key: cord-0806769-1lx85o1f
authors: Walker, Adam G.; Sibbel, Scott; Wade, Curtis; Moulton, Nick; Marlowe, Gilbert; Young, Amy; Fadem, Stephen Z.; Brunelli, Steven M.
title: SARS-CoV-2 Antibody Seroprevalence Among Maintenance Dialysis Patients in the United States
date: 2021-02-05
journal: Kidney Med
DOI: 10.1016/j.xkme.2021.01.002
sha: bf53a91db9dec0e88e279a4f2f0f0d3bcc120e34
doc_id: 806769
cord_uid: 1lx85o1f

RATIONALE & OBJECTIVE: Reported COVID-19 cases underestimate the actual number of SARS-CoV-2 infections. Patients receiving maintenance dialysis are at high risk for COVID-19, and higher case rates have been reported relative to the general population. To better understand infection patterns, we performed a seroprevalence study among maintenance dialysis patients at a large dialysis organization in the United States. STUDY DESIGN: Cross-sectional SETTING & PARTICIPANTS: We measured IgG antibodies in an IRB-approved study of remnant serum samples collected for routine laboratory screenings in a national sample of 12,932 maintenance dialysis patients (27 May-01 Jul 2020). EXPOSURE: State, sex, age, and race. OUTCOMES: Seropositivity; ratio of seropositivity to known COVID-19 case rate. ANALYTIC APPROACH: Seropositivity was calculated overall and by state, sex, age, and race. Ratio of seropositivity to known COVID-19 cases was calculated overall and by state. RESULTS: Overall, 747 (5.8%) of samples were seropositive. Seroprevalence varied by state and was lowest in Kentucky (1.0%) but highest in New York (23.6%). Seroprevalence was similar among men and women. Among samples from patients < 70 years, 6.0%-6.5% were seropositive; whereas 5.2% and 3.9% of samples from patients 70-79 and ≥ 80 years, respectively, were seropositive. Samples from Black and Hispanic patients were 7.3% and 7.7% positive, respectively, compared to 2.8% of samples from White patients. After adjustment, risk differences among racial groups were lower, but not eliminated. During the study period, the known COVID-19 case rate was 3.3%. The ratio of seropositivity to known COVID-19 cases was 1.7. LIMITATIONS: Imperfect assay sensitivity; results represent infections occurring before July 2020; deidentification prevented comparison of antibodies to previous COVID-19 status for individual patients; may not generalize to patients dialyzing with other providers or in other countries. CONCLUSIONS: Seroprevalence was 5.8% among dialysis patients as of 01 July 2020. This indicates the actual number of infections was 1.7-times greater than reported cases. This ratio is lower than reported in the general population, suggesting there were fewer unknown infections among maintenance dialysis patients

Coronavirus disease 2019 (COVID-19), caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic on 11 March 2020. 1 As of 31 July 2020, there were more than 17 million confirmed cases worldwide, including nearly 5 million in the United States. SARS-CoV-2 infection can result in a spectrum of clinical manifestations ranging from asymptomatic to severe symptomatology, including hypoxia, respiratory failure, and death. 2 Because any infected patient can transmit SARS-CoV-2, 3 it is vital to understand the actual burden of infection above and beyond the reported case rates of symptomatic COVID-19.

In the United States, shortages in testing supplies and infrastructural limitations have precluded large-scale surveillance efforts. Fortunately, the seropositivity of anti-SARS-CoV-2 antibodies can be used to illuminate the underlying infection rates post hoc. Not surprisingly, given challenges in testing and surveillance, data from the general population in the United States demonstrate a large number of unreported SARS-CoV-2 infections that exceed the number of reported COVID-19 cases by many fold. [4] [5] [6] End-stage kidney disease patients receiving maintenance dialysis represent a special case, as they are enriched for several characteristics that are putative risk factors for COVID-19, including older age, high proportions of people of color, dense urban geographic footprint, as well as disproportionate rates of heart failure, diabetes, and obesity. 2, 7 Therefore, it may not be surprising that reported case rates are higher in these patients than in the general population. 8 However, the vast majority of maintenance dialysis patients are treated with hemodialysis. Following guidance from the Centers for Disease Control and Prevention, US dialysis organizations have put into place robust J o u r n a l P r e -p r o o f entrance screening procedures, whereby all patients entering a clinic are asked about symptoms, high-risk contacts, or both; patients who screen positive then undergo testing for viral RNA. 9 These procedures, as well as the high rate of interaction with the health care system (~13 clinic visits per month for dialysis treatments), may lead to a narrower gap between viral infections and reported cases among maintenance dialysis patients..

Because dialysis patients undergo routine monthly laboratory testing, leftover patient samples provide an opportunity to explore SARS-CoV-2 seropositivity. We performed this national seroprevalence survey among patients receiving dialysis from a single provider organization to understand better: 1) the prevalence of SARS-CoV-2 infection nationally and within individual states; 2) how SARS-CoV-2 seropositivity varies across subgroups of patients; and 3) the magnitude of the gap between SARS-CoV-2 seropositivity and known COVID-19 case rates.

The protocol for this study was reviewed by an independent institutional review board (IntegReview IRB) and was determined that under Title 45, part 46, of the US Department of Health and Human Services' Code of Federal Regulations, this study was exempt and that informed consent was not required. This study utilized deidentified remnant serum samples collected for routine laboratory screening from a national sample of maintenance dialysis patients treating with DaVita in the United States. Blood samples were collected prior to dialysis treatment in a 5-mL serum separation tube, clotted for 30 minutes, centrifuged, and refrigerated prior to shipment. All samples were processed at a if the corresponding test reading was > 1 arbitrary unit/mL, and negative otherwise. In addition to IgG concentration, patient sex, age, race, zip code, and collection date were recorded for each sample. Because this was a remnant sample study, no attempts were made to identify patients or to link findings to medical record data.

Reported COVID-19 cases and deaths among patients with a COVID-19 diagnosis through 01 July 2020 were ascertained from DaVita electronic medical records overall and by US state. Beginning in March 2020, universal screening was performed upon entrance to DaVita clinics. All DaVita clinics utilize standardized screening tools and all clinic personnel are trained to perform screening in standardized manner. Patients screening positive for COVID-19 symptoms or indicating recent contact with individuals diagnosed with COVID-19 were subsequently tested for viral RNA with a nasal swab and a polymerase chain reaction (PCR) assay. Patients with a positive PCR test were assigned a COVID-19 diagnosis. Additionally, patients reporting receipt of a positive COVID-19 test result from another health care setting, such as a hospital or department of health screening center, were also assigned a COVID-19 diagnosis.

Seroprevalence was determined by calculating the proportion of samples considered IgG positive overall and stratified by sample collection date, sex, age, race, and state. Confidence intervals were estimated using an exact binomial distribution.

Seroprevalence estimates by patient race were also adjusted for age, population density, median income and geographic COVID-19 prevalence using a generalized linear model. Given the deidentified nature of the sample collection, correspondence between COVID-19 case status and serologic status could not be examined at the level of individual patients. Instead, we considered the ratio of aggregate known case rate to J o u r n a l P r e -p r o o f aggregate seropositivity rate, henceforth termed the infection discovery ratio. The infection discovery ratio was considered at the national level as well as at the level of individual states. Because patients who had died of COVID-19 prior to the sample collection period otherwise counted as cases, but were not sampled for seroprevalence, they were not counted toward the numerator of the infection discovery ratio. The infection discovery ratio was calculated as a cross-section as of 01 July 2020.

We tested 12,932 remnant serum samples for IgG antibodies for SARS-CoV-2. Table 1 contains demographic characteristics of the patients from which the samples were obtained. Overall, 747 (5.8%) of the samples were seropositive. There was no longitudinal trend observed in seropositivity ( Figure 1 ). Figure 2 shows the seroprevalence by patient sex, age, and race. There was no difference in seroprevalence among samples from men and women. Seroprevalence was 6.0%-6.5% among samples from patients < 70 years old, 5 Overall, the reported COVID-19 case rate was 3.3% of all patients. The reported COVID-19 case rate ranged from 1.9%-9.4% of patients by state. The highest reported COVID-19 case rates were in New York (9.4%) and lowest in Oregon (1.9%). Overall, the infection discovery ratio was 1.7 but ranged from 0.5-4.5 for individual states.

In this study, we found that seroprevalence of antibodies to SARS-COV-2 among maintenance dialysis patients in the United States varied by geography, age, race, and ethnicity. Moreover, our data indicate that there were more infections than known COVID-19 cases among the maintenance dialysis patient population as of 01 July 2020.

Globally, there is evidence that reported COVID-19 case rates underestimate the true burden of SARS-CoV-2 infection. Maintenance dialysis patients have many characteristics that put them at high risk for COVID-19, and it has been reported that case rates are higher than in the general population. Here, we measured antibodies to SARS-CoV-2 using remnant serum samples in a large, national sample of US dialysis patients.

We sought to understand the prevalence of SARS-CoV-2 infection nationally and within individual states, the variability of seropositivity among patient subgroups, and the magnitude of the gap between SARS-CoV-2 seropositivity and known COVID-19 case rates among maintenance dialysis patients.

We estimated the national seroprevalence of SARS-CoV-2 among US maintenance dialysis patients to be 5.8% as of 01 July 2020. Unfortunately, there have been no published national seroprevalence studies among the US general population to J o u r n a l P r e -p r o o f compare to our estimates in dialysis patients. Moreover, there are salient differences between the US general population and the dialysis patient population in terms of characteristics, health status, and the ability to shelter in place; therefore, we did not attempt to standardize our estimates in order to extrapolate seroprevalence to the US general population. At the state level, seropositivity rates in our sample were directionally similar to reported case rates. For example, New York and New Jersey, states with high reported case burdens, had among the highest seropositivity rates in our sample, and Kentucky and Arkansas, states with low reported case burdens, had among the lowest seropositivity rates in our sample. Direct comparison of seropositivity rates in our sample to the general population of states must be interpreted cautiously for 2 important reasons: 1) our seroprevalence data were from a later period in time and are subject to be higher as the epidemic progressed; 2) the high-risk nature of maintenance dialysis patients.

However, for states where general population data have been reported, seroprevalence in the dialysis population was approximately 2-3 times that in the general population:

Louisiana (16.5% vs 5.8%), Connecticut (15.2% vs 4.9%), Missouri (5.0% vs 2.7%), and New York (23.6% vs 12.5%). 4, 5 Notwithstanding the above limitations (which would tend to bias in a direction that exaggerates risk in the dialysis population), this difference in seroprevalence is substantively lower than the 5-fold difference in reported case rates between maintenance dialysis patients and the general population. 8 Next, we sought to understand how seropositivity differs by patient demographics. Similar to other seroprevalence studies, we did not observe a difference between samples from men and women. 4, 10-12 Samples from patients older than 70 years were less likely to be seropositive. Mortality is higher among older patients diagnosed Finally, we compared seroprevalence estimates to known COVID-19 cases to quantify the gap between recognized and unrecognized infections in the maintenance dialysis patient population. Comparison of the known COVID-19 cases (3.3%) to SARS-CoV-2 seroprevalence (5.8%) indicates that there were actually 1.7 times more infections than known cases as of 01 July 2020. Similar estimates were reported for hemodialysis J o u r n a l P r e -p r o o f patients in China and the United Kingdom. 20, 21 However, our estimate is lower than reported for the general population, which ranged from 6-43 times more than the number of known cases in US states for which data have been reported and 10-16 times in European locales. 4-6, 10, 11, 22 The lower number of unrecognized infections among dialysis patients is likely related to higher testing rates relative to the general population. The majority of DaVita patients visit a clinic 3 times per week for hemodialysis treatments, are screened upon clinic entry, and referred for testing if symptoms are present. Therefore, it is highly probable that infections among dialysis patients are recognized at a greater rate than in the general population.

Another recently published study measured seroprevalence of SARS-CoV-2 antibodies in serum samples from 28,503 patients treating at various independent dialysis providers throughout the US. 12 In general, we observed similar patterns of infection among patient types and geographies as they reported. However, their overall seroprevalence estimate was higher than in our study (8.3% vs 5.8%). This difference is most likely due to the fact that their samples were collected in July 2020, when national case rates were quickly rising, whereas the majority of our samples were collected in June, when case rates were relatively steady. Another key difference is that our study was performed among patients dialyzing with a single provider, which treats approximately one-third of all maintenance dialysis patients in the US and therefore, our results may be more representative of the patient population in the US.

There are limitations to our study. The sensitivity of the antibody assay is imperfect; therefore, it is likely the seroprevalence and the number of undetected infections estimated here are low. Samples were collected 27 May -01 July 2020, when J o u r n a l P r e -p r o o f the daily new case rate in the United States was at a steady state after the initial peak in April. There was a national resurgence in cases beginning late June, which is not reflected in antibodies measured here, possibly due to insufficient time for seroconversion before study end. Because dialysis patients have impaired antibody responses, it is possible that some infected patients did not develop or lost IgG to SARS-CoV-2 and, therefore, were misclassified as never infected. The remnant samples were deidentified, and we could not match samples to previously known COVID-19 cases; therefore, we could not determine the actual proportion of cases that were truly asymptomatic or the relationship between symptom onset and antibody levels for those who were considered COVID-19 positive. Finally, this study was limited to patients at a single dialysis organization in the United States and may not generalize to maintenance dialysis patients treating with other providers or in other countries.

In conclusion, we analyzed antibodies to SARS-CoV-2 in blood samples from more than 12,000 dialysis patients in the United States and observed a seroprevalence of 5.8% as of 01 July 2020. We observed similar patterns of infection among specific demographic groups and US geographies, as reported for the US general population. Our results indicate that there are 1.7 times as many SARS-CoV-2 infections as known COVID-19 cases among dialysis patients. However, due to tight surveillance, the number of unknown infections among dialysis patients appears to be substantially lower than reported among the general population.

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