The COVID-19 Serology Studies Workshop: Recommendations and Challenges.

The development, validation, and appropriate application of serological assays to detect antibodies to SARS-CoV-2 are essential to determining seroprevalence of this virus in the United States and globally and in guiding government leadership and the private sector on back-to-work policies. An interagency working group of the US Department of Health and Human Services convened a virtual workshop to identify knowledge gaps and key outstanding scientific issues and to develop strategies to fill them. Key outcomes of the workshop included recommendations for (1) advancing serology assays as a tool to better understand SARS-CoV-2 infection and (2) conducting crucial serology field studies to advance an understanding of immunity to SARS-CoV-2, leading to protection and duration of protection, including the correlation between serological test results and risk of reinfection.

Intrinsic risk factors for alpha-gal syndrome in a case-control study, 2019 to 2020.

BACKGROUND: Alpha-gal syndrome (AGS) is an allergy to galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in most mammals. Evidence indicates that AGS develops after a tick bite, and in the United States, AGS is most associated with bites from Amblyomma americanum (lone star tick); however, not all persons bitten by ticks develop clinical AGS. OBJECTIVE: To investigate intrinsic risk factors associated with the development of AGS. METHODS: We performed a case-control study among adults presenting for diagnosis or management of AGS at an allergy clinic in North Carolina during 2019 to 2020 and compared them with controls enrolled from 2 nearby internal medicine clinics. A questionnaire gathered epidemiologic and tick exposure data, and blood was obtained for alpha-gal-specific IgE and other testing. RESULTS: The 82 enrolled case patients and 191 controls did not differ significantly by age or sex. Case patients were more likely than controls to have A or O blood types (non B-antigen), have experienced childhood allergies, and have a family history of AGS and other food allergies. Case patients were also more likely to report experiencing long healing times for insect bites or stings and a family history of allergy to stinging or biting insects. CONCLUSION: This study suggested that intrinsic factors contribute to risk of developing AGS. Some traits are genetic, but common behaviors among households and family units likely also contribute. Identification of these risk factors can inform personal risk, aid health care providers in understanding susceptible populations, and contribute to ongoing understanding of AGS epidemiology.

Clinical and laboratory features of patients diagnosed with alpha-gal syndrome-2010-2019.

BACKGROUND: Alpha-gal syndrome (AGS) is an IgE-mediated allergy to galactose-alpha-1,3-galactose. Clinical presentation ranges from hives to anaphylaxis; episodes typically occur 2-6 h after exposure to alpha-gal-containing products. In the United States, lone star tick bites are associated with the development of AGS. To characterize features of AGS, we evaluated a cohort of patients presenting for care at the University of North Carolina, focusing on symptoms, severity, and identifying features unique to specific alpha-gal-containing product exposures. METHODS: We performed a chart review and descriptive analysis of 100 randomly selected patients with AGS during 2010-2019. RESULTS: Median age at onset was 53 years, 56% were female, 95% reported White race, 86% reported a history of tick bite, and 75% met the criteria for anaphylaxis based on the involvement of ≥2 organ systems. Those reporting dairy reactions were significantly less likely to report isolated mucocutaneous symptoms (3% vs. 24%; ratio [95% CI]: 0.1 [0.1, 0.3]) than those who tolerated dairy, and were more likely to report gastrointestinal symptoms (79% vs. 59%; ratio [95% CI]: 1.3 [0.7, 2.6]), although this difference was not statistically significant. Dairy-tolerant patients demonstrated higher alpha-gal sIgE titers (as a percentage of total IgE) than dairy-reactive patients (GM 4.1 [95% CI: 2.7, 6.1] vs. GM 2.5 [95% CI: 1.3, 4.8], respectively; ratio -1.6 [95% CI: -1.0, 3.9]). CONCLUSION: While tick exposure is common in the southern United States, nearly all AGS patients reported a tick bite. Gastrointestinal symptoms were prominent among those reporting reactions to dairy. Anaphylaxis was common, underscoring the severity and need to raise awareness of AGS among patients and providers.

Tick bite as a risk factor for alpha-gal-specific immunoglobulin E antibodies and development of alpha-gal syndrome.

BACKGROUND: The disaccharide galactose-α-1,3-galactose (alpha-gal) is expressed in mammals other than humans, apes, and old-world monkeys. In humans, elevated immunoglobulin E (IgE) antibodies specific for alpha-gal can result in allergic hypersensitivity known as alpha-gal syndrome (AGS). Case reports and series suggest that tick bites can induce alpha-gal-specific IgE (sIgE) antibodies. OBJECTIVE: To evaluate tick exposure as a risk factor for AGS and elevated alpha-gal sIgE level. METHODS: We conducted a case-control study comparing patients with AGS from a North Carolina allergy clinic with controls who were patients at a nearby internal medicine clinic. Cases and controls were administered a questionnaire to obtain information about demographics, home environment, outdoor activities, and recollection of tick bite. Serum samples taken at the time of enrollment were tested for total IgE, alpha-gal sIgE, and antibodies to other tick-borne pathogens. RESULTS: The patients with AGS were more likely to recall finding a tick on themselves (odds ratio [OR], 11.20; 95% confidence interval [CI], 4.97-25.15), live near wooded forest (OR, 2.27; 95% CI, 0.92-5.55), and spend 17 or more hours per week outdoors in wooded areas (OR, 5.58; 95% CI, 2.56-12.19). The patients with AGS were also more likely to report 4 or more tick bites (OR, 33.05; 95% CI, 9.92-155.12) and reactions at the site of tick bites (OR, 7.93; 95% CI, 3.74-16.80). Furthermore, elevated alpha-gal sIgE level was observed in 33% of the controls and was associated with tick exposure in the controls (OR, 4.25; 95% CI, 2.21-8.18). CONCLUSION: The results define tick bite as a risk factor for AGS and elevated alpha-gal sIgE level.

Reinfection With Severe Acute Respiratory Syndrome Coronavirus 2 Among Previously Infected Healthcare Personnel and First Responders.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus testing among first responders and healthcare personnel who participated in a May 2020-August 2020 serosurvey that assessed spike protein antibodies provided an opportunity to assess reinfection. METHODS: Serology survey data were merged with virus testing results from Rhode Island (1 March 2020-17 February 2021) and New York City (10 March 2020-14 December 2020). Participants with a positive virus test ≥14 days before their serology test were included. Reinfection was defined as a second positive SARS-CoV-2 test ≥90 days after the first positive test. The association between serostatus and reinfection was assessed with a proportional hazards model. RESULTS: Among 1572 previously infected persons, 40 (2.5%) were reinfected. Reinfection differed by serostatus: 8.4% among seronegative vs 1.9% among seropositive participants (P < .0001). Most reinfections occurred among Rhode Island nursing home and corrections personnel (n = 30) who were most frequently tested (mean 30.3 tests vs 4.6 for other Rhode Island and 2.3 for New York City participants). The adjusted hazard ratio (aHR) for reinfection in seropositive vs seronegative persons was 0.41 (95% confidence interval [CI], .20-.81). Exposure to a household member with coronavirus disease 2019 (COVID-19) before the serosurvey was also protective (aHR, 0.34; 95% CI, .13-.89). CONCLUSIONS: Reinfections were uncommon among previously infected persons over a 9-month period that preceded widespread variant circulation. Seropositivity decreased reinfection risk. Lower reinfection risk associated with exposure to a household member with COVID-19 may reflect subsequently reduced household transmission.

Duration of Viral Nucleic Acid Shedding and Early Reinfection With Severe Respiratory Syndrome Coronavirus 2 in Healthcare Workers and First Responders.

We estimated the distributions of duration of SARS-CoV-2 nucleic acid shedding and time to reinfection among 137 persons with at least 2 positive nucleic acid amplification test (NAAT) results from March to September 2020. We analyzed gaps of varying length between subsequent positive and negative NAAT results and estimated a mean duration of nucleic acid shedding of 30.1 days (95% confidence interval [CI], 26.3-34.5). Mean time to reinfection was 89.1 days (95% CI, 75.3-103.5). Together, these indicate that a 90-day period between positive NAAT results can reliably define reinfection in immunocompetent persons although reinfection can occur at shorter intervals.

Coronavirus Disease 2019 Symptoms and Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Positivity in a Large Survey of First Responders and Healthcare Personnel, May-July 2020.

A severe acute respiratory syndrome coronavirus 2 serosurvey among first responder/healthcare personnel showed that loss of taste/smell was most predictive of seropositivity; percent seropositivity increased with number of coronavirus disease 2019 symptoms. However, 22.9% with 9 symptoms were seronegative, and 8.3% with no symptoms were seropositive. These findings demonstrate limitations of symptom-based surveillance and importance of testing.

Lack of Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a Large Cohort of Previously Infected Persons.

BACKGROUND: Reports suggest that some persons previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lack detectable immunoglobulin G (IgG) antibodies. We aimed to determine the proportion IgG seronegative and predictors for seronegativity among persons previously infected with SARS-CoV-2. METHODS: We analyzed serologic data collected from healthcare workers and first responders in New York City and the Detroit metropolitan area with a history of a positive SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) test result and who were tested for IgG antibodies to SARS-CoV-2 spike protein at least 2 weeks after symptom onset. RESULTS: Of 2547 persons with previously confirmed SARS-CoV-2 infection, 160 (6.3%) were seronegative. Of 2112 previously symptomatic persons, the proportion seronegative slightly increased from 14 to 90 days post symptom onset (P = .06). The proportion seronegative ranged from 0% among 79 persons previously hospitalized to 11.0% among 308 persons with asymptomatic infections. In a multivariable model, persons who took immunosuppressive medications were more likely to be seronegative (31.9%; 95% confidence interval [CI], 10.7%-64.7%), while participants of non-Hispanic Black race/ethnicity (vs non-Hispanic White; 2.7%; 95% CI, 1.5%-4.8%), with severe obesity (vs under/normal weight; 3.9%; 95% CI, 1.7%-8.6%), or with more symptoms were less likely to be seronegative. CONCLUSIONS: In our population with previous RT-PCR-confirmed infection, approximately 1 in 16 persons lacked IgG antibodies. Absence of antibodies varied independently by illness severity, race/ethnicity, obesity, and immunosuppressive drug therapy. The proportion seronegative remained relatively stable among persons tested up to 90 days post symptom onset.

SARS-CoV-2 Infection and Mitigation Efforts among Office Workers, Washington, DC, USA.

Despite mitigation efforts, 2 coronavirus disease outbreaks were identified among office workers in Washington, DC. Moderate adherence to workplace mitigation efforts was reported in a serologic survey; activities outside of the workplace were associated with infection. Adherence to safety measures are critical for returning to work during the pandemic.

Severe Acute Respiratory Syndrome Coronavirus 2 Seropositivity among Healthcare Personnel in Hospitals and Nursing Homes, Rhode Island, USA, July-August 2020.

Healthcare personnel are recognized to be at higher risk for infection with severe acute respiratory syndrome coronavirus 2. We conducted a serologic survey in 15 hospitals and 56 nursing homes across Rhode Island, USA, during July 17-August 28, 2020. Overall seropositivity among 9,863 healthcare personnel was 4.6% (95% CI 4.2%-5.0%) but varied 4-fold between hospital personnel (3.1%, 95% CI 2.7%-3.5%) and nursing home personnel (13.1%, 95% CI 11.5%-14.9%). Within nursing homes, prevalence was highest among personnel working in coronavirus disease units (24.1%; 95% CI 20.6%-27.8%). Adjusted analysis showed that in hospitals, nurses and receptionists/medical assistants had a higher likelihood of seropositivity than physicians. In nursing homes, nursing assistants and social workers/case managers had higher likelihoods of seropositivity than occupational/physical/speech therapists. Nursing home personnel in all occupations had elevated seropositivity compared with hospital counterparts. Additional mitigation strategies are needed to protect nursing home personnel from infection, regardless of occupation.

Prevalence of SARS-CoV-2 Antibodies in First Responders and Public Safety Personnel, New York City, New York, USA, May-July 2020.

We conducted a serologic survey in public service agencies in New York City, New York, USA, during May-July 2020 to determine prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among first responders. Of 22,647 participants, 22.5% tested positive for SARS-CoV-2-specific antibodies. Seroprevalence for police and firefighters was similar to overall seroprevalence; seroprevalence was highest in correctional staff (39.2%) and emergency medical technicians (38.3%) and lowest in laboratory technicians (10.1%) and medicolegal death investigators (10.8%). Adjusted analyses demonstrated association between seropositivity and exposure to SARS-CoV-2-positive household members (adjusted odds ratio [aOR] 3.52 [95% CI 3.19-3.87]), non-Hispanic Black race or ethnicity (aOR 1.50 [95% CI 1.33-1.68]), and severe obesity (aOR 1.31 [95% CI 1.05-1.65]). Consistent glove use (aOR 1.19 [95% CI 1.06-1.33]) increased likelihood of seropositivity; use of other personal protective equipment had no association. Infection control measures, including vaccination, should be prioritized for frontline workers.

Evaluating Differences in Whole Blood, Serum, and Urine Screening Tests for Zika Virus, Puerto Rico, USA, 2016.

We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015-2016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens.

Diagnostic testing for galactose-alpha-1,3-galactose, United States, 2010 to 2018.

BACKGROUND: Alpha-gal syndrome (AGS) is an emerging immunoglobulin E (IgE)-mediated allergy to galactose-alpha-1,3-galactose (alpha-gal). The geographic distribution and burden of AGS in the United States are unknown. OBJECTIVE: To characterize alpha-gal IgE testing patterns and describe the trends and distribution from 2010 to 2018 in the United States. METHODS: This retrospective analysis included all persons tested for alpha-gal IgE antibodies by Viracor-IBT Laboratories (Lee's Summit, Missouri), the primary site of testing in the United States. Data included age and sex of person tested, specimen state of origin, collection date, and result value; persons with at least 1 positive test result (≥0.1 kU/L) were compared with negatives. Proportions tested and with positive test results were calculated using the US Census population estimates. RESULTS: Overall, 122,068 specimens from 105,674 persons were tested for alpha-gal IgE during July 1, 2010, to December 31, 2018. Nearly one-third (34,256, 32.4%) had at least 1 positive result. The number of persons receiving positive test results increased 6-fold from 1110 in 2011 to 7798 in 2018. Of those receiving positive test results, mean [SD] age was 46.9 (19.8) years; men were more likely to test positive than women (43.3% vs 26.0%). Arkansas, Virginia, Kentucky, Oklahoma, and Missouri had the highest number of persons who were tested and had a positive result per 100,000 population. CONCLUSION: More than 34,000 persons, most presumably symptomatic, have received positive test results for IgE antibodies to alpha-gal, suggesting AGS is an increasingly recognized public health problem. The geographic distribution of persons who tested positive is consistent with exposure to Amblyomma americanum ticks.

SARS-CoV-2 Seroprevalence among Healthcare, First Response, and Public Safety Personnel, Detroit Metropolitan Area, Michigan, USA, May-June 2020.

To estimate seroprevalence of severe acute respiratory syndrome 2 (SARS-CoV-2) among healthcare, first response, and public safety personnel, antibody testing was conducted in emergency medical service agencies and 27 hospitals in the Detroit, Michigan, USA, metropolitan area during May-June 2020. Of 16,403 participants, 6.9% had SARS-CoV-2 antibodies. In adjusted analyses, seropositivity was associated with exposure to SARS-CoV-2-positive household members (adjusted odds ratio [aOR] 6.18, 95% CI 4.81-7.93) and working within 15 km of Detroit (aOR 5.60, 95% CI 3.98-7.89). Nurse assistants (aOR 1.88, 95% CI 1.24-2.83) and nurses (aOR 1.52, 95% CI 1.18-1.95) had higher likelihood of seropositivity than physicians. Working in a hospital emergency department increased the likelihood of seropositivity (aOR 1.16, 95% CI 1.002-1.35). Consistently using N95 respirators (aOR 0.83, 95% CI 0.72-0.95) and surgical facemasks (aOR 0.86, 95% CI 0.75-0.98) decreased the likelihood of seropositivity.

Possible Congenital Zika Syndrome in Older Children Due to Earlier Circulation of Zika Virus.

Congenital Zika syndrome (CZS) was identified following a large Zika virus (ZIKV) outbreak in Brazil in 2015. Two children with clinical presentations consistent with CZS, ages 7 and 8 years old, are described. Both mothers lived in Cambodia, a region with known ZIKV, during their pregnancies and reported fever and rash in the second trimester. The infants were born with severe microcephaly. Testing for congenital infection at birth and genetic testing were unremarkable. In 2017, serologic testing for both mothers were consistent with prior ZIKV infection. Review of infant neuroimaging demonstrated ventriculomegaly, severe cerebral atrophy, and subcortical calcifications consistent with CZS. Given the maternal symptoms suggesting ZIKV infection during pregnancy and the combination of clinical and radiological features unique to CZS, CZS is strongly suspected in these children, suggesting that CZS occurred before the 2013-2014 French Polynesia outbreak. As such, CZS should be considered in older children with congenital microcephaly of unknown etiology and a history consistent with possible ZIKV exposure.

Update: Interim Guidance for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus for Men with Possible Zika Virus Exposure - United States, August 2018.

Zika virus infection can occur as a result of mosquitoborne or sexual transmission of the virus. Infection during pregnancy is a cause of fetal brain abnormalities and other serious birth defects (1,2). CDC has updated the interim guidance for men with possible Zika virus exposure who 1) are planning to conceive with their partner, or 2) want to prevent sexual transmission of Zika virus at any time (3). CDC now recommends that men with possible Zika virus exposure who are planning to conceive with their partner wait for at least 3 months after symptom onset (if symptomatic) or their last possible Zika virus exposure (if asymptomatic) before engaging in unprotected sex. CDC now also recommends that for couples who are not trying to conceive, men can consider using condoms or abstaining from sex for at least 3 months after symptom onset (if symptomatic) or their last possible Zika virus exposure (if asymptomatic) to minimize their risk for sexual transmission of Zika virus. All other guidance for Zika virus remains unchanged. The definition of possible Zika virus exposure remains unchanged and includes travel to or residence in an area with risk for Zika virus transmission (https://wwwnc.cdc.gov/travel/page/world-map-areas-with-zika) or sex without a condom with a partner who traveled to or lives in an area with risk for Zika virus transmission. CDC will continue to update recommendations as new information becomes available.

Vital Signs: Trends in Reported Vectorborne Disease Cases - United States and Territories, 2004-2016.

INTRODUCTION: Vectorborne diseases are major causes of death and illness worldwide. In the United States, the most common vectorborne pathogens are transmitted by ticks or mosquitoes, including those causing Lyme disease; Rocky Mountain spotted fever; and West Nile, dengue, and Zika virus diseases. This report examines trends in occurrence of nationally reportable vectorborne diseases during 2004-2016. METHODS: Data reported to the National Notifiable Diseases Surveillance System for 16 notifiable vectorborne diseases during 2004-2016 were analyzed; findings were tabulated by disease, vector type, location, and year. RESULTS: A total 642,602 cases were reported. The number of annual reports of tickborne bacterial and protozoan diseases more than doubled during this period, from >22,000 in 2004 to >48,000 in 2016. Lyme disease accounted for 82% of all tickborne disease reports during 2004-2016. The occurrence of mosquitoborne diseases was marked by virus epidemics. Transmission in Puerto Rico, the U.S. Virgin Islands, and American Samoa accounted for most reports of dengue, chikungunya, and Zika virus diseases; West Nile virus was endemic, and periodically epidemic, in the continental United States. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Vectorborne diseases are a large and growing public health problem in the United States, characterized by geographic specificity and frequent pathogen emergence and introduction. Differences in distribution and transmission dynamics of tickborne and mosquitoborne diseases are often rooted in biologic differences of the vectors. To effectively reduce transmission and respond to outbreaks will require major national improvement of surveillance, diagnostics, reporting, and vector control, as well as new tools, including vaccines.

Epidemiology of Zika Virus Infection.

Long known to be endemic in Africa and Southeast Asia and a rare cause of acute febrile illness, Zika virus (ZIKAV) arose from obscurity when an Asian genotype ZIKAV caused an outbreak of mild febrile illness in 2007 in Yap State, Federated States of Micronesia. Subsequent viral spread in the Pacific led to a large outbreak in French Polynesia commencing in 2013. After its recognition in the Americas through March 2017, the Pan American Health Organization has received reports of >750000 suspected and laboratory-confirmed cases of autochthonous ZIKAV transmission. Outbreaks in most countries in the Americas peaked in early to mid-2016. Increased surveillance in several Southeast Asian counties has led to increased case recognition, including an outbreak in Singapore, and the first reports of birth defects linked to ZIKAV in the region. As of April 2017, the World Health Organization reported 84 countries or territories with current or previous ZIKAV transmission.

Modes of Transmission of Zika Virus.

For >60 years, Zika virus (ZIKV) has been recognized as an arthropod-borne virus with Aedes species mosquitoes as the primary vector. However in the past 10 years, multiple alternative routes of ZIKV transmission have been identified. We review the available data on vector and non-vector-borne modes of transmission and interventions undertaken, to date, to reduce the risk of human infection through these routes. Although much has been learned during the outbreak in the Americas on the underlying mechanisms and pathogenesis of non-vector-borne ZIKV infections, significant gaps remain in our understanding of the relative incidence of, and risk from, these modes compared to mosquito transmission. Additional research is urgently needed on the risk, pathogenesis, and effectiveness of measures to mitigate non-vector-borne ZIKV transmission.

Zika Virus -10 Public Health Achievements in 2016 and Future Priorities.

The introduction of Zika virus into the Region of the Americas (Americas) and the subsequent increase in cases of congenital microcephaly resulted in activation of CDC's Emergency Operations Center on January 22, 2016, to ensure a coordinated response and timely dissemination of information, and led the World Health Organization to declare a Public Health Emergency of International Concern on February 1, 2016. During the past year, public health agencies and researchers worldwide have collaborated to protect pregnant women, inform clinicians and the public, and advance knowledge about Zika virus (Figure 1). This report summarizes 10 important contributions toward addressing the threat posed by Zika virus in 2016. To protect pregnant women and their fetuses and infants from the effects of Zika virus infection during pregnancy, public health activities must focus on preventing mosquito-borne transmission through vector control and personal protective practices, preventing sexual transmission by advising abstention from sex or consistent and correct use of condoms, and preventing unintended pregnancies by reducing barriers to access to highly effective reversible contraception.