For Physicians. By Physicians.™

ObGFirst: Get guideline notifications, fast. First month free!Click here

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

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

SUMMARY:

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

Viral Testing

Specimen Collection

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

How is SARS-CoV-2 RNA Testing Performed?

RT-PCR

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

Antigen

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

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

Breath Sample Analysis

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

Diagnostic Testing

Signs or Symptoms of COVID-19

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

Testing to determine resolution of infection

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

Screening Testing

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

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

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

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

Performance of RT-PCR Viral Tests

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

Antibody Testing

General CDC Antibody Guidance

  • According to the CDC

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

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

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

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

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

What Are the Different Types of Antibody Tests?

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

When Can Antibody Testing be Helpful?

Antibody testing may be helpful in the following situations

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

Vaccination and Test Interpretation

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

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

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

Learn More – Primary Sources:

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

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

CDC: Overview of Testing for SARS-CoV-2

Interpreting SARS-CoV-2 Test Results

The Promise and Peril of Antibody Testing for COVID-19

EUA Authorized Serology Test Performance

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

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

SUMMARY:

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



COVID-19 Categories (NIH Panel)

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

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

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

Symptoms

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

Those at Risk Based on Evidence (CDC)

  • Age
    • 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

Learn More – Primary Sources:

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

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

CDC: Clinical Presentation | Clinical Care Considerations

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

Clinical Questions about COVID-19: Questions and Answers

WHO: Novel coronavirus Information Page

JAMA: Coronavirus Disease 2019

FDA: Coronavirus Disease 2019

BMJ: Coronavirus Updates

NEJM: 2019 Novel Coronavirus

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

JAMA: What Is a Pandemic?

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 

Learn More – Primary Sources: 

SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses 

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

Learn More – Primary Sources:

High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19)

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
    • Severe: Dyspnea | Respiratory rate ≥30 breaths | Oxygen saturation ≤93% | Pneumonia
    • 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

Learn More – Primary Sources:

Characteristics and Outcomes of 241 Births to Women With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection at Five New York City Medical Centers

The SAFER Study: What is the Risk to Healthcare Workers for COVID-19 During the Pandemic Peak?

BACKGROUND AND PURPOSE:

  • Houlihan et al. (The Lancet, 2020) evaluate the risk of HCWs contracting and transmitting COVID-19

METHODS:

  • Prospective cohort study (March 26 to April 8, 2020)
    • SARS-CoV-2 Acquisition in Frontline Healthcare Workers—Evaluation to inform Response (SAFER)
  • Setting
    • National Health Service hospital trust in London, UK
  • Participants
    • Patient-facing healthcare workers (HCWs)
  • Study design
    • Nasopharyngeal swabs were collected twice weekly for RT-PCR testing | RT-PCR tests were done twice a week
    • HCWs symptom data were tracked

RESULTS:

  • Total of 200 HCWs were enrolled
    • Median age: 34 (IQR 29 to 44) years
    • Evidence of COVID-19 at any time point: 44% (87 of 200 HCWs)
      • 21% had at least 1 positive RT-PCR test
      • Antibodies: 20% seroconverted and 25% were already seropositive at study entry
    • No hospitalizations reported
  • Mean duration of SARS-CoV-2 detection: 12.9 days (95% CI, 9.4 to 17.3)
    • Longest duration: 29 days
  • Trend towards a higher infection rate in younger HCWs <30 years (p=0.0199)
    • <30: 55%
    • >50: 33%
  • Asymptomatic carriage
    • Symptoms within 7 days of positive test: 48%
    • No symptoms within 7 days of positive test: 38%
  • Infection rates
    • Infection rate within 1 month in those with negative RT-PCR test and without antibodies: 13% (14 of 112 HCWs)
    • Infection rate in HCWs in those who had antibodies with negative RT-PCR at enrollment: 3% (1 of 33 HCWs)
    • Most infections occurred during the week with the highest number of new cases in London

CONCLUSION:

  • 44% of HCWs had evidence of SARS-CoV-2 infection through RT-PCR or serology
    • Higher than other international reports
    • Percentage >2x that of the general population in London
  • The authors suggest that urgent policies are needed
    • HCWs need adequate PPE
    • Adequately protect against asymptomatic transmission into the general population from HCWs (through surveillance testing)

Learn More – Primary Sources:

Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers

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

Learn More – Primary Sources:

Hydroxychloroquine in Nonhospitalized Adults With Early 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

Learn More – Primary Sources:

Association Between Universal Masking in a Health Care System and SARS-CoV-2 Positivity Among Health Care Workers

Mode of Delivery in the Setting of COVID-19

BACKGROUND AND PURPOSE:

  • 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%)
    • Pneumonia: 45.2%
      • Oxygen support: 36.8%
      • Critical care unit: 21.1%
  • Mode of delivery
    • Vaginal: 57.1%
    • Elective cesarean: 42.9% (18 women)
      • COVID-19 indication (e.g. worsening dyspnea): 10 cases
      • Unrelated to COVID-19: 8 cases
  • Neonatal outcomes
    • Spontaneous term: 30 cases (71.4%)
    • Spontaneous preterm birth: 5 cases
    • Elective cesarean: 6 cases
    • 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

Learn More – Primary Sources:

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis


CDC Reports on Pregnancy and COVID-19 Outcomes

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%)
    • Pregnant women less frequently reported
      • Headache | Muscle aches | Fever | Chills | Diarrhea
  • Comorbidities
    • More frequently reported in pregnant women
      • Chronic lung disease | Diabetes mellitus | CVD
  • Hospitalization
    • Significantly higher in pregnant women (adjusted)
    • Pregnant: 31.5% | Nonpregnant: 5.8%
    • aRR: 5.4 (95% CI, 5.1 to 5.6)
  • ICU admission
    • Significantly higher in pregnant women (adjusted)
    • Pregnant: 1.5% | Nonpregnant: 0.9%
    • aRR: 1.5 (95% CI, 1.2 to 1.8)
  • Mechanical ventilation
    • Significantly higher in pregnant women (adjusted)
    • Pregnant: 0.5% | Nonpregnant 0.3%
    • aRR: 1.7 (95% CI, 1.2 to 2.4)
  • Maternal mortality
    • There was no difference between groups
    • Pregnant : 0.2% (16 patients) | Nonpregnant: 0.2% (208 patients)
    • aRR: 0.9 (95% CI, 0.5 to 1.5)

Conclusions

  • Limitations include
    • 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

Learn More – Primary Sources:

CDC (MMWR): Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020

CDC Who Needs Extra Precautions: People of Any Age with Underlying Medical Conditions

ACOG: Novel Coronavirus 2019 (COVID-19)

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

Learn More – Primary Sources:

Comparison of Clinical Characteristics of Patients with Asymptomatic vs Symptomatic Coronavirus Disease 2019 in Wuhan, China