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
Can High Dose Nitric Oxide Improve Respiratory Function in Pregnant Women with Severe COVID-19?
PURPOSE:
There is limited data on how best to manage respiratory failure in pregnant women with COVID-19
Safaee Fakhr et al. sought to determine if administering high concentrations of nitric oxide could improve the clinical course of pregnant women with respiratory failure
METHODS:
Case series (April to June 2020)
6 pregnant patients admitted with severe or critical COVID-19
Patients received high-dose (160–200 ppm) nitric oxide by mask twice daily
Treatment sessions lasted 30 minutes to 1 hour
For those patients requiring mechanical ventilation, the high dose regimen was stopped and restarted after extubation | During intubation, the patients received continuous low dose nitric oxide through the ventilator
RESULTS:
Total of 39 treatments
Cardiopulmonary function improved with administration of nitric oxide
Systemic oxygenation: Improved following each administration session in hypoxemic patients
Tachypnea: Reduced among all patients each session
3 deliveries while in hospital
4 neonates
28-day follow-up: All mothers and infants in good condition at home
3 remaining patients:
Discharged home and still pregnant at time of publication
There were no adverse events documented
CONCLUSION:
While acknowledging the small cohort size, the authors also conclude that
Nitric oxide at 160–200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure
Pregnant Women with COVID-19 at Time of Delivery: NYC Cohort Characteristics and Outcomes
BACKGROUND AND PURPOSE:
Khoury et al. (Obstetrics & Gynecology, 2020) characterized clinical features and disease course among the initial cohort of pregnant women during the COVID-19 pandemic in New York City admitted for delivery
METHODS:
Prospective cohort study (March 13 to April 12, 2020 with follow-up completed April 20, 2020)
Setting
Five New York City medical centers
Participants
Pregnant women admitted for delivery
Confirmed COVID-19
Study design
Data collected: Demographics | Presentation | Comorbidities | Maternal and Neonatal outcomes | COVID-19 clinical course
COVID-19 cases were defined as
Asymptomatic
Mild: no additional oxygen supplementation required
Critical: Respiratory failure | Septic shock | Multiple organ dysfunction or failure
RESULTS:
241 women included
Asymptomatic on admission: 61.4% | 69% remained asymptomatic
Clinical status at time of hospitalization for delivery
Mild: 26.5%
Severe: 26.1%
Critical: 5%
Singleton preterm birth rate: 14.6%
Critical outcomes
ICU admission: 7.1% of women (17 women)
Intubation during delivery: 3.7% (9 women)
Maternal deaths: 0 women
BMI ≥30 associated with COVID-19 severity (P=0.001)
Cesarean delivery rates
Severe COVID-19: 52.4%
Critical COVID-19: 91.7%
Linear trend across COVID-19 severity groups for cesarean risk (P<.001)
245 liveborn neonates
Resuscitation at delivery beyond normal requirements: 30%
NICU admission: 25.7% | Hospitalization <2 days in 62.4%
Newborn outcomes
Prematurity and low birth weight: 8.7% (most common complications)
RDS: 5.8%
No complications: 79.3%
97.5% of newborns tested negative for SARS-CoV-2 at 24 to 96 hours
IUFD: 2 cases
Case 1: 38 weeks without fetal movement | Symptoms of COVID-19 pneumonia including chest imaging | No supplemental oxygen required | Patient declined autopsy and further work up for COVID-19 | No abnormalities were seen on placental pathology
Case 2: 29 weeks of gestation | FGR <1%tile | HELLP syndrome | Severe COVID-19 pneumonia
CONCLUSION:
Majority of pregnant women admitted for delivery were asymptomatic for COVID-19
Approximately 1/3 remained asymptomatic
Obesity was associated with COVID-19 severity
For women with COVID-19 (particularly severe and critical) there is an increased risk for cesarean and preterm birth
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
Universal Masking and COVID-19 Infection Rates in Healthcare Personnel
PURPOSE:
Wang et al. (JAMA, 2020) assessed whether a program of universal masking in a large healthcare system was associated with the SARS-CoV-2 infection rate among healthcare personnel
METHODS:
Retrospective cohort study
Mass General Brigham (MGB) |12 hospitals 75 000 employees
Hospital system initiated a COVID-19 infection reduction strategy that included
Systematic SARS-CoV-2 testing of symptomatic healthcare personnel
Universal masking of all healthcare personnel and patients (surgical masks)
3 phases
Preintervention period before universal masking: March 1 to 24, 2020
Transition period until implementation of universal masking of patients: March 25 to April 5, 2020
Lag period to allow for manifestations of symptoms: April 6 to 10, 2020
Intervention period; April 11 to 30, 2020
Positivity rate
Numerator: First positive test result for all healthcare personnel
Denominator: Healthcare personnel who never tested positive plus those who tested positive that day
Statistical analysis
Mean trends calculated based on overall slope of each period was calculated using linear regression
Change in overall slope compared between the preintervention vs intervention periods
RESULTS:
9850 Healthcare Personnel underwent testing
Positive results: 12.9% | Median age, 39 years
73% female | 7.4% physicians or trainees | 26.5% nurses or PAs | 17.8% technologists or nursing support | 48.3% other
Preintervention period: SARS-CoV-2 positivity rate increased exponentially from 0% to 21.32% | Weighted mean increase of 1.16% per day | Case doubling time of 3.6 days (95% CI, 3.0 to 4.5 days)
Intervention period: SARS-CoV-2 positivity rate decreased linearly from 14.65% to 11.46% | Weighted mean decline of 0.49% per day
Net slope change: 1.65% more decline per day compared with the preintervention period (95% CI, 1.13% to 2.15%; P < .001)
CONCLUSION:
Universal masking was associated with a decrease in SARS-CoV-2 infection rates among healthcare personnel
The authors acknowledge the possibility of confounding due to other transmission prevention measures such as social distancing
The authors state that
Randomized trials of universal masking of HCWs during a pandemic are likely not feasible
Nonetheless, these results support universal masking as part of a multipronged infection reduction strategy in health care settings
Ferrazzi et al. (BJOG, 2020) report on the mode of delivery and immediate neonatal outcomes in women infected with COVID-19 in Lombardy, Italy
METHODS:
Retrospective study
Setting
12 hospitals in northern Italy
Participants
Confirmed COVID-19 prior to or within 36 hours after delivery
Delivered from March 1 to March 20, 2020
All consecutive cases admitted to maternity ward for delivery
Study design
Data derived from clinical records
General maternal characteristics | Medical or obstetric co-morbidity | Course of pregnancy | Clinical signs and symptoms | Treatment of COVID 19 infection | Mode of delivery | Neonatal data and breastfeeding
Primary outcome
Mode of delivery
Neonatal outcome
RESULTS:
Total 42 women with COVID-19
Mean maternal age: 32.9 years (range 21 to 44 years)
COVID-19 diagnosis
Known before admission: 19 cases
On hospital admission: 10 cases
Delivery room: 27 cases
Within 36 hours of delivery: 5 cases (patients still admitted)
Maternal clinical features
Most common symptoms: Fever, cough and mild dyspnoea (80%)
Two women breastfed without a mask because COVID-19 infection was diagnosed in the postpartum period
Their newborns tested positive for COVID-19 (days 1 and 3)
In one case, a newborn had a positive test after a vaginal operative delivery | Mother did not breastfeed
Symptoms day 3 | Recovered after 1 day of mechanical ventilation
CONCLUSION:
Authors acknowledge that vertical transmission risk with vaginal delivery cannot be excluded
However, results from this study would suggest that vaginal delivery is associated with a low risk of COVID-19 transmission
In addition, the author conclude that
Vaginal delivery is appropriate in mild cases and caesarean section should be reserved for women with severe respiratory problems, where delivering the baby will allow improved ventilation
NOTE: The NIH panel has updated guidance regarding antithrombotic therapy based on the latest evidence, including recommending against the use of antiplatelet therapy to prevent COVID-19 progression or death in noncritically ill patients. 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
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
Medications for Nonhospitalized Mild to Moderate COVID-19 at High Risk of Progression
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)
Bebtelovimab
175 mg as a single IV infusion, administered as soon as possible and within 7 days of symptom onset in those aged ≥12 years and weighing ≥40 kg
Laboratory and Phase 2 clinical data for bebtelovimab, coupled with the aggregate evidence for this class of agents, support the use of bebtelovimab in high-risk patients when other options are not available, feasible to deliver, or clinically appropriate
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
Sotrovimab
Because the Omicron BA.2 subvariant is now the dominant circulating subvariant in all regions of the United States, the distribution of sotrovimab has been paused, and the Panel no longer recommends using sotrovimab to treat COVID-19
Note: NIH refers to the CDC guidance to determine at increased risk for progression | See ‘Learn More – Primary Care’ for reference
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 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
How Do Clinical Characteristics of COVID-19 Infection Differ Between Symptomatic and Asymptomatic Patients?
BACKGROUND AND PURPOSE:
Yang et al. (JAMA Netw Open., 2020) describe clinical characteristics of both symptomatic and asymptomatic patients with confirmed SARS-CoV-2 infection
METHODS:
Case series (December 24, 2019, to February 24, 2020)
Setting
Wuhan, China
Participants
Consecutive hospitalized cases with lab confirmed COVID-19
Recruited from 26 cluster cases who had
Confirmed history of exposure to the Hunan seafood market or
Close contact with another patient who had been hospitalized for COVID-19
Study design
RT-PCR on nasopharyngeal swabs was performed every 24 to 48 hours
CT scan: On admission with a second chest CT at 4 to 6 days and third CT at 6 to 7 days after the second scan
Additional CT for worsening status
CD4+T lymphocyte count was tested every 5 to 6 days
RESULTS:
78 patients
Median (IQR) number of patients per cluster: 3 (2-3) patients
Range: 2 to 10 patients per cluster
Symptomatic vs asymptomatic
Symptomatic cases: 57.7% of cases (45 patients)
Asymptomatic: 42.3% of cases (33 patients)
Patients who were asymptomatic tended to
Be younger (P < 0.001)
Asymptomatic: median (IQR) age 37 (26 to 45) years
Symptomatic: 56 (34 to 63) years
Be women (P = 0.002)
Asymptomatic: 66.7% were women (22 patients)
Symptomatic: 31.0% were women (14 patients)
Not have biochemical evidence of liver injury (P = 0.03)
Asymptomatic: 3% had a liver injury (1 patient)
Symptomatic: 20.0% had a liver injury (9 patients)
Have higher CD4+T lymphocyte counts (P = 0.001)
Asymptomatic: median (IQR) 719 (538 to 963) per uL
Symptomatic: 474 (354 to 811) per ul
Have faster lung recovery based on CT scan (P = 0.001)
Asymptomatic: median (IQR) duration 9 (6 to 18) days
Symptomatic: 15 (11 to 18) days
Have a shorter duration of viral shedding on nasopharyngeal swabs (P = 0.001)
Asymptomatic: median (IQR) duration 8 (3 to 12) days
Symptomatic: 19 (16 to 24) days
Have more stable SARS-CoV-2 testing results
Asymptomatic: 12.1% had fluctuated results (4 patients)
Symptomatic: 33.3% had fluctuated results (15 patients)
CONCLUSION:
Compared to symptomatic COVID-19 patients, asymptomatic patients experienced less organ injury and CT scans improved more rapidly
Consumption of CD4 lymphocytes was lower, suggesting less damage to the immune system
Asymptomatic patients appear to have a shorter duration of viral shedding, suggesting that they may be infectious for a shorter period of time
Cord prolapse (was induced for worsening respiratory status): 1 patient
Vaginal delivery: 1 patient
CONCLUSION:
2 patients (1 pregnant, 1 postpartum) hospitalized with COVID-19 died following ICU admission
15% of patients admitted to ICU and 25% of patients on mechanical ventilation
The authors state
…pregnant and postpartum women admitted to the ICU with COVID-19 are at risk for maternal death, which may occur even in the absence of significant baseline comorbidities
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