Increased household secondary attacks rates with Variant of Concern SARS-CoV-2 index cases

TLDR: In this article, a propensity-score matched cohort was derived to calculate adjusted estimates of the secondary attack rate for VOC index cases in households and showed that asymptomatic and pre-symptomatic transmission may be of particular importance for index cases.

Abstract: IMPORTANCEHigher secondary attack rates related to variant of concern (VOC) index cases have been reported, but have not been explored within households, which continue to be an important source of coronavirus disease 2019 (COVID-19) transmission OBJECTIVETo compare secondary attack rates in households with VOC versus non-VOC index cases DESIGNA retrospective cohort study of household index cases reported from February 7 - 27, 2021 A propensity-score matched cohort was derived to calculate adjusted estimates SETTINGOntario, Canada PARTICIPANTSA population-based cohort of all private households with index cases We excluded cases in congregate settings, as well as households with one individual or with >1 case with the same earliest symptom onset date EXPOSUREVOC status, defined as either individuals confirmed as B117 using whole genome sequencing or those that screened positive for the N501Y mutation using real-time PCR MAIN OUTCOME AND MEASUREHousehold secondary attack rate, defined as the number of household secondary cases that occurred 1-14 days after the index case divided by the total number of household secondary contacts RESULTSWe included 1,259 index VOC and non-VOC cases in the propensity score-matched analysis The secondary attack rate for VOC index cases in this matched cohort was 131 times higher than non-VOC index cases (RR=131, 95%CI 114-149), similar to the unadjusted estimate In stratified analyses, the higher secondary attack rate for VOC compared to non-VOC index cases was accentuated for asymptomatic index cases (RR=191, 95% CI 096-380) and presymptomatic cases (RR=341, 95%CI 113-1026) CONCLUSIONS AND RELEVANCEThis study provides strong evidence of increased transmissibility in households due to VOCs and suggests that asymptomatic and pre-symptomatic transmission may be of particular importance for VOCs Our study suggests that more aggressive public health measures will be needed to control VOCs and that ongoing research is needed to understand mechanisms of VOC transmissibility to curb their associated morbidity and mortality

Figures

Table 1. Characteristics of index cases by VOC status and household secondary attack rate

Figure 1. Risk ratio comparing household secondary attack rate associated with VOC vs. non-VOC index cases by characteristic of index case, unadjusted (black) and adjusted by 1:1 propensity-score matching (green) estimates

Full text

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Title: Increased household secondary attacks rates with Variant of Concern SARS-CoV-2 index cases
Authors:
Sarah A. Buchan, PhD
a
sarah.buchan@oahpp.ca
Semra Tibebu, MPH
a
semra.tibebu@oahpp.ca
Nick Daneman, MD
a
nick.daneman@sunnybrook.ca
Michael Whelan, MSc
a
michael.whelan@oahpp.ca
Thuva Vanniyasingam, PhD
a
thuva.vanniyasignam@oahpp.ca
Michelle Murti, MDa michelle.murti@oahpp.ca
Kevin A. Brown, PhD
a
kevin.brown@oahpp.ca
Affiliations:
a
Health Protection, Public Health Ontario, 661 University Ave., Floor 17, Toronto, ON, M5G 1M1,
Canada
Corresponding Author:
Sarah Buchan, PhD
Public Health Ontario
661 University Avenue, Floor 17
Toronto, Ontario, M5G 1M1
Tel: 647-260-7274
Email: sarah.buchan@oahpp.ca
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 5, 2021. ; https://doi.org/10.1101/2021.03.31.21254502doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

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Abstract
IMPORTANCE: Higher secondary attack rates related to variant of concern (VOC) index cases have been
reported, but have not been explored within households, which continue to be an important source of
coronavirus disease 2019 (COVID-19) transmission
OBJECTIVE: To compare secondary attack rates in households with VOC versus non-VOC index cases.
DESIGN: A retrospective cohort study of household index cases reported from February 7 – 27, 2021. A
propensity-score matched cohort was derived to calculate adjusted estimates.
SETTING: Ontario, Canada.
PARTICIPANTS: A population-based cohort of all private households with index cases. We excluded
cases in congregate settings, as well as households with one individual or with >1 case with the same
earliest symptom onset date.
EXPOSURE: VOC status, defined as either individuals confirmed as B.1.1.7 using whole genome
sequencing or those that screened positive for the N501Y mutation using real-time PCR.
MAIN OUTCOME AND MEASURE: Household secondary attack rate, defined as the number of
household secondary cases that occurred 1-14 days after the index case divided by the total number of
household secondary contacts.
RESULTS: We included 1,259 index VOC and non-VOC cases in the propensity score-matched analysis.
The secondary attack rate for VOC index cases in this matched cohort was 1.31 times higher than non-
VOC index cases (RR=1.31, 95%CI 1.14-1.49), similar to the unadjusted estimate. In stratified analyses,
the higher secondary attack rate for VOC compared to non-VOC index cases was accentuated for
asymptomatic index cases (RR=1.91, 95% CI 0.96-3.80) and presymptomatic cases (RR=3.41, 95%CI
1.13-10.26)
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 5, 2021. ; https://doi.org/10.1101/2021.03.31.21254502doi: medRxiv preprint

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CONCLUSIONS AND RELEVANCE: This study provides strong evidence of increased transmissibility
in households due to VOCs and suggests that asymptomatic and pre-symptomatic transmission may be of
particular importance for VOCs. Our study suggests that more aggressive public health measures will be
needed to control VOCs and that ongoing research is needed to understand mechanisms of VOC
transmissibility to curb their associated morbidity and mortality.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 5, 2021. ; https://doi.org/10.1101/2021.03.31.21254502doi: medRxiv preprint

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Introduction
The prevalence of variants having the N501Y mutation have rapidly increased globally,
1
including in
Ontario, Canada, where this prevalence increased dramatically in February, 2021. These patterns of rapid
strain replacement suggest increased transmissibility of variants with the N501Y mutation, which is
present across variants of concern (VOC), including B.1.1.7, B.1.351, and P.1 lineages.
2
However the
exact degree of increased transmissibility, and specific settings when increased transmissibility occurs,
remains unclear.
1, 3,4,5
Higher secondary attack rates related to VOC index cases have been reported,
6
but
have not been explored within households, which continue to be an important source of coronavirus
disease 2019 (COVID-19) transmission.
7
The objective of this study was to compare secondary attack
rates in households with VOC versus non-VOC index cases in Ontario, Canada.
Methods
We identified individuals with laboratory-confirmed COVID-19 reported in the Public Health Case and
Contact Management Solution (CCM), Ontario’s COVID-19 reporting system, and included households
with index cases reported from February 7 to 27, 2021. VOC cases included either individuals confirmed
as B.1.1.7 using whole genome sequencing or those that screened positive for the N501Y mutation using
real-time PCR. B.1.1.7 accounted for 94% of confirmed VOC cases reported in Ontario until February 27,
2021.
8
All PCR-positive specimens in Ontario with cycle threshold
≤
35 underwent screening for the
N501Y mutation during the study period using real-time PCR. Non-VOC cases were those that screened
negative for the N501Y mutation.
We grouped cases living in the same household based on residential address.
9
Index cases were defined as
the first case in the household based on symptom onset date (or specimen collection date, if symptom
onset date was not available) and secondary cases were included if they occurred 1-14 days after the
index case. We excluded cases in congregate settings, as well as households with one individual or with
>1 case with the same earliest symptom onset date. We used reported household size to calculate
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 5, 2021. ; https://doi.org/10.1101/2021.03.31.21254502doi: medRxiv preprint

5
secondary attack rates by dividing the number of secondary cases by the total number of household
secondary contacts (i.e., household size minus one). Cases with and without symptoms were classified
based on symptom information and onset date reported in CCM.
Poisson regression was performed for the unadjusted and adjusted analyses, overall and by strata. The
models were specified with the count of household secondary cases as the outcome, the logarithm of
household size as the offset and VOC status as a binary exposure covariate. Clustering was accounted for
with a random intercept for household to account for known overdispersion.
Our unadjusted risk ratios (RR) included the entire cohort of households with a VOC or non-VOC index
case in Ontario. Adjusted RRs were based on a propensity score matched analysis. VOC index cases were
1:1 matched to non-VOC index cases based on gender and age group, and matched on the logit of the
propensity score, using a caliper width of 0.2 times the standard deviation.
10
The propensity score was
based on a logistic regression model of VOC status as a function of five covariates: reported date, time
between symptom onset and testing, association with a reported outbreak, as well as the neighbourhood
proportion of visible minority residents (non-white and non-Indigenous population) and household
crowding as determined using 2016 Canadian Census data.
11
Regression estimates were reported using
RRs and 95% confidence intervals (CI). Statistical analysis was performed in R version 4.0.4.
12
This study was approved by Public Health Ontario’s Research Ethics Board.
Results
We identified 5,617 index cases and 3,397 secondary cases across the study period. Amongst index cases,
1,318 were classified as VOC (151 B.1.1.7 and 1,167 N501Y) and 4,299 were classified as non-VOC.
The overall secondary attack rate was higher for VOC index cases (25.9%) compared to non-VOC
(20.5%, p<0.01) with consistently higher secondary attack rates for VOCs across individual
characteristics of the index cases (Table 1). The secondary attack rate of VOC index cases was 1.28 times
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 5, 2021. ; https://doi.org/10.1101/2021.03.31.21254502doi: medRxiv preprint

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Title: increased household secondary attacks rates with variant of concern sars-cov-2 index cases authors:" ?

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Q2. What are the limitations of this study?

13,14Limitations of this study include potential misclassification of secondary cases as index cases and small sample sizes in some subgroups. 

Q3. What was the prevalence of VOC cases in Ontario?

VOC cases included either individuals confirmed as B.1.1.7 using whole genome sequencing or those that screened positive for the N501Y mutation using real-time PCR. 

Q4. What is the effect of VOCs on the health of people with unknown disease status?

While measures effective for persons with unknown disease status such as physical distancing and masking may continue to be highly effective, measures focused on symptomatic individuals, such as public health contact tracing, may be increasingly ineffective unless extremely rapid. 

Q5. What was the propensity score for the outbreak?

The propensity score was based on a logistic regression model of VOC status as a function of five covariates: reported date, time between symptom onset and testing, association with a reported outbreak, as well as the neighbourhood proportion of visible minority residents (non-white and non-Indigenous population) and household crowding as determined using 2016 Canadian Census data.11 Regression estimates were reported using RRs and 95% confidence intervals (CI). 

Q6. What was the objective of this study?

The objective of this study was to compare secondary attack rates in households with VOC versus non-VOC index cases in Ontario, Canada. 

Q7. What was the secondary attack rate for the index cases?

Ontario implemented more stringent measures for close contacts of all cases (not just VOC cases) in early February in response to VOC introductions, including increased frequency of testing during quarantine and outbreaks. 

Q8. How many cases were matched to the unadjusted estimate?

The secondary attack rate for VOC index cases in this matched cohort was 1.31 times higher than non-VOC index cases (RR=1.31, 95%CI 1.14-1.49), similar to the unadjusted estimate. 

Q9. What are the patterns of rapid strain replacement?

These patterns of rapid strain replacement suggest increased transmissibility of variants with the N501Y mutation, which is present across variants of concern (VOC), including B.1.1.7, B.1.351, and P.1 lineages. 

Q10. What is the association between the N501Y mutation and ACE2?

The N501Y mutation has also been associated with enhanced binding affinity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to angiotensin-converting enzyme 2 ( ACE2) receptors. 

Q11. What is the effect of VOCs on the health of people?

This study provides strong evidence of increased transmissibility in households due to VOCs and suggests that asymptomatic and pre-symptomatic transmission may be of particular importance for VOCs. 

Q12. What is the significance of the secondary attack rate in the study?

Their estimates of increased transmission from asymptomatic and pre-symptomatic VOC index cases has not previously been reported and suggests an increased importance of prevention measures when individuals are not aware of their infection. 

Q13. What is the secondary attack rate of VOC index cases?

In their cohort, the authors estimated that the household secondary attack rate of VOC index cases was 31% higher than non-VOC index cases, providing evidence of increased transmissibility. 

Q14. What was the overall secondary attack rate for VOC index cases?

The overall secondary attack rate was higher for VOC index cases (25.9%) compared to non-VOC (20.5%, p<0.01) with consistently higher secondary attack rates for VOCs across individual characteristics of the index cases (Table 1).