice daily
Sarilumab
Humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)
FDA approved to treat rheumatoid arthritis
Dose
Use the single-dose, prefilled syringe (not the prefilled pen) for SQ injection
Reconstitute sarilumab 400 mg in 100 cc 0.9% NaCl and administer as an IV infusion over 1 hour
Use as an alternative immunomodulatory drug if tocilizumab is not available or not feasible to use
Therapeutic Management of Nonhospitalized Adults With COVID-19
NIH refers to the CDC guidance to determine at increased risk for progression | See ‘Learn More – Primary Care’ for reference
In Order of Preference
Paxlovid (for more information, see ‘oral antivirals below’)
Orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥12 years and weighing ≥40 kg
Remdesivir
200 mg IV on Day 1, followed by remdesivir 100 mg IV daily on Days 2 and 3, initiated as soon as possible and within 7 days of symptom onset in those aged ≥12 years and weighing ≥40 kg
Alternative Therapies to be used ONLY if none of the preferred therapies are available, feasible to deliver, or clinically appropriate (listed in alphabetical order)
Molnupiravir
800 mg orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥18 years ONLY when none of the above options can be used
Note: BQ.1 and BQ.1.1 subvariants appear to be resistant to bebtelovimab and as of 11/30/2022, bebtelovimab is not currently authorized for emergency use in any US region | The Panel continues to recommend Paxlovid, followed by remdesivir for treatment of mild to moderate COVID-19 in nonhospitalized adults who are at high risk for progression
More on Oral Antivirals
Ritonavir-Boosted Nirmatrelvir (Paxlovid)
Nirmatrelvir
Orally bioavailable protease inhibitor
Works by inhibiting viral protease MPRO (protease that plays an essential role in viral replication)
Active against all coronaviruses known to infect humans
Packaged with ritonavir (as Paxlovid)
Ritonavir is a cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting agent
Boosts nirmatrelvir concentrations to the target therapeutic ranges
Note: Review other medications to assess drug interactions including OTCs and herbal supplements | University of Liverpool has a site with COVID-19 Drug Interactions (included in the NIH Panel guidelines – see “Learn More – Primary Resources’ below)
Molnupiravir
Oral prodrug of beta-D-N4-hydroxycytidine (NHC)
NHC is a ribonucleoside with antiviral activity against RNA viruses
NHC uptake by viral RNA-dependent RNA-polymerases results in viral mutations and lethal mutagenesis
Note: Pregnancy and COVID-19 Oral Antivirals
Paxlovid
SMFM supports the use of Paxlovid in pregnancy as indicated (see ‘Primary Sources – Learn More’ below)
Molnupiravir
Although FDA concluded that there is a low risk for genotoxicity, due to concern regarding mutagenesis, the FDA EUA recommends against use during pregnancy
The NIH Panel states “However, when other therapies are not available, pregnant people with COVID-19 who are at high risk of progressing to severe disease may reasonably choose molnupiravir therapy after being fully informed of the risks, particularly those who are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The prescribing clinician should document that a discussion of the risks and benefits occurred and that the patient chose this therapy”
KEY POINTS:
Serologic or Antibody Testing for Diagnosis of SARS-CoV-2 Infection
The Panel does not recommend using serologic testing as the sole basis for diagnosing acute SARS-CoV-2 infection
Serologic or antibody tests can detect recent or prior SARS-CoV-2 infection
It may take ≥21 days after symptoms for seroconversion to occur (i.e., IgM and/or IgG antibodies to SARS-CoV-2)
NAATs and antigen tests for SARS-CoV-2 occasionally yield false negative results
Serologic tests have been used in some settings as an additional diagnostic test for patients who are strongly suspected to have SARS-CoV-2 infection
Using a serologic test in combination with a NAAT to detect IgG or total antibodies 3 to 4 weeks after symptom onset maximizes the sensitivity and specificity to detect past infection
Concomitant Medications in Patients with COVID-19
Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs) and Statins (HMG-CoA Reductase Inhibitors)
Continue taking these medications as prescribed
The Panel recommends against the use of ACE inhibitors or ARBs for the treatment of COVID-19 outside of the setting of a clinical trial
Chronic Corticosteroids
For patients on oral corticosteroid therapy used prior to COVID-19 diagnosis for another underlying condition (e.g., rheumatological diseases)
Corticosteroids should not be discontinued
Supplemental or stress-dose steroids: Determine use on a case-by-case basis
Asthma and chronic obstructive pulmonary disease for control of airway inflammation (daily use)
Should not be discontinued
Pregnancy Considerations
Betamethasone and dexamethasone cross the placenta and are therefore used for fetal benefit to decrease the risk of RDS in the setting or threatened preterm delivery
The Panel recommends “using dexamethasone in pregnant women with COVID-19 who are mechanically ventilated or who require supplemental oxygen but who are not mechanically ventilated”
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Continue taking NSAIDs for a co-morbid condition as previously directed by physician
“The Panel recommends that there be no difference in the use of antipyretic strategies (e.g., with acetaminophen or NSAIDs) between patients with or without COVID-19”
Coagulopathy Considerations
Antithrombotic Therapy for Nonhospitalized Patients without VTE
The Panel recommends against the use of anticoagulants and antiplatelet therapy (aspirin or P2Y12 inhibitors) for the prevention of VTE or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial
The Panel recommends against routinely continuing VTE prophylaxis for patients with COVID-19 after hospital discharge, except in a clinical trial
For patients who are at high risk for VTE and low risk for bleeding, there is insufficient evidence to recommend either for or against continuing anticoagulation after hospital discharge unless another indication for VTE prophylaxis exists
General Considerations for Hospitalized Patients
The Panel recommends against using anticoagulant or antiplatelet therapy to prevent arterial thrombosis outside of the usual standard of care for patients without COVID-19
In hospitalized patients, low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) is preferred over oral anticoagulants, because these 2 types of heparin have shorter half-lives and the effect can be reversed quickly, can be administered intravenously or subcutaneously, and have fewer drug-drug interactions
When heparin is used, LMWH is preferred over UFH
Hospitalized, Nonpregnant Adults Who Require Low-Flow Oxygen and Are Not Receiving Intensive Care Unit Level of Care
Use therapeutic-dose heparin for patients who have a D-dimer above the upper limit of normal and have no increased bleeding risk
LMWH is preferred over unfractionated heparin
Contraindications for therapeutic anticoagulation for COVID-19 due to an increased bleeding risk
Platelet count <50 x 109/L
Hemoglobin <8 g/dL
Need for dual antiplatelet therapy
Known bleeding within the last 30 days requiring an emergency room visit or hospitalization
Known history of a bleeding disorder
Inherited or active acquired bleeding disorder
If no VTE
Continue therapeutic treatment for 14 days or until hospital discharge, whichever comes first
The Panel recommends using prophylactic-dose heparin (LMWH or unfractionated heparin) for patients who are not administered therapeutic heparin unless a contraindication exists
Note: Oral anticoagulants for VTE prophylaxis or prevention of COVID-19 progression are not recommended for hospitalized patients, except in a clinical trial
Hospitalized, Nonpregnant Adults Who Are Receiving ICU Level of Care (Including Patients Who Are Receiving High-Flow Oxygen)
Use prophylactic-dose heparin as VTE prophylaxis unless a contraindication exists
The Panel recommends against the following except in a clinical trial
Use of intermediate-dose (e.g., enoxaparin 1 mg/kg daily)
Therapeutic-dose anticoagulation for VTE prophylaxis
For patients who start on therapeutic-dose heparin while on low-flow oxygen due to COVID-19 and then transfer to the ICU
Switch from therapeutic to prophylactic-dose heparin unless a VTE is confirmed
There is insufficient evidence for the Panel to recommend either for or against antiplatelet therapy in critically ill patients with COVID-19
Pregnant Adults
The Panel recommends that pregnant patients who are receiving anticoagulant or antiplatelet therapies for underlying conditions continue these medications after they receive a diagnosis of COVID-19
Use prophylactic-dose anticoagulation for pregnant patients hospitalized for manifestations of COVID-19 unless otherwise contraindicated
Because pregnant patients have not been included in most clinical trials evaluating therapeutic anticoagulation in the setting of COVID-19, there is currently insufficient evidence to recommend either for or against therapeutic anticoagulation for pregnant patients with COVID-19 in the absence of a known VTE
Influenza and COVID-19
Vaccine Considerations
It is important to ensure that vaccination programs to protect against influenza continue during the pandemic
Patients with COVID-19 can receive inactivated influenza vaccine
Moderately or Severely Ill with SARS-CoV-2
Consider deferring influenza vaccination until the patients have completed the COVID-19 isolation period and are no longer moderately or severely ill
Asymptomatic or not moderately or severely ill with SARS-CoV-2
Influenza vaccination can be given when infected individual no longer require isolation
Vaccinate sooner if they are in a health care setting for other reasons
Note: Influenza vaccine and a COVID-19 vaccine may be administered concurrently at different injection sites
Testing for Influenza
Test for both viruses in all hospitalized patients with acute respiratory illness
The Panel recommends influenza testing in addition to SARS-CoV-2 testing in outpatients with acute respiratory illness if
Results will change the clinical management strategy for the patient such as initiating antiviral treatment for influenza
Consider testing patients for other pathogens based on their specific clinical circumstances
Additional testing is especially important for patients with influenza who have a high risk of acquiring bacterial superinfections
Treatment for Influenza
Antiviral treatment of influenza is the same in all patients with or without SARS-CoV-2 coinfection
Hospitalized patients with suspected influenza
Start on empiric treatment for influenza with oseltamivir as soon as possible
Do not wait for influenza test results
Stop antiviral treatment for influenza when influenza has been ruled out by nucleic acid detection assay
Nonintubated: Negative report for upper respiratory tract specimens
Intubated: Negative report for both upper and lower respiratory tract specimens
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
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
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.
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
The CDC states
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
Does Hydroxychloroquine Provide Benefit in Nonhospitalized Patients with Early COVID-19 Infection?
PURPOSE:
Skipper et al. (Annals of Internal Medicine, 2020) sought to determine if hydroxychloroquine is of benefit to individuals with COVID-19 early in their clinical course
METHODS:
Multisite, international, randomized, double-blind, placebo-controlled trial (March 22 through May 20, with final hospital outcomes available June 15, 2020)
40 states (US) | 3 provinces (Canada)
Researchers collected self-reported survey data using the Research Electronic Data Capture (REDCap) system | Outreach traditional and through social media
Participants
Nonhospitalized | ≤4 days of symptoms with
Laboratory-confirmed COVID-19 or COVID-19–compatible symptoms and in contact with COVID-19 positive individual
Symptomatic health care workers with high-risk exposure but whose contact had PCR results pending were also included
Randomized 1:1 to the following
Oral hydroxychloroquine: 800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days
Masked placebo
Measurements
Symptoms and severity at baseline and then at days 3, 5, 10, and 14
Assessed using a 10-point visual analogue scale
Outcomes
The primary end point was changed to an overall symptom severity score over the course of 14 days
RESULTS:
423 contributed primary end point data (out of 491 randomized)
Median age: 40 years | 56% women | Identified as Black or African American were underrepresented (3%)
Enrolled within 1 day of onset of symptoms: 56% (236 of 423)
Change in symptom severity over 14 days did not differ between groups
Absolute difference in symptom severity: −0.27 points (95% CI, −0.61 to 0.07 points; P=0.117)
There was no difference in proportion of patients with ongoing symptoms at 14 days (P=0.21)
Hydroxychloroquine: 24%
Placebo: 30%
Medication adverse effects were more frequent with hydroxychloroquine (P < 0.001)
Hydroxychloroquine: 43%
Placebo: 22%
There was no significant difference in hospitalization or death (P = 0.29)
Hydroxychloroquine: 4 hospitalizations occurred | 1 nonhospitalized death
Placebo: 10 hospitalizations (2 non–COVID-19–related) | 1 hospitalized death
CONCLUSION:
The authors note that the population was relatively young, with few comorbid conditions and therefore these outcomes may not be generalizable to all population groups | A substantial proportion of patients were enrolled based on symptoms and not SARS-CoV-2 testing (due to limited availability)
The authors conclude that
Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19
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 now includes a separate page on COVID-19 and pregnancy data (see ‘Learn More – Primary Sources’). The initial dataset is based on the MMWR review (June 26, 2020) and the page will be updates as new data becomes available
Summary of MMWR study
Methods
CDC receives reports of COVID-19 cases through
Electronic standardized case report form or The National Notifiable Diseases Surveillance System
Data updated by health departments
Case reports for this study: January 22 to June 7 and updated as of June 17, 2020
Participants
Women aged 15 to 44 years (reproductive age) from 50 states, the District of Columbia, and New York City
Lab confirmed SARS-CoV-2 infection
Data collected included
Demographics | Pregnancy status | Underlying medical conditions | Clinical course | Outcomes (maternal)
Missing data
To avoid overestimating the risk for adverse outcomes, “Outcomes with missing data were assumed not to have occurred (i.e., if data were missing on hospitalization, women were assumed to not have been hospitalized)”
Statistical analysis
Outcomes: Logistic regression, using crude and adjusted risk ratios and 95% CIs
Risk ratios (RR) adjusted for
Age | Presence of underlying chronic conditions | Race/ethnicity
Results
Women of reproductive age and positive for SARS-CoV-2: 326,335
Pregnancy status
28% (91,412) of all reproductive age women had pregnancy status available | Among those women with pregnancy information, 9% (8,207) were reported as pregnant
Symptoms
Cough: Similar between pregnant and nonpregnant women (>50%)
Shortness of breath: Similar between pregnant and non-pregnant (30%)
Pregnancy status was missing for approximately 75% of women of reproductive age
Data on race/ethnicity, symptoms, underlying conditions, and outcomes were missing “for a large proportion of cases”
Data not available for the following
Trimester at time of infection was not available
Whether hospitalization was related to COVID-19
Current routine case surveillance does not capture pregnancy or birth outcomes
CDC concludes that
These findings suggest that among women of reproductive age with COVID-19, pregnant women are more likely to be hospitalized and at increased risk for ICU admission and receipt of mechanical ventilation compared with nonpregnant women, but their risk for death is similar
Is There a ‘Preeclampsia-Like’ Syndrome in Pregnant Women with COVID-19?
PURPOSE:
There is overlapping symptomatology between preeclampsia (PE) and COVID-19 including liver injury and coagulopathy
Being able to differentiate between the two could have significant implications for clinical care as PE with severe features usually requires delivery
Mendoza et al. (BJOG, 2020) sought to investigate pregnancies with COVID-19 and determine, based on clinical, ultrasound and biochemical findings if patients with true PE vs ‘PE-like’ features could be distinguished
METHODS:
Prospective observational study
Tertiary referral hospital
Participants
Singleton pregnancies
Confirmed or suspected COVID-19
>20w0d gestation
Classified in to two groups: Severe vs nonsevere COVID-19, based on presence of severe pneumonia
Aside from clinical outcomes, the following ultrasound and biochemical parameters were also assessed in patients with suspected PE
“UtAPI >95th centile for gestational age, and sFlt-1/PlGF values ≥85 (at <34 weeks) or ≥110 (at ≥34 weeks) were considered highly suggestive of underlying placental disease”
RESULTS:
42 consecutive pregnancies were recruited
Nonsevere: 34
Severe (requiring ICU admission): 8
Clinical course of severe group
Prior to onset of severe pneumonia, all 8 women were normotensive and only 1 patient had elevated UtAPI
Median age of severe cases (39.4 years) were significantly higher than nonsevere (30.9 years); p=0.006
Following severe pneumonia onset, 6 women (14.3% of total cohort) met PE criteria including
New onset hypertension and proteinuria and/or thrombocytopenia and/or elevated liver enzymes
No cases met diagnostic criteria in the nonsevere group
All required antihypertensive medication
Only 1 patient had abnormal LDH level >600 UI/L, sFlt-1/PlGF, and UtAPI
4 cesarean births
HELLP syndrome (1 case)
Worsening COVID-19 (3 cases)
Two cases were still pregnant after recovery from severe pneumonia
PE-like syndrome resolved in both cases
CONCLUSION:
Pregnant women with severe COVID-19 can develop a PE-like syndrome
The authors suggest that only 1 out of the 8 cases demonstrated ultrasound and biochemical features compatible with placental dysfunction
PE-like syndrome vs PE could possibly be differentiated based on these biochemical markers (sFlt-1/PlGF, LDH) and Doppler (UtAPI) features
Based on the resolution in 2 of the cases, the authors state that
PE-like syndrome might not be an indication for earlier delivery in itself since it might not be a placental complication and could resolve spontaneously after recovery from severe pneumonia.
The ‘Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial’ is a national program in the UK to study multiple potential therapies for SARS-CoV-2 infection. The program involves thousands of doctors, nurses, pharmacists, and research personnel. The dexamethasone branch of the RECOVERY Trial program was halted on June 8th because the steering committee felt there was sufficient evidence to make a determination whether there was benefit to this therapy. The chief investigators, Professors Horby and Landray, reported the findings on June 16, 2020.
The preliminary results found that
Overall dexamethasone reduced the 28-day mortality rate by 17% (0.83 [0.74 to 0.92]; P=0.0007) with a highly significant trend showing greatest benefit among those patients requiring ventilation (test for trend p<0.001)
Methods
Randomized controlled trial (RCT)
Participants
Patients hospitalized with COVID-19
Randomization
Dexamethasone 6 mg daily (oral or IV) vs usual care alone
Primary Outcomes
Within 28 days after randomization: Death | Discharge | Need for ventilation | Need for renal replacement therapy
Additional data collected
Age | Sex | Major co-morbidity | Pregnancy | COVID-19 onset date and severity
Results
Dexamethasone group: 2104 patients | Usual care alone: 4321 patients
Usual care group
28-day mortality rates
Requiring ventilation: 41%
Oxygen only: 25%
No respiratory intervention: 13%
Dexamethasone group: Reduction in deaths vs usual care alone
Requiring ventilation: Rate ratio (RR) 0.65 (95% CI, 0.48 to 0.88]; p=0.0003)
Oxygen only: RR 0.80 (95% CI, 0.67 to 0.96; p=0.0021)
No respiratory intervention: RR 1.22 (95% CI, 0.86 to 1.75; p=0.14)
Need to treat
Ventilated patients: 1 death would be prevented by treatment of approximately 8 patients
Oxygen alone: 1 death prevented by treatment of approximately 25 patients
KEY POINTS:
Reduction in deaths for hospitalized patients with COVID-19 with the use of low dose dexamethasone
Reduced deaths by one-third in ventilated patients
Reduced deaths by 20% for oxygen only patients
No benefit for patients not requiring respiratory support
Full report will be published
Professor Hornsby, one of the chief investigators states that
…dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide
FDA Revokes Hydroxychloroquine and Chloroquine EUA for the Treatment of COVID-19
SUMMARY:
The FDA has revoked the Emergency Use Authorization (EUA) for chloroquine phosphate and hydroxychloroquine sulfate. Based on the available data, these medications do not appear to be effective in the treatment of COVID-19 and also present harms, specifically related to cardiac arrhythmias.
An EUA is different than a full FDA approval
EUA based on an FDA evaluation of evidence and risks vs potential or known benefits of “unproven” products during an emergency
Chloroquine phosphate and hydroxychloroquine sulfate, donated to the Strategic National Stockpile, received an EUA to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was unavailable, or participation in a clinical trial was not feasible
Based on benefits/harms analysis, these medications no longer meet the EUA requirements
KEY POINTS:
Research has demonstrated the following regarding hydroxychloroquine and chloroquine (see ‘Related ObG Entries’ below)
Hydroxychloroquine showed no benefit on mortality or in speeding recovery (RCT)
Suggested dosing regimens for chloroquine and hydroxychloroquine are unlikely to kill or inhibit the virus that causes COVID-19
“The totality of scientific evidence currently available indicate a lack of benefit”
FDA approved use of chloroquine and hydroxychloroquine
Still both FDA-approved to treat or prevent malaria
Hydroxychloroquine is also approved to treat autoimmune conditions such as chronic discoid lupus erythematosus, systemic lupus erythematosus in adults, and rheumatoid arthritis
Note: “FDA approved products may be prescribed by physicians for off-label uses if they determine it is appropriate for treating their patients, including during COVID”
Possible Drug Interaction with Remdesivir
The FDA also released a warning regarding a potential drug interaction between remdesivir and chloroquine and hydroxychloroquine
Data derived from a non-clinical laboratory study demonstrated possible reduction in the antiviral activity of remdesivir activity when co-administered with these medications
The FDA is not currently aware of reduced activity in the clinical setting and continues to evaluate data on this subject
Neonatal Infection: COVID-19 and Risk for Vertical Transmission
PURPOSE:
Walker et al. (BJOG, 2020) sought to investigate the risk for vertical transmission in women with COVID-19 around the time of delivery
A systematic analysis was performed, including an effort to address duplicate reporting in previous studies
METHODS:
Systematic review and critical analysis (Search from April through May, 2020)
Authors sought out full text copies of any studies that may be eligible for inclusion
Eligibility criteria for studies
Pregnant women with confirmed (positive test or high clinical suspicion) COVID-19
Case reports or case series | No language restriction
Rates of infection were determined for the following
Mode of birth (cesarean or vaginal)
Breast or formula feeding
Rooming in or isolation
Studies underwent disambiguation to avoid duplication of patients among different reports
RESULTS:
49 studies included
666 neonates | 655 pregnant women
11 twins
Infected neonates: 4%
Duplicate pregnancies (in Chinese data) were identified and were properly accounted for in subsequent analyses
Mode of Delivery
Neonatal infection rates based on mode of delivery
Vaginal delivery: 2.7%
Cesarean: 5.3%
Breast vs Formula Feeding
Among neonates with confirmed COVID-19
Breast fed: 7
Formula: 3
Expressed breast milk: 1
Unreported: 17
Rooming In vs Isolation
Among neonates with confirmed COVID-19
Isolated: 7
Rooming in: 5
Not reported: 16
CONCLUSION:
Overall, there was a low rate of neonatal infection following maternal COVID-19 infection
There does not appear to be a greater risk for vertical SARS-CoV-2 transmission based on mode of delivery, breast feeding or rooming in
The authors acknowledge limitations including
Not all newborns tested for SARS-CoV-2
Case series have possibility of bias | More severe cases are more likely to be reported
“…disappointing that details of outcome and care” were not available and should be considered a “missed opportunity”
Due to low newborn infection rate, ‘n’ of infected neonates is still relatively small and appropriate caution should be used in interpreting the data
The authors conclude that
There is no evidence that isolating the baby away from the mother is beneficial if such precautions are taken, and encouraging the baby to spend time with its mother is likely to help with breastfeeding and bonding
We recommend that separation only occurs where this is necessary for clinical indications
Do Warmer Temperatures Decrease the Incidence of COVID-19?
BACKGROUND AND PURPOSE:
Sehra et al. (Clinical Infectious Diseases, 2020) investigated the effects of temperature, precipitation, and UV Light on community transmission of SARS-CoV-2
METHODS:
Observational analysis of case data
Data analyzed (January 22 to April 3, 2020)
Daily reported cases of SARS-CoV-2 and daily weather patterns across the US
Analysis
Null hypothesis: There is no association between daily temperatures and COVID-19 spread
Modeling techniques were used to investigate whether daily maximum temperature, precipitation, UV Index and the SARS-CoV-2 incidence 5 days later were related
Sensitivity analyses to assess transmission lags were performed at 3 days, 7 days and 9 days
RESULTS:
974 daily observations
Max temperature of >52°F associated with a lower rate of new cases at 5 days
Incidence rate ratio (IRR) 0.85 (95% CI 0.76 to 0.96; p = 0.009)
Temperature
Temperature <52°F was inversely associated with case rate at 5 days
IRR 0.98 (95% CI 0.97 to 0.99; p = 0.001)
Modeling results: Rate of new cases was lower for theoretical states where daily temperature remained >52°F
At this temperature threshold, modeling predicted that there would be 23-fewer cases per-million per-day by 25 days of the epidemic
UV Index
A 1-unit higher UV index associated with a lower rate at 5 days
IRR 0.97(95% CI 0.95 to 0.99; p = 0.004)
Precipitation
Precipitation was not associated with a greater rate of cases at 5 days
IRR 0.98 (95% CI 0.89 to 1.08; p = 0.65)
CONCLUSION:
COVID-19 incidence was lower at warmer vs cooler temperatures
Incidence declined with increasing temperature until 52°F
The authors state that while statistically significant, the actual association is small and therefore
…unlikely to provide significant effect beyond current strategies for mitigation
…although there is an association between daily temperature and subsequent case volume the disease may continue to spread in the United States even in periods of warmer weather
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