key: cord-0863582-3y6velaz
authors: Waltenburg, Michelle A.; Whaley, Melissa J.; Chancey, Rebecca J.; Donnelly, Marisa A.P.; Chuey, Meagan R.; Soto, Raymond; Schwartz, Noah G.; Chu, Victoria T.; Sleweon, Sadia; McCormick, David W.; Uehara, Anna; Retchless, Adam C.; Tong, Suxiang; Folster, Jennifer M.; Petway, Marla; Thornburg, Natalie J.; Drobeniuc, Jan; Austin, Brett; Hudziec, Meghan M.; Stringer, Ginger; Albanese, Bernadette A.; Totten, S.E.; Matzinger, Shannon R.; Staples, J. Erin; Killerby, Marie E.; Hughes, Laura J.; Matanock, Almea; Beatty, Mark; Tate, Jacqueline E.; Kirking, Hannah L.; Hsu, Christopher H.
title: Household Transmission and Symptomology of SARS-CoV-2 Alpha Variant Among Children—California and Colorado, 2021
date: 2022-04-18
journal: J Pediatr
DOI: 10.1016/j.jpeds.2022.04.032
sha: 5a96b58da9995fa46ba0d444cacbc082d65c3184
doc_id: 863582
cord_uid: 3y6velaz

OBJECTIVE: To assess the household secondary infection risk (SIR) of B.1.1.7 (Alpha) and non-Alpha lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children. STUDY DESIGN: During January–April 2021, we prospectively followed households with a SARS-CoV-2 infection. We collected questionnaires, serial nasopharyngeal swabs for RT-PCR testing and whole genome sequencing, and serial blood samples for serology testing. We calculated SIRs by primary case age (pediatric vs. adult), household contact age, and viral lineage. We evaluated risk factors associated with transmission and described symptom profiles among children. RESULTS: Among 36 households with pediatric primary cases, 21 (58%) had secondary infections. Among 91 households with adult primary cases, 51 (56%) had secondary infections. SIRs among pediatric and adult primary cases were 45% and 54%, respectively (OR: 0.79 [95% CI 0.41–1.54]). SIRs among pediatric primary cases with Alpha and non-Alpha lineage were 55% and 46%, respectively (OR: 1.52 [CI 0.51–4.53]). SIRs among pediatric and adult household contacts were 55% and 49%, respectively (OR: 1.01 [CI 0.68–1.50]). Among pediatric contacts, no significant differences in odds of acquiring infection by demographic or household characteristics were observed. CONCLUSIONS: Household transmission of SARS-CoV-2 from children and adult primary cases to household members was frequent. Risk of secondary infection was similar among child and adult household contacts. Among children, household transmission of SARS-CoV-2 and risk of secondary infection was not influenced by lineage. Continued mitigation strategies (e.g., masking, physical distancing, vaccination) are needed to protect at-risk groups regardless of virus lineage circulating in communities.

including children, as of January 2022. 1 Compared with adults, children frequently exhibit SARS-CoV-2 infections that are less severe and are more often asymptomatic. 2, 3 Prior US household transmission investigations demonstrated that children acquired SARS-CoV-2 infection at similar rates as adults [4] [5] [6] ; however, less is known about transmission from children, and how transmission might be affected by emerging variant lineages.

Several variants of concern (VOCs) have emerged during the pandemic, which have affected SARS-CoV-2 transmission, susceptibility, and disease severity. 7, 8 The SARS-CoV-2 B.1.1.7 (Alpha) lineage was first identified in the United Kingdom in September 2020 and J o u r n a l P r e -p r o o f emerged in the United States in December 2020, 9 becoming the predominant variant within four months. 7 From December 2020-September 2021, the Alpha variant was classified as a VOC in the United States. Prior studies have indicated that the Alpha variant was more efficiently transmitted compared with previous lineages. 10, 11 We conducted a household transmission investigation pre-B.1.617.2 (Delta) and pre-B.1.1.529 (Omicron) variant emergence, during the months of January-April 2021 when Alpha was the most prevalent lineage in the United States. Using detailed epidemiological data and multiple testing modalities, we estimate household secondary infection risks (SIRs), describe characteristics associated with transmission and infection, and compare symptom profiles of children infected with Alpha and non-Alpha SARS-CoV-2 lineages in household settings.

During January-April 2021, the US Centers for Disease Control and Prevention (CDC) was invited to collaborate with state and local health departments in San Diego County, California and metropolitan Denver (Adam, Arapahoe, and Douglas counties), Colorado to conduct household transmission investigations. 12 Public health agencies reported persons in households with a positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) specimen to CDC's investigation team to be screened for enrollment eligibility. 12 Households were eligible if the primary case was not hospitalized at enrollment, lived with ≥1 person, did not live in a congregate setting, and had illness onset ≤10 days prior to enrollment ( Figure 1 ; available at www.jpeds.com).

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The primary case was defined as the person within the household with the earliest illness onset date. Illness onset date was defined as symptom onset date, or, if asymptomatic, collection date of initial SARS-CoV-2 RT-PCR-positive specimen. Household contacts were household members spending ≥1 night in the household during the infectious period of the primary case, defined as two days before through ten days after the illness onset date. 13 Households were excluded if all household members were lost to follow-up, withdrew during the 14-day followup, or if the primary case could not be determined because multiple persons in a household became symptomatic or tested positive on the same day (i.e., co-primary infections).

Primary and secondary case classifications were retroactively assigned following the evaluation. Secondary cases were defined as household contacts who had a positive RT-PCR for SARS-CoV-2 during the investigation period, converted from SARS-CoV-2 IgG negative on enrollment to SARS-CoV-2 IgG positive on closeout without a history of vaccination, or were seropositive on enrollment with new-onset symptoms without a history of vaccination or a previous SARS-CoV-2 infection. Pediatric household members (aged <18 years) were classified as young children (≤11 years) or adolescents (12-17 years) .

An in-person visit was conducted at enrollment (Day 0) and closeout (Day 14).

Questionnaires capturing demographic characteristics, medical histories, recent symptoms, previous SARS-CoV-2 testing, and preventive behaviors were administered to all household members at enrollment and closeout. For young children, a parent or guardian assisted them in completing the questionnaire. A household-level questionnaire captured physical characteristics of the residence (e.g., square footage, number of bedrooms and bathrooms).

Blood for serology and nasopharyngeal (NP) swabs for RT-PCR were collected from household members on enrollment and closeout. Household members self-completed daily symptom diaries using a standardized form with yes/no responses. At enrollment, some households were offered daily home antigen testing by QuickVue® At-Home OTC COVID-19

Test (Quidel; San Diego, CA). Household members were asked to perform an antigen test each day, regardless of symptom status. Antigen test results were submitted daily to the investigation team. During the 14-day follow-up period, if a household contact developed new or worsening symptoms, or newly tested positive by home antigen testing, an interim visit was conducted to collect a NP swab for RT-PCR from all household members. A parent or guardian used discretion to determine if children needed assistance with daily antigen testing and symptom diaries during the 14-day follow-up.

Individuals were considered fully vaccinated ≥14 days after completion of all recommended doses of an FDA-authorized COVID-19 vaccine (the primary series), partially vaccinated if <14 days since completing the primary series or did not complete the series, and unvaccinated if no COVID-19 vaccine was received. 14 Date and type of SARS-CoV-2 vaccination was verified through direct observation of vaccination cards when available.

Symptoms were categorized as constitutional (measured or subjective fever, chills, myalgia, and fatigue), upper respiratory (runny nose, nasal congestion, and sore throat), lower respiratory (cough, difficulty breathing, shortness of breath, wheezing, and chest pain), neurologic (headache, loss of taste, and loss of smell), and gastrointestinal (nausea and/or vomiting, diarrhea, and abdominal pain). The Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN) was used to assign SARS-CoV-2 lineages to sequenced genomes. 15 A lineage was assigned to each household as determined by the lineage of a representative sequence obtained from the primary case or sequenced household member if sequencing results were unavailable for the primary case. VOCs were defined based on the CDC variant classification scheme at the time the evaluation occured. 8

Demographic characteristics of pediatric household members were described by case classification (i.e., primary case, secondary case, or uninfected household contact) and lineage (Alpha or non-Alpha lineages). Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized estimating equations (GEEs) to compare frequencies of J o u r n a l P r e -p r o o f symptoms between pediatric and adult cases, and among pediatric cases by lineage. GEEs with an exchangeable correlation matrix were used to account for household clustering. 4 Wilcoxon rank sum tests were used to compare symptom duration between pediatric and adult cases, and among pediatric cases by lineage. Those who remained symptomatic at closeout were treated as if their symptoms had resolved on Day 14.

SIRs were calculated as the proportion of secondary cases among all non-excluded household contacts. Contacts were excluded from SIR calculations and risk factor analyses if they were fully vaccinated or had a previously documented SARS-CoV-2 infection. SIRs were estimated 1) by age and lineage (Alpha versus non-Alpha) of the primary case and 2) by age and lineage of household contacts. ORs and 95% CIs were calculated using GEEs to compare SIRs in each primary and household contact age group and lineage group.

Among pediatric household contacts, unadjusted ORs and 95% CIs were estimated using GEEs to assess risk factors for infection. Within the GEE framework, type III tests were used to assess differences in percent positivity among age groups and lineage; p-values were based on the limiting chi-square distributions.

Using Fishers exact tests, amino acid polymorphisms in the S-gene were screened for associations between the age of the primary case (pediatric or adult) and SIR (≥50% or <50%), evaluating each site at which two different amino acids were observed in ≥5 of the household representative sequences. P-values <0.05 were considered statistically significant. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC); figures were prepared using Microsoft Excel and R version 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria).

This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. [16] [17] [18] [19] [20] All household members provided written consent, child assent with parental permission, or parent permission before participation.

Individuals from 151 households were enrolled; 24 households were excluded during analysis ( Figure 1 ). After exclusion, 127 households with a single primary case and 316 household contacts were available for analysis. The median time interval from primary case illness onset to enrollment was six days (range: 2-10). Pediatric household members represented 28% (36/127) of primary cases and 36% (115/316) of household contacts.

Of 151 pediatric household members (including cases and household contacts), 73 (48%)

were young children and 78 (52%) were adolescents ( Table I) . The median age of pediatric household members was 12 years (interquartile range [IQR]: 7-15). Underlying medical conditions were uncommon; the most frequently reported condition was chronic lung disease (13%). No pediatric cases were hospitalized, and none died. Most (147/151, 97%) pediatric household members were unvaccinated; four (3%) (two primary and two secondary cases) were partially vaccinated. Alpha was the most common SARS-CoV-2 lineage identified in pediatric primary cases (n = 21, 58%) and secondary cases (n = 39, 64%). Demographic and clinical characteristics among pediatric cases with Alpha and non-Alpha lineages are displayed in Table   II (available at www.jpeds.com).

Four pediatric household contacts were seropositive at enrollment or reported prior SARS-CoV-2 infection and were excluded from RT-PCR positivity, SIR, and risk factor J o u r n a l P r e -p r o o f analyses. Among the 36 pediatric primary cases and 111 non-excluded pediatric household contacts, 96 (65%) had a SARS-CoV-2 RT-PCR-positive specimen collected during the evaluation (Table III; available at www.jpeds.com). One pediatric case with Alpha lineage never tested positive by RT-PCR but was classified as a case based on Day 0 seropositivity and newonset of symptoms without a history of infection or vaccination.

RT-PCR-positivity did not differ significantly by age; among pediatric cases, positivity did not differ significantly by lineage. Overall, 75% (105/140) of pediatric and 76% (172/227) of adult household members participated in daily antigen testing. Blood specimens for serological assessment were not available for 56 pediatric and 17 adult household members. 

Among 36 households with pediatric primary cases, 21 (58%) had >1 secondary case.

Among 91 households with adult primary cases, 51 (56%) had ≥1 secondary case. SIRs for household contacts of pediatric and adult primary cases were 45% and 54%, respectively (OR: 0.79; 95% CI, 0.41-1.54) ( Figure 4 and Table IV ; available at www.jpeds.com). SIRs for household contacts of pediatric primary cases with Alpha and non-Alpha lineages were 55% and 46%, respectively (OR: 1.52 95% CI, 0.51-4.53). SIRs for household contacts of young child and adolescent primary cases were 46% and 43%, respectively (OR: 1.02; 95% CI, 0.35-3.0) ( Figure 5 ; available at www.jpeds.com).

Among the 111 non-excluded pediatric contacts, 61 (55%) tested RT-PCR-positive or seroconverted during the 14-day follow-up. SIRs for pediatric and adult household contacts were 55% and 49%, respectively (OR: 1.01; 95% CI, 0.68-1.50) ( Figure 6 and Table IV) . SIRs for J o u r n a l P r e -p r o o f pediatric contacts in households with Alpha and non-Alpha lineages were 64% and 56%, respectively (OR: 1.08; 95% CI, 0.40-2.98). SIRs for young child and adolescent household contacts were 60% and 50%, respectively (OR: 1.09 95% CI, 0.60-1.97) (Figure 7 ; available at www.jpeds.com). Inclusion of household contacts who were fully vaccinated or had a previously documented SARS-CoV-2 infection in SIR calculations did not result in significantly different SIRs than when these individuals were excluded (data not shown).

There were no significant differences in the odds of acquiring infection among pediatric contacts by age, sex, race/ethnicity, underlying medical conditions, relationship to primary case, school or daycare attendance, number of household members, sharing of bedrooms and bathrooms, having direct or indirect contact with the primary case, maintaining physical distance (≥6 feet) with the primary case, or genomic lineage (Table V ; available at www.jpeds.com).

Sequence data were obtained for specimens from 212 household members from 104 households. Genetic analyses of RT-PCR-positive specimens showed no evidence of multiple introductions into households. Among the 59 households where SARS-CoV-2 sequences were recovered from multiple participants, lineages always matched, with sequences varying by 0-2 single nucleotide polymorphisms (SNPs) in 57 households and by 4 and 5 SNPs, respectively, in the remaining two households. No genetic association was detected with SIR differences between households or primary case age, based on the phylogeny of household representative sequences or with any of 13 S-gene amino acid polymorphisms from the same sequences ( Figure   8 ; available at www.jpeds.com).

We present an analyses of SARS-CoV-2 household transmission among children immediately prior to the Delta wave of the pandemic when the Alpha variant was the most prominent lineage in the United States. Household transmission of SARS-CoV-2 from child and adult primary cases to household members was frequent. We found similar SIRs among child and adult primary cases, contrary to prior household transmission investigations reporting SARS-CoV-2 transmission from adults at higher proportions than children [21] [22] [23] [24] . Similarly, we found similar SIRs among young children and adolescent primary cases, despite prior studies reporting age-related differences in transmissibility 11, 25, 26 . These findings could be explained by our universal testing independent of symptoms, allowing for comprehensive secondary case ascertainment among household contacts. Our ability to identify primary cases early in the acute phase of infection when they were likely most transmissible 27,28 may have increased the robustness of our SIR estimates.

We also found that pediatric household contacts were as likely as adult contacts to become infected with SARS-CoV-2. There is conflicting literature regarding how SARS-CoV-2 susceptibility among children compares with adults. Some studies have reported that children and adults acquired SARS-CoV-2 infection at similar proportions, 4-6 and others have reported that children had lower susceptibility compared with adults. [29] [30] [31] Elucidating pediatric susceptibility is complicated, as transmission rates can be influenced by differences in behavior, exposure, and testing practice (i.e., preferential testing of symptomatic individuals), which could lead to an underestimation of SARS-CoV-2 infections in children, who are less likely than adults to have symptoms when infected. Daily antigen testing likely facilitated early identification of secondary cases and may have allowed us to identify more infections among asymptomatic J o u r n a l P r e -p r o o f household members compared with previous studies. the absolute proportion of symptomatic children in this investigation was higher than reported in previous studies. 32, 33 This finding could be attributed to differences in reporting symptoms daily, as was done in this investigation, compared with reporting symptoms retrospectively, which may underestimate the proportion of symptomatic children.

Although surveillance and modeling suggested that Alpha had increased transmissibility in community settings compared with non-Alpha lineages circulating at that time, 10, 11 J o u r n a l P r e -p r o o f b These individuals either identified as Non-Hispanic Black, Asian, American Indian/Alaska Native, Native Hawaiian/Pacific Islander, belonging to a race/ethnicity not listed on the questionnaire or belonging to multiple races/ethnicities. Individuals were grouped together for analysis to increase power of analysis. c Other chronic conditions included hypothyroidism (1), neurological condition (3), anxiety/depression (3), attention deficit disorder (1), attention deficit hyperactivity disorder (6), allergies (1), juvenile idiopathic arthritis (1), and/or Celiac disease (1). d Individuals were considered fully vaccinated ≥14 days after completion of all recommended doses of an FDA-authorized COVID-19 vaccine, partially vaccinated if <14 days since completing the primary series or did not complete the series, and unvaccinated if no COVID-19 vaccine was received.

J o u r n a l P r e -p r o o f Abbreviations: RT-PCR, reverse transcription polymerase chain reaction. a Four pediatric and 45 adult household contacts reported prior SARS-CoV-2 infection or seropositivity and were excluded from the RT-PCR positivity analysis. One pediatric case with B.1.1.7 (Alpha) lineage never tested positive by RT-PCR but was classified as a case based on serology testing and new-onset of symptoms. b Type III tests were used to assess differences in percent positivity among the four groups by age and genomic lineage; p-values <0.05 were considered statistically significant. c Percent of cases who were symptomatic. Individuals were classified as symptomatic if they reported symptoms at any time during the investigation. d Specimens from five primary pediatric cases did not undergo sequencing and therefore a lineage was not assigned to these individuals. Lineages were assigned to uninfected pediatric household contacts based on the lineage of the household primary case.

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