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Summary
Background
Many patients receiving dialysis in the USA share the socioeconomic characteristics of underserved communities, and undergo routine monthly laboratory testing, facilitating a practical, unbiased, and repeatable assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence.
Methods
For this cross-sectional study, in partnership with a central laboratory that receives samples from approximately 1300 dialysis facilities across the USA, we tested the remainder plasma of 28 503 randomly selected adult patients receiving dialysis in July, 2020, using a spike protein receptor binding domain total antibody chemiluminescence assay (100% sensitivity, 99·8% specificity). We extracted data on age, sex, race and ethnicity, and residence and facility ZIP codes from the anonymised electronic health records, linking patient-level residence data with cumulative and daily cases and deaths per 100 000 population and with nasal swab test positivity rates. We standardised prevalence estimates according to the overall US dialysis and adult population, and present estimates for four prespecified strata (age, sex, region, and race and ethnicity).
Findings
The sampled population had similar age, sex, and race and ethnicity distribution to the US dialysis population, with a higher proportion of older people, men, and people living in majority Black and Hispanic neighbourhoods than in the US adult population. Seroprevalence of SARS-CoV-2 was 8·0% (95% CI 7·7–8·4) in the sample, 8·3% (8·0–8·6) when standardised to the US dialysis population, and 9·3% (8·8–9·9) when standardised to the US adult population. When standardised to the US dialysis population, seroprevalence ranged from 3·5% (3·1–3·9) in the west to 27·2% (25·9–28·5) in the northeast. Comparing seroprevalent and case counts per 100 000 population, we found that 9·2% (8·7–9·8) of seropositive patients were diagnosed. When compared with other measures of SARS-CoV-2 spread, seroprevalence correlated best with deaths per 100 000 population (Spearman’s ρ=0·77). Residents of non-Hispanic Black and Hispanic neighbourhoods experienced higher odds of seropositivity (odds ratio 3·9 [95% CI 3·4–4·6] and 2·3 [1·9–2·6], respectively) compared with residents of predominantly non-Hispanic white neighbourhoods. Residents of neighbourhoods in the highest population density quintile experienced increased odds of seropositivity (10·3 [8·7–12·2]) compared with residents of the lowest density quintile. County mobility restrictions that reduced workplace visits by at least 5% in early March, 2020, were associated with lower odds of seropositivity in July, 2020 (0·4 [0·3–0·5]) when compared with a reduction of less than 5%.
Interpretation
During the first wave of the COVID-19 pandemic, fewer than 10% of the US adult population formed antibodies against SARS-CoV-2, and fewer than 10% of those with antibodies were diagnosed. Public health efforts to limit SARS-CoV-2 spread need to especially target racial and ethnic minority and densely populated communities.
Funding
Ascend Clinical Laboratories.
Introduction
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and asymptomatic
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infection. Seroprevalence of SARS-CoV-2 antibodies in a population thus serves as a reasonable measure of exposure and spread. Seroprevalence surveys in the USA, however, have been restricted to single hotspots
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or under-represented high-risk or vulnerable populations.
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Moreover, these studies face challenges to timely repetition and longitudinal follow-up, limiting their utility for surveillance.
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Evidence before this study
Measuring the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies provides a comprehensive assessment of its community spread. Community seroprevalence surveys require considerable infrastructure and expense, and face implementation challenges during the COVID-19 pandemic due to restricted outreach in the worst-affected communities. Of the two largest seroprevalence surveys in the USA, one was limited only to New York state (n=15 101) and used convenience sampling at grocery stores. A second survey used remainder plasma from people visiting commercial laboratories in six cities (n=11 933), but lacked details on race and ethnicity and other community-level risk factors.
Added value of this study
We tested the remainder plasma of 28 503 patients receiving dialysis throughout the USA, using a chemiluminescence assay with high sensitivity and specificity. To our knowledge, we provide the first nationally representative estimate of SARS-CoV-2 seroprevalence in the US dialysis and US adult population, and estimates for differences in seroprevalence by neighbourhood race and ethnicity, poverty, population density, and mobility restriction. We also evaluate which of the existing measures of COVID-19 incidence most closely correlate with seroprevalence. Most importantly, we show that as patients receiving dialysis have monthly blood draws, without fail and without bias, and are a population with increased representation of racial and ethnic minorities, repeated cross-sectional analyses of seroprevalence within this sentinel population can be implemented as a practical and unbiased surveillance strategy in the USA.
Implications of all the available evidence
Similar to data from other highly affected countries and regions (eg, Spain and Wuhan, China), despite the intense strain on resources and unprecedented excess mortality being experienced in the USA during the COVID-19 pandemic, fewer than 10% of US adults had formed antibodies to SARS-CoV-2 as of July, 2020. There was significant regional variation from less than 5% prevalence in the west to more than 25% in the northeast. Public health efforts to curb the spread of the virus need to continue, with focus on some of the highest-risk communities that we identified, such as majority Black and Hispanic neighbourhoods, poorer neighbourhoods, and densely populated metropolitan areas. A surveillance strategy relying on monthly testing of remainder plasma of patients receiving dialysis can produce unbiased estimates of SARS-CoV-2 spread inclusive of hard-to-reach, disadvantaged populations in the USA. Such surveillance can inform disease trends, resource allocation, and effectiveness of community interventions during the COVID-19 pandemic.
informing risks faced by a susceptible population while ensuring representation from racial and ethnic minorities. In addition, seroprevalence surveys in patients receiving dialysis can be linked to patient-level and community-level data to enable evaluation and quantification of differences in SARS-CoV-2 prevalence by demographic and neighbourhood strata, and thus facilitate effective mitigation strategies targeting the highest-risk individuals and communities.
In partnership with a commercial clinical laboratory, we tested seroprevalence of SARS-CoV-2 antibodies in a randomly selected representative sample of patients. Our goal was to provide a nationwide estimate of exposure to SARS-CoV-2 during the first wave of COVID-19 in the USA, up to July, 2020, with stratification by region, age, sex, and race and ethnicity. We also harnessed population data on SARS-CoV-2 cases and deaths and percentage testing positive using nasal swab testing to assess how seroprevalence estimates correlated with other epidemiological measures of COVID-19 incidence. Finally, to inform preventive strategies for the high-risk dialysis population as well as the general population, we investigated community-level correlates for seropositivity.
Results
Figure 1Patient sampling and analytic cohort
Table 1Comparison of sampled population, US adult dialysis population, and US adult population
US adult population given is for 2018 and US adult patients dialysis population as of Jan 1, 2017. ZCTA=ZIP code tabulation area.
seroprevalence ranged from 8·2% (7·9–8·5) to 9·4% (9·1–9·8) in our sampled population (appendix p 7). When standardised to the US dialysis population, seroprevalence was 8·3% (8·0–8·6), with high regional variation in seroprevalence (ranging from 3·5% [3·1–3·9] in the west to 27·2% [25·9–28·5] in the northeast; table 2). Seroprevalence was similar by sex and modestly lower in people aged 80 years or older compared with those aged 45–64 years (table 2). Differences in seroprevalence by race and ethnicity were similar using both our patient-level (electronic health record) and neighbourhood-level (ZCTA majority race and ethnicity) measures, with non-Hispanic Black patients having the highest seropositivity, followed by Hispanic patients, and non-Hispanic white patients having the lowest.
Table 2Seroprevalence of SARS-CoV-2 antibodies in patients receiving dialysis in the USA
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. ZCTA=ZIP code tabulation area.
Table 3Seroprevalence estimates for the US adult population
ZCTA=ZIP code tabulation area.
Figure 2Prevalence of SARS-CoV-2 antibodies in sampled population, by state
Bolded borders represent states with more than 100 patients in the sample. The median number of patients sampled by state was 176 (IQR 83–536). States in white were not sampled. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
Figure 3Cumulative cases (A) and cumulative deaths (B) per 100 000 population, by state
Figure 4Forest plot for odds of SARS-CoV-2 seropositivity
All variables are at a neighbourhood (ie, ZCTA) level, except for reduction in workplace visits, which is at a county level, and are modelled separately, accounting for age and sex. Poverty level is defined as percentage of people living below the federal poverty level in the ZCTA. Population density quintiles are derived from the ZCTA (median 2884 people per square mile [IQR 603–6800]). Reductions in workplace visits were measured during the first 2 weeks of March, 2020, compared with a baseline in January–February, 2020. OR=odds ratio. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. ZCTA=ZIP code tabulation area.
Discussion
do not have evidence of exposure or immune response. Furthermore, we find increased likelihood of SARS-CoV-2 seropositivity in residents of predominantly Black and Hispanic neighbourhoods (two to three times higher), poorer areas (two times higher), and the most densely populated areas (ten times higher). Early reduction in community mobility in March, 2020, was associated with 60% lower likelihood of individual-level seroconversion by July that year.
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patients included in our study sample had antibodies measured from blood collected as part of routine medical care. Thus, our prevalence estimates should not be subject to selection bias due to presence versus absence of symptoms, availability of testing materials, local or regional testing strategies, geography, income, educational attainment, language proficiency, immigration status, mobility, anxiety, fear, or other factors. Moreover, since end-stage kidney disease qualifies affected patients for Medicare insurance, and since end-stage kidney disease disproportionately affects Black, Hispanic, and other disadvantaged populations,
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we are able to determine—with a high level of precision—differences in seroprevalence among patient groups within and across regions of the USA. Of the two larger seroprevalence surveys published from the USA thus far, one was confined to New York state (n=15 101), employed a convenience sampling technique at grocery stores, and relied on a microsphere immunoassay with lower sensitivity.
The second, the Centers for Disease Control and Prevention (CDC) Six Sites study (n=11 933), used remainder plasma from people getting testing for undefined clinical indications, and did not have detailed sociodemographic information about the tested people.
Our data might overestimate overall seroprevalence in the general population since patients on dialysis are disproportionately from racial and ethnic minorities;
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for example, Black Americans have a nearly four-times higher risk of end-stage kidney disease than white Americans.
Moreover, the process of undergoing in-centre haemodialysis might include the use of public or non-public shared transportation to and from the facility, and 10–12 h of care delivered in indoor facilities.
and more likely to restrict their mobility and social activity due to advanced age and frailty;
therefore, they might have fewer opportunities to acquire the infection, particularly from asymptomatic individuals. Extrapolating from multiple prospective hepatitis B immunisation studies—in which 50–75% of vaccinated patients receiving dialysis mounted a response compared with 95% or more people from the general population—patients receiving dialysis might mount a weaker immune response and thus be less likely to seroconvert.
Finally, patients receiving dialysis might have been more likely to die or have been hospitalised due to complications of SARS-CoV-2 infection. If so, these patients would not have been present for testing in the dialysis facilities, creating a survival bias and yielding lower estimates of exposure.
the CDC Six Sites study,
and in a population-representative analysis from Geneva.
Thus, our findings comport with other seroprevalence estimates. We confirm that as in other studies from COVID-19 hotspots,
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a minority of the population has evidence of exposure and immune response, and a vast majority, including people at high risk for mortality (ie, the population on dialysis), remain vulnerable. In fact, even if the seroprevalence estimates derived from the US dialysis population overestimated true seroprevalence in the overall US adult population, our data nonetheless support that fewer than 10% of the US population has seroconverted as of July, 2020, and herd immunity remains out of reach, as has been the conclusion from large international surveys from the UK
and Spain,
where intense outbreaks of COVID-19 occurred during the spring and summer of 2020.
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calling into question whether Black and Hispanic populations are experiencing more severe illness versus facing higher likelihoods of exposure. Some US state dashboards also report higher cumulative cases among Black and Hispanic people compared with non-Hispanic white people,
but none have as precisely quantified differences on a national level.
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and in populous regions across the world.
Rocklöv and Sjödin suggest that the basic reproduction number (R0) of SARS-CoV-2 increases linearly with population density.
Our data also show slightly lower likelihood of seropositivity among older people, as was seen in a recent report from Geneva
and attributed to better adherence to physical distancing measures by the authors. A higher competing risk from hospitalisations or mortality after SARS-CoV-2 exposure might be a larger contributing factor in the observed lower seroprevalence in older compared with younger age groups.
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advocate for repeated cross-sectional analyses of seroprevalence as a disease tracking system able to most completely measure the true incidence of SARS-CoV-2, since these can more likely capture incidence of exposure in both symptomatic and asymptomatic individuals. In fact, we observed substantial heterogeneity in the correlation between seroprevalence and other measures of SARS-CoV-2 that are currently being used—with the exception of deaths per 100 000, which are a late outcome
—supporting the use of rapidly instituted seroprevalence surveys as a complementary surveillance tool. Additional public health implications of seroprevalence surveys include assessing testing adequacy. For example, in states where the difference between seropositive and diagnosed cases is decreasing over time, testing capacity is likely to be increasing. Furthermore, following seroconversion rates over time can presage hospitalisations and intensive care unit stays, since the time between exposure and seroconversion is relatively short (median 10 days),
and can therefore facilitate resource allocation. Finally, as we show by assessing community mobility restrictions, seroprevalence surveys can measure the effects of interventions to treat or prevent infection with SARS-CoV-2.
Repeated serological surveys, if done in a community setting, would require extensive resources and yet remain subject to selection bias. However recurring monthly testing of remainder plasma of randomly selected sets of people—as is practically feasible in patients receiving dialysis—can serve as a representative surveillance system in the USA, with minimal phlebotomy or infrastructure requirement, and as our data show, include traditionally under-represented and socially disadvantaged groups.
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The study sample was highly representative of the US dialysis population and, as noted, we used remainder plasma from specimens used in routine clinical care. The sample size and sampling scheme allowed us to estimate with precision prevalence across several patient characteristics. Moreover, linking to US Census and other publicly available data sources assembled during the pandemic provides valuable context when considering the implications of these data to the general population. There are also several important limitations. As noted previously, it is plausible that seroprevalence estimates from the US dialysis population overestimate seroprevalence in the US adult population. We do not have patient-level data on symptoms nor nasal swab testing results, and thus cannot test whether the likelihood of seroconversion differs in patients receiving dialysis from generally healthy adults, although preliminary data from London, UK, suggest no differences.
We also do not have patient-level data on health status, employment status, income, household size, living space, and other sociodemographic factors, and so relied on neighbourhood proxies for some of these domains. Dialysis units are more often located in urban areas, and thus we have under-representation of rural areas. Finally, while large, our study was designed for precise regional, not state-level or county-level, estimates.
In conclusion, we present SARS-CoV-2 seroprevalence data in a broadly representative sample of patients receiving dialysis across the USA and show striking differences in seroprevalence by several patient characteristics, with higher seroprevalence in younger patients, Black and Hispanic patients, and patients living in poorer and majority-minority neighbourhoods. These data can help to inform surveillance and management strategies during the next phase of the pandemic. Serial sampling of dialysis remainder plasma should be used to determine trends in disease prevalence and the effect of various strategies being implemented around the USA to reduce the burden of COVID-19 on the general population.
SA assisted with data cleaning and analysis planning, and manuscript writing. MM-R developed the analysis plan, generated census data tables, supervised data analysis, and contributed to manuscript writing. JH undertook data cleaning and analysis, including linkage to external data and figure generation, and contributed to manuscript writing. JB undertook sample processing and data preparation and contributed to manuscript writing. RK selected seroprevalence testing, supervised sample processing, and contributed to manuscript writing. PB co-conceived the study, secured seroprevalence testing, and supervised sample processing and data preparation. JP supervised the study analysis plan, identified relevant external data, contributed to data interpretation, and supervised manuscript writing. GMC co-conceived the study, supervised the study analysis plan, and co-wrote the manuscript.
JB, RK and PB are employed by Ascend Clinical Laboratories. GMC is on the Board of Directors of Satellite Healthcare, a not-for-profit dialysis organisation. All remaining authors declare no competing interests.
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