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
The CDC currently recommends COVID-19 vaccination for individuals 6 months and older in the United States for the prevention of coronavirus disease 2019 (COVID-19) including booster dose. Vaccination during pregnancy and lactation period is encouraged to mitigate the significant risks associated with COVID.
The SMFM document refers clinicians to the CDC recommendations (links can be found in ‘Learn More – Primary Sources’ below)
CDC recognizes pregnant women are at risk for severe health effects from COVID-19 and recommends COVID-19 vaccination during pregnancy
While a conversation with a healthcare provider may be of benefit, it is not a requirement prior to vaccination
Counseling should include the following elements
Available data on vaccine safety
Discussion about limited data regarding fetal risk
Pregnant patients have higher risk of moderate to severe disease
Level of COVID-19 community transmission
Maternal and Obstetric Risk
With symptomatic COVID-19, pregnancy is an independent risk factor compared to symptomatic non-pregnant patients for
ICU admission: 3-fold increase
Mechanical ventilation
ECMO: 2 to 4 fold increase
Death: 1.7 fold increase
May increase preterm birth and stillbirth
Other risk factors for severe COVID-19 disease include
Cancer | Chronic kidney disease | COPD | Heart conditions | Immunocompromised state | Sickle cell disease | Smoking
Hispanic or Latinx and Black patients are disproportionally affected by higher prevalence of COVID-19
More severe maternal morbidity | Higher risk of death
Vaccine Mechanism
Three COVID-19 vaccines are currently available in US | None are live vaccines
mRNA Vaccines (Pfizer | Moderna)
Contain mRNA for SARS-CoV-2 spike S protein
Pfizer-BioNTech BNT162b2
Moderna mRNA 1273 vaccines
Two-dose vaccine (Pfizer 3 weeks apart; Moderna 4 weeks apart)
Protein Subunit Vaccine (Novavax)
Contains combination of spike proteins
Also includes an adjuvant that improves immune response
Similar technology to that used for HepB and HPV
Two-dose vaccine (3 to 8 weeks apart)
Adenoviral-Vector Vaccine (Janssen Biotech Ad26.COV2.S; Pharmaceutical company of Johnson & Johnson)
One-dose vaccine
Adenovirus carries the gene for the coronavirus spike S protein, which is then produced by the host cell
The presence of spike protein on the host cell’s membrane will induce an immunogenic response
Note: Due to increased risk for thrombosis with thrombocytopenia syndrome (TTS), the FDA has limited the authorized use of the Janssen COVID-19 Vaccine to (1) individuals 18 years of age and older for whom other authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, and (2) to individuals 18 years of age and older who elect to receive the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine
Considerations for Administration
Pregnancy test prior to vaccination is not recommended
No need to delay pregnancy following vaccine administration
No trimester-specific indications at this time
Efficacy
mRNA Vaccines
Optimal efficacy 1 to 2 weeks after second dose
Pfizer-BioNTech: 95.0% (95% CI, 90.3% to 97.6%)
Moderna: 94.1% (95% CI, 89.3% to 96.8%)
Novavax
89.7% (95% CI, 80.2% to 94.6%)
Johnson & JohnsonAdenoviral-Vector Vaccine (Janssen Biotech)
1 time dose
72% effective at preventing moderate to severe disease
85% effective at preventing severe disease
100% effective at preventing COVID-19–related hospitalization and death 28 days after vaccination
Primary Series Dosing
Pfizer-BioNTech: 2-dose primary series
5 to 11 years: 10 µg dose | 3 weeks apart
≥12 years: 30 µg dose | 3 to 8 weeks apart
Moderna: 2-dose primary series
6 to 11 years: 50 µg | 4 to 8 weeks apart
≥12 years: 100 µg | 4 to 8 weeks apart
Novavax: 2-dose primary series
≥12 years: 5 µg rS and 50 µg of Matrix-M™ adjuvant
Janssen: Single dose primary series
≥18 years: 5×1010 viral particles
Primary Series for Children From 6 Months Through 5 Years of Age
Pfizer (6 months through 4 years)
3 primary doses are recommended
Monovalent Pfizer-BioNTech vaccine is administered for the first and second doses, followed by 1 bivalent Pfizer-BioNTech vaccine as the third primary series dose, at least 8 weeks after the second monovalent primary series dose
Moderna (6 months through 5 years)
2 primary doses are recommended
25 µg per dose (1/4 adult dose)
Interval between 1st and 2nd dose: 4 to 8 weeks
Note: Spacing between first and second can be up to 8 weeks with both Pfizer and Moderna vaccines (CDC) | Although absolute risk for myocarditis associated with mRNA vaccine is small, some studies suggest that among adolescents and adults, the risk for myocarditis may be reduced and peak antibody responses and vaccine effectiveness may be increased with an interval longer than 4 weeks | Original interval is still recommended for “people who are moderately or severely immunocompromised; adults ages 65 years and older; and others who need rapid protection due to increased concern about community transmission or risk of severe disease”
COVID-19 Vaccines for People who are Moderately or Severely Immunocompromised
CDC has specific recommendations for COVID vaccine schedules for individuals who are moderately or severely immunocompromised | See ‘Learn More – Primary Sources’ for the most current information for the most current schedules
Children ages 5 through 11 years
Should receive a primary series of 3 doses of Pfizer-BioNTech COVID-19 vaccine
Additional booster not recommended at this time
People ≥12 years
Should receive a total of 4 doses of mRNA COVID-19 vaccine to stay up to date
The 4 doses include a primary series of 3 doses of Pfizer-BioNTech or Moderna COVID-19 vaccine plus 1 booster of Pfizer-BioNTech or Moderna COVID-19 vaccine (4th dose)
Only Pfizer-BioNTech COVID-19 vaccine is available for teens ages 12 to 17 years
Moderate or severe immunocompromising conditions that include (but not limited to)
Active treatment for solid tumor and hematologic malignancies
Receipt of solid-organ transplant and taking immunosuppressive therapy
Receipt of CAR-T-cell therapy or hematopoietic cell transplant (HCT) (within 2 years of transplantation or taking immunosuppression therapy)
Moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome)
Advanced or untreated HIV infection (people with HIV and CD4 cell counts <200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
Treatments: High-dose corticosteroids (i.e., ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks) | Alkylating agents, antimetabolites | Transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive | Tumor necrosis factor (TNF) blockers | Other biologic agents that are immunosuppressive or immunomodulatory
Booster (CDC)
Children ages 6 months to 4 years who complete a Moderna primary series
To receive 1 bivalent Moderna booster dose at least 2 months after completion of the primary series
Children age 5 years who complete a Moderna primary series
May receive either the previously authorized bivalent Pfizer-BioNTech booster dose or the newly authorized bivalent Moderna booster dose at least 2 months after completion of the Moderna primary series
Children ages 6 months to 4 years who have received a Pfizer-BioNTech 3-dose primary series, including children who previously received a 3-dose monovalent Pfizer-BioNTech primary series
A booster dose is not authorized for children in this age group
Everyone ages 5 years and older who is eligible is recommended to receive 1 bivalent mRNA booster dose after completion of a monovalent primary series or previously received monovalent booster dose(s)
Bivalent vaccines have replaced old monovalent formulations for booster doses, though they remain the mainstay of initial vaccination
Omicron BA.4 and BA.5 spike proteins were added to the original vaccine
The booster is a bivalent vaccine, since it targets both omicron and the original SARS-Cov2 strain
5 to 17 years
Recommendations for use of a bivalent Moderna booster dose in people ages 6 to 17 years
Recommendations for use of a bivalent Pfizer-BioNTech booster dose in people ages 5 to 17 years
Adults ≥18 years
Pfizer or Moderna COVID vaccine ≥2 months after completion of primary mRNA vaccine series
Moderately or severely immunocompromised: Pfizer or Moderna COVID vaccine bivalent ≥2 months after the final dose in the primary series
Pregnancy and bivalent boosters
ACOG recommends that those who are pregnant or are within the 6 week postpartum period receive a bivalent mRNA COVID-19 vaccine booster dose following the completion of their last COVID-19 primary vaccine dose or monovalent booster
Note: Considered ‘up to date’ immediately after getting 1st booster
Fetal Considerations
Limited data | Preclinical studies have been reassuring
mRNA vaccines
Available data suggests low risk
Rapid degradation (approximately 10 to 20 days)
Does not enter the cell’s nucleus or become integrated into the DNA; therefore, “no risk of genetic modification to people receiving the vaccine”
Adenovector vaccines
Available data suggests low risk
Viral DNA is not integrated into the host’s DNA
Other adenovirus vector vaccines (Ebola, HIV, and RSV) showed no adverse pregnancy outcomes
Maternal antibodies cross the placenta | May provide neonatal protection
CDC Adverse Event Data
V-safe
CDC “smartphone-based tool that uses text messaging and web surveys to provide personalized health check-ins” that can be used by an individual to report side effects following COVID-19 vaccination
Women continue to enroll in CDC’s v-safe COVID-19 Vaccine Pregnancy Registry | No serious safety signals have been identified thus far (see ‘Learn More – Primary Resources’ and ‘Related ObG Topics’ below)
Reactogenicity (expected inflammatory response to vaccination) and adverse events did not raise any concerns regarding increased risk for maternal or neonatal complications
Vaccine Adverse Event Reporting (VAERS)
Miscarriage was highest pregnancy related adverse event
Rates around 15% in keeping with normal background
General findings from current available data
No pattern suggesting of safety issue
Vaccine reactions are usually mild to moderate
Occur within the first 3 days and resolve within 1 to 2 days
Most often symptoms occur after second dose
Acetaminophen can be used to treat fever
Allergic reactions: rare (2.5 to 4.7 per million)
Lactating Persons
Vaccination is recommended for lactating persons
Counseling should provide balance with respect to lack of data vs the patients’ individual risk for infection and severe disease
Although there is a lack of data “the theoretical risks regarding the safety of vaccinating lactating people do not outweigh the potential benefits of the vaccine”
Antibody Titers in Pregnancy
Studies have demonstrated vaccine-induced antibody titers to be similar in pregnant women compared to nonpregnant women
Transfer of antibodies to newborns following maternal vaccination may confer neonatal protection
Vaccine-induced IgG is transferred to the neonate
Higher umbilical cord blood titers are associated with longer time intervals from vaccination
Second vaccine dose increases cord blood IgG levels
KEY POINTS:
The COVID-19 vaccine should be offered to all eligible individuals 6 months and older including pregnant and lactating patients
ACOG recommends that “all people, including pregnant people receive a bivalent mRNA COVID-19 vaccine booster dose following the completion of their last COVID-19 primary vaccine dose or monovalent booster”
Providers should discuss individual risks and benefits of the vaccine during pregnancy
Safety profile from the CDC Adverse Event Monitoring site shows no increased risk of worse pregnancy outcomes post-vaccination with more data to be published
COVID-19 vaccines and other vaccines may now be administered without regard to timing
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
mRNA-Based COVID-19 Vaccines Induce Robust, Persistent Immune Responses in Humans
BACKGROUND AND PURPOSE:
The mRNA-based COVID-19 vaccines are 95% effective at preventing COVID-19, but immune system dynamics induced by the vaccines are not clear
Turner et al. (Nature, 2021) examined antigen-specific B cell responses in peripheral blood and lymph nodes in individuals who received 2 doses of the Pfizer vaccine
METHODS:
Observational study
Participants
Healthy US adults who received both doses of Pfizer’s COVID-19 vaccine
Study design
Blood samples were collected at baseline (before first dose), and at weeks 3 (pre-second dose), 4, 5, 7, and 15
Fine needle aspirates of the draining axillary lymph nodes were also collected from some participants
An enzyme linked immune absorbent spot assay was used to measure antibody-secreting plasmablasts (cells that differentiate into non-dividing plasma cells [aka antibody-secreting cells])
RESULTS
41 adults
Evidence of previous SARS-CoV-2 infection: 8 participants
Aspirates collected from lymph nodes: 14 participants
Circulating IgG- and IgA-secreting plasmablasts peaked one week after the second dose and then declined | Undetectable 3 weeks later
Plasmablasts exhibited neutralizing activity against the early circulating SARS-CoV-2 strain and emerging variants
Previously infected participants had the most robust serological response
Aspirates from the draining axillary lymph nodes identified germinal center B cells that bound the SARS-CoV-2 spike protein in all participants who had received first dose
The draining lymph nodes sustained high levels of spike-binding germinal center B cells and plasmablasts for at least 12 weeks after the second dose
Spike-binding monoclonal antibodies derived from germinal center B cells mostly targeted the receptor-binding domain of the spike protein
Fewer clones did cross-react and bind to the N-terminal domain or to epitopes shared with the spike proteins of human betacoronaviruses
These cross-reactive clones had higher levels of somatic hypermutation vs those specific to SARS-CoV-2 spike protein, suggesting a memory B cell origin
CONCLUSION
mRNA-based COVID-19 vaccines induce a persistent germinal center B cell response, which leads to robust humoral immunity
The authors state
To our knowledge, this is the first study to provide direct evidence for the induction of a persistent antigen-specific germinal centre B cell response after vaccination in humans
Elicitation of high affinity and durable protective antibody responses is a hallmark of a successful humoral immune response to vaccination
By inducing robust germinal centre reactions, SARS-CoV-2 mRNA-based vaccines are on track for achieving this outcome
AstraZeneca and Pfizer Side Effects and Efficacy: Real World Data from the UK
BACKGROUND AND PURPOSE:
In phase 3 clinical trials of the Pfizer-BioNTech vaccine, injection-site pain (71 to 83%), fatigue (34 to 47%), and headache (25 to 42%) were commonly seen
Menni et al. (The Lancet Infectious Diseases, 2021) investigate the safety and effectiveness of the Pfizer and AstraZeneca vaccines in a UK community setting
METHODS:
Prospective observational study
Data source
COVID Symptom Study app data
Between Dec 8 through March 10, 2021
Population
General UK population
Exposure
One or two doses of the Pfizer -BioNTech vaccine
One dose of the AstraZeneca vaccine
Unvaccinated controls
Study design
All analyses were adjusted by
Age (≤55 years vs >55 years)
Sex
Health-care worker status (binary variable)
Obesity (BMI <30 kg/m2 vs ≥30 kg/m2)
Comorbidities (binary variable, with or without comorbidities)
Primary outcome
Proportion and probability of self-reported systemic and local side effects within 8 days of vaccination
Secondary outcome
SARS-CoV-2 infection rates in vaccinated individuals
RESULTS:
627,383 vaccinated individuals
At least one dose of Pfizer-BioNTech: 282,103 individuals | Two doses of Pfizer-BioNTech: 28,207 individuals
One dose of AstraZeneca: 345,280 individuals
Systemic Side Effects
Report rates of systemic side effects after vaccination
After first dose of Pfizer-BioNTech: 13.5% | After second dose of Pfizer-BioNTech: 22.0%
After first dose of AstraZeneca: 33.7%
Most common systemic side effects
Fatigue and headache
Usually within first 24 hours after vaccination | Lasted a mean of 1.01 days
Systemic side effects were more common among those with a history of previous SARS-CoV-2 infection
After first dose of Pfizer-BioNTech: 2.9 times more likely
After first dose of AstraZeneca: 1.6 times more likely
Adverse systemic events were more common in
Women vs men: 16.2% vs 9.3% after first dose of Pfizer-BioNTech (OR 1.89 [95% CI, 1.85 to 1.94]; p<0·0001) and similarly after first dose of AstraZeneca
≤55 years vs >55 years: 20.7% vs 10.6% after first dose of Pfizer-BioNTech (OR 2.19 [95% CI, 2.14 to 2.24]; p<0.0001) and similarly after first dose of AstraZeneca
Similar pattern in women and younger individuals were also noted for local side effects
Local Side Effects
Most common local side effects
Tenderness and local pain around the injection site
Usually on the day after injection | Lasted a mean of 1.02 days
Local side effects after vaccination
After first dose of Pfizer-BioNTech: 71.9% | After second dose of Pfizer-BioNTech: 68.5%
After first dose of AstraZeneca: 58.7%
Local side effects were also higher in individuals previously infected with SARS-CoV-2
After first dose of Pfizer-BioNTech: 1.2 times more likely to experience side effects
After first dose of AstraZeneca: 1.4 times more likely
Vaccine Effectiveness
SARS-CoV-2 positive tests
Vaccinated: 3% (3106 infections per 103,622 vaccinated)
Unvaccinated: 11% (50,340 infections per 464,356 unvaccinated)
Significant reductions in infection risk were seen starting at 12 days after the first dose and increased over time
At 21 to 44 days
Pfizer-BioNTech: 69% (95% CI 66 to 72)
AstraZeneca: 60% (95% CI 49 to 68)
At 45 to 59 days
Pfizer-BioNTech: 72% (95% CI 63 to 79)
CONCLUSION:
Systematic and local side effects with Pfizer and AstraZeneca COVID-19 vaccination were more common in women, individuals ≤55 years, and those with previous COVID-19 infection
A reduction in infection risk was observed starting 12 days after the first dose for both vaccines
The authors conclude
Localised and systemic side effects after vaccination are less common in a real-world community setting than reported in phase 3 trials, mostly minor in severity, and self-limiting
Our data will enable prediction of side-effects based on age, sex, and past COVID-19 status to help update guidance to health professionals to reassure the population about the safety of vaccines
Johnson & Johnson COVID-19 Vaccine: Safety and Efficacy Data from the Phase 3 Trial
BACKGROUND AND PURPOSE:
Ad26.COV2.S, known as the Johnson & Johnson COVID-19 vaccine in the US, is a viral vector vaccine that uses an adenovirus vector encoding SARS-CoV-2 spike protein
Sadoff et al. (NEJM, 2021) report the primary analyses of an ongoing phase 3 trial to evaluate the safety and efficacy of a single dose for prevention of COVID-19 and SARS-CoV-2 infection in adults
ASH Guidelines: Diagnosis and Management of COVID-19 Vaccine-Induced Thrombosis with Thrombocytopenia
SUMMARY:
Although very rare, thrombosis with thrombocytopenia syndrome (TTS) has been associated with AD26.COV2.S (J&J) vaccine in the US and similar events have been documented outside the US with use of the CHaDOx1 nCov-19 (AstraZeneca) vaccine. This syndrome has been referred to by alternate names in the literature, including vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) or ‘vaccine-induced immune thrombotic thrombocytopenia (VITT)’. TTS is being used by the FDA and CDC. The American Society of Hematology has provided guidance on diagnosis and when to refer.
TTS Diagnostic Criteria
All 4 criteria must be met
J&J or AstraZeneca vaccine within 4 to 30 days
Venous or arterial thrombosis (often cerebral or abdominal)
Note: In early stage of TTS, thrombosis may be present prior to platelet count decrease
Clinical Findings
Severe headache
Visual changes
Abdominal pain
Nausea and vomiting
Back pain
Shortness of breath
Leg pain or swelling
Petechiae, easy bruising, or bleeding
Work-Up
Labs
CBC with platelet count and peripheral smear
Mean platelet count in published reports: 20,000/μL | There is a range from profound to mild
D-dimers: Most patients have significantly elevated levels
Fibrinogen: Some patients have low levels
PF4-heparin ELISA: almost all cases reported have positive assays | Most will have optical density >2.0 to 3.0
Note: Do not use non-ELISA rapid immunoassays for HIT | Non-ELISA tests are not sufficiently sensitive nor specific for TTS
Imaging for Thrombosis
Imaging based on symptoms
Focus on cerebral sinus venous thrombosis (CSVT) with use of CT or MRI venogram
Patients may also have splanchnic thrombosis, pulmonary emboli, and/or DVT
Treatment
IVIG 1 g/kg daily for two days
Non-heparin anticoagulation
Parenteral direct thrombin inhibitors (argatroban or bivalrudin if aPTT is normal) or
Direct oral anticoagulants without lead-in heparin phase or
Fondaparinux or
Danaparoid
When to Treat
While waiting for PF4 ELISA
Begin IV immune immunoglobin and nonheparin anticoagulation if there is clinical evidence of serious thrombosis AND ≥1 of the following
Positive imaging
Low platelets
If PF4 ELISA returns negative and there is no thrombocytopenia, TTS is ruled out
Treat for venous thromboembolism using standard protocols
KEY POINTS:
TTS is suspected
Obtain immediate CBC with platelet count and imaging for thrombosis based on symptoms
If thrombosis and/or thrombocytopenia is present, referral to hematologist with expertise in hemostasis is recommended
Do not use non-ELISA rapid immunoassays for HIT
Avoid heparin until TTS ruled out or other reasonable diagnosis has been established
In addition
If thrombocytopenia but no thrombosis and negative PF4 ELISA, likely ITP
Microangiopathy with red cell fragmentation and hemolysis have not been features of reported cases, thus distinguishing this syndrome from TTP/HUS is straightforward
Avoid platelet transfusions unless other treatments have been initiated AND life-threatening bleeding or imminent surgery
Consider referral to tertiary care center if TTS is confirmed
The clinical trials for mRNA-based COVID-19 vaccines did not include any pregnant women, so safety data in this group was initially limited
However, many pregnant women in the general population have since received these vaccines, providing a cohort in which to assess safety data
Shimabukuro et al. (NEJM, 2021) reported preliminary findings regarding mRNA COVID-19 vaccine safety in pregnant persons from three U.S. vaccine safety monitoring systems
METHODS:
Setting
United States
Data from December 14, 2020, to February 28, 2021
Data sources
The “V-safe after vaccination health checker” surveillance system
The V-safe pregnancy registry | Telephone-based survey collects detailed information
The Vaccine Adverse Event Reporting System (VAERS)
Primary outcomes
Non–pregnancy-specific adverse events
Pregnancy- and neonatal-specific adverse events
Note: Pregnancy and neonatal outcomes were derived from patients who enrolled in the registry
RESULTS:
35,691 v-safe participants self-identified as pregnant
Majority of the participants were
Between 25 to 34 years of age | Non-Hispanic White (approximately 75%)
3958 participants were enrolled in the registry
Vaccine-related side effects (V-safe)
Injection-site pain was reported more frequently among pregnant women than among nonpregnant women
The following were reported less frequently among pregnant women
Headache
Myalgia
Chills
Fever
Pregnancy Outcomes
827 participants completed pregnancy
Live birth: 86.1%
Spontaneous abortion: 12.6%
Stillbirth (0.1%)
Other outcomes (induced abortion and ectopic pregnancy): 1.2%
Neonatal Outcomes
Preterm birth: 9.4%
Small for gestational age: 3.2%
There were no neonatal deaths
Adverse Events (VAERS)
221 reports
Nonpregnant related: 70.1%
Pregnancy related: 29.9%
Most frequently reported pregnancy-related adverse events
Spontaneous abortion (37 first trimester, 2 second trimester, 7 unknown or not reported)
No congenital anomalies (EUA reporting requirement)
CONCLUSION:
While not directly comparable, the proportions of adverse outcomes in vaccinated women were similar to those reported in studies involving pregnant women before the pandemic
Further longitudinal study is important, especially in women vaccinated in the first trimester
The authors conclude that
Early data from the v-safe surveillance system, the v-safe pregnancy registry, and the VAERS do not indicate any obvious safety signals with respect to pregnancy or neonatal outcomes associated with Covid-19 vaccination in the third trimester of pregnancy
Does COVID-19 Vaccination in Breastfeeding Women Produce Detectable Levels of Antibodies in Breast Milk?
BACKGROUND AND PURPOSE:
Breastfeeding women were not included in COVID-19 vaccine trials, so there are limited data on vaccine-related safety in this group
Perl et al. (JAMA, 2021) investigated whether maternal immunization led to detection of SARS-CoV-2 antibodies in breast milk
METHODS:
Prospective cohort study
Setting
Israel, between December 23, 2020, and January 15, 2021
Participants
Breastfeeding women (exclusive or partial)
Elected to be vaccinated
Exposure
All participants fully vaccinated with Pfizer-BioNTech vaccine
Study design
Participants were recruited through advertisements and social media
Breast milk samples were collected
Before administration of the vaccine
Once weekly for 6 weeks starting at week 2 after the first dose
IgG and IgA antibody levels were assessed
Weekly questionnaires coupled to breast milk collection asked participants for information about interim well-being and vaccine-related adverse events
Primary outcomes
Presence and levels of SARS-CoV-2 antibodies in breast milk
RESULTS:
84 women | 504 breast milk samples
Women: mean age 34 years
Infants: mean age 10.32 months
Mean levels of SARS-CoV-2- IgA antibodies in breast milk increased rapidly and remained elevated throughout follow-up
2 weeks after first dose: 61.8% of samples tested positive
4 weeks after first dose: 86.1% of samples tested positive
6 weeks after first dose: 65.7% of samples tested positive
IgG antibodies remained low for the first 3 weeks, with an increase at week 4, which remained high throughout follow-up
4 weeks after first dose: 91.7% of samples tested positive (P=0.004)
5 and 6 weeks after first dose: 97% of samples tested positive
Adverse events were experienced by a majority of women, but were generally mild, with local pain being the most common complaint
Reported events after the first dose: 55.9% of women
Reported events after the second dose: 61.9% of women
No mother or infant experienced any serious vaccine-related adverse event
Four infants developed a fever after maternal vaccination
CONCLUSION:
Both IgA and IgG SARS-CoV-2 antibodies were detected in breast milk of vaccinated mothers
IgA presence was evident as early as 2 weeks after the first vaccine dose
IgG spiked 4 weeks after the first dose
IgA and IgG levels remained elevated throughout the follow-up period
No major adverse events in mothers or infants were reported
The authors conclude
Antibodies found in breast milk of these women showed strong neutralizing effects, suggesting a potential protective effect against infection in the infant
Potential Pathology Behind AstraZeneca COVID-19 Vaccination and Blood Clots
BACKGROUND AND PURPOSE:
Schultz et al. (NEJM, 2021) describes 5 cases of severe thrombosis and thrombocytopenia following vaccination with the ChAdOx1 (AstraZeneca) COVID-19 vaccine
METHODS:
Case reports
Setting
Oslo University Hospital, Norway
Cases included
5 healthcare workers
32 to 54 years old
Study design
Serum antibodies tested (ELISA)
Platelet factor 4 (PF4)-polyanion complexes
SARS-CoV-2 spike and nucleocapsid proteins
RESULTS:
4 patients had severe cerebral venous thrombosis with intracranial hemorrhage | Fatal in 3 patients
At time of admission
Levels of D-dimer were elevated in all patients
Screening for thrombophilia with proteins C and S and antithrombin was negative
Platelet immunologic testing
All five patients had high levels of IgG antibodies to PF4–polyanion complexes
Platelets in serum from Patients 1, 3, 4, and 5 were clearly activated in the absence of added heparin
All patients were negative for SARS-CoV-2 antibodies, suggesting previous infection was unlikely
CONCLUSION:
5 individuals developed severe venous thromboembolism in unusual sites and concomitant thrombocytopenia 7 to 10 days after vaccination (AstraZeneca)
All 5 patients had a high level of antibodies to PF4–polyanion complexes
The authors suggest
…that these cases represent a vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia (VITT)
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