key: cord-0909871-417cyfrs
authors: Rainwater-Lovett, K.; Redd, J. T.; Stewart, M. A.; Elias Calles, N.; Cluff, T.; Fang, M.; Panaggio, M. J.; Lambrou, A. S.; Thornhill, J. K.; Bradburne, C.; Imbriale, S.; Freeman, J. D.; Anderson, M.; Kadlec, R. P.
title: Real-world Effect of Monoclonal Antibody Treatment in COVID-19 Patients in a Diverse Population in the United States
date: 2021-04-10
journal: nan
DOI: 10.1101/2021.04.08.21254705
sha: faa19f8c74a812a253e7f6ba39d52738581f83c0
doc_id: 909871
cord_uid: 417cyfrs

Background: Monoclonal antibodies (mAbs) against SARS-CoV-2 are a promising treatment for limiting the progression of COVID-19 and decreasing strain on hospitals. Their use, however, remains limited, particularly in disadvantaged populations. Methods: Electronic health records were reviewed from SARS-CoV-2 patients at a single medical center in the United States that initiated mAb infusions in January 2021 with the support of the U.S. Department of Health and Human Services' National Disaster Medical System. Patients who received mAbs were compared to untreated patients from the time period before mAb availability who met eligibility criteria for mAb treatment. We used logistic regression to measure the effect of mAb treatment on the risk of hospitalization or emergency department (E.D.) visit within 30 days of laboratory-confirmed COVID-19. Results: Of 598 COVID-19 patients, 270 (45%) received bamlanivimab and 328 (55%) were untreated. Two hundred and thirty-one patients (39%) were Hispanic. Among treated patients, 5/270 (1.9%) presented to the E.D. or required hospitalization within 30 days of a positive SARS-CoV-2 test, compared to 39/328 (12%) untreated patients (p<0.001). After adjusting for age, gender, and comorbidities, the risk of E.D. visit or hospitalization was 82% lower in mAb-treated patients compared to untreated patients (95% confidence interval [CI]: 66%-94%). Conclusions: In this diverse, real-world COVID-19 patient population, mAb treatment significantly decreased the risk of subsequent E.D. visit or hospitalization. Broader treatment with mAbs, including in disadvantaged patient populations, can decrease the burden on hospitals and should be facilitated in all populations in the United States to ensure health equity.

In late 2019, a new respiratory infection was detected in China and alarmed global health experts with its 51 growing case incidence and clinical severity [1, 2] . Over the course of a few months, severe acute 52 respiratory syndrome-coronavirus-2 (SARS-CoV-2) spread around the world, overwhelming health 53 systems. While a substantial proportion of patients remain asymptomatic [3] , coronavirus disease 2019 54 can rapidly progress and require hospitalization and intensive care. Severe disease is 55 associated with older age, obesity, and several chronic medical conditions including cardiovascular, 56 kidney, and pulmonary comorbidities [4] [5] [6] [7] . 57 58 As of late January 2021, approximately 15,000 new COVID-19 hospital admissions were occurring per 59 day in the United States (U.S.) and hospital bed capacity exceeded 72% [8, 9] . As healthcare systems 60 continued to approach maximum bed capacity, a critical need for therapeutic interventions to reduce COVID symptoms in randomized, controlled phase 2/3 trials by more than 70% [10] . 71 72 Monoclonal antibodies are underutilized as a treatment for reducing severe disease and could significantly 73 decrease hospitalizations and potentially long-term COVID effects [13] . Utilization can be particularly 74 challenging in minority, disadvantaged populations, in whom prevalence of risk factors for COVID-19 75 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 10, 2021. ; https://doi.org/10.1101/2021.04.08.21254705 doi: medRxiv preprint chronic liver disease, hypertension, immunosuppressive condition, chronic kidney disease, obesity or 127 overweight, and organ transplant. Pre-existing conditions were captured from the Chief Complaint of 128 health records within the six months prior to the date of SARS-CoV-2 testing. Laboratory values and 129 clinical exam measurements were not extracted to define pre-existing conditions. 130 131 Race categories were defined as American Indian/Alaskan Native, Asian, Black, Hawaiian/Pacific 132 Islander, White, and other. Ethnicity was defined as Hispanic or Non-Hispanic. Body mass index (BMI) 133 was calculated as kilograms per meter-squared. In the absence of height and weight, the pre-existing 134 conditions of "obesity" and "overweight" were used for BMI categorization. The composite outcome of a 135 medical visit was defined as the first instance of COVID-19-related E.D. visit or hospitalization after 136 positive SARS-CoV-2 viral test result and was obtained from the electronic health record. A medical visit 137 was COVID-related if one or more of the following chief complaints were identified: blood in sputum, 138 chest congestion, chest pain, cough, COVID-19 screening, difficulty breathing, fever, flu-like symptoms, 139 hypoxia, shortness of breath, sore throat, or weakness [20] [21] [22] [23] . Dates of COVID-19 symptom onset and 140 positive SARS-CoV-2 antigen test results performed at the infusion center were recorded on paper-based 141 forms upon arrival of patients for mAb treatment, but were not recorded in electronic health records. 142 143 Characteristics of patients were compared using Welch t-tests for continuous variables and Chi-squared 144 test for categorical variables. Age was categorized as younger than or equal to 65 years of age or older 145 than 65 years. Logistic regression was used to evaluate the effect of mAb treatment on medical visits that 146 occurred within 30 days of SARS-CoV-2-positive viral test by applying a generalized linear model with a 147 logits link function. The occurrence of a medical visit was evaluated as a binary outcome. Variables 148 included in the model were those deemed epidemiologically relevant. Model diagnostics indicated that no 149 data points substantially influenced model estimates, as assessed by Cook's distance. All data processing 150 and analyses were conducted using R version 4.0.3 [24] . 151 152 . CC-BY-NC-ND 4.0 International license It 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)

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Medical records were available from 875 SARS-CoV-2-positive patients ( Figure 1 ) confirmed during July 154 1 through December 20, 2020. Of these, 547 patients did not meet eligibility criteria for mAb treatment 155 Among the 598 patients, no statistically significant differences in sex or ethnicity were identified between 162 the treated and untreated study groups (Table 2) . Untreated patients were an average of three years 163 younger than the treated patients (p=0.02), and health records were more likely to report untreated 164 patients as overweight or obese and with a history of hypertension or cardiovascular disease (all p<0.001). with a 2.10-fold increased risk but this was not statistically significant (95% CI: 0.97, 4.77). 178 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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This study demonstrated that a single infusion of bamlanivimab within 10 days of COVID-19 symptom 181 onset decreased the risk of COVID-related hospitalization and E.D. visits among a real-world, diverse 182 patient population in the U.S. who were at risk of progression to severe disease compared with an 183 historical untreated population. The association between treatment and improved clinical outcome 184 remained significant after controlling for gender, age, race, ethnicity, and pre-existing conditions. A BMI 185 of greater than 35 remained highly associated with disease progression requiring a medical visit after 186 adjusting for mAb treatment and other co-factors. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The use of electronic health records is a strength of the current study. Due to the medical center's 206 electronic record system, we were able to assemble a SARS-CoV-2-positive cohort who would have been 207 eligible for mAb treatment at the time of their diagnosis based on pre-existing risk factors, had the 208 therapeutics been available at that time. An additional strength of this study was the diverse patient 209 population in the area, resulting in the inclusion of a large proportion of patients of Hispanic ethnicity 210 (39%). Our results are consistent with prior clinical trial data showing a 70% reduction in medical visits 211 by mAb-infused patients compared to placebo controls [10] . A BMI of 35 or higher was a strong 212 independent predictor of an increased risk of medical visits, which was consistent with other COVID-19 213 studies [7] . 214

A significantly larger proportion of untreated patients had co-morbidities that increase the risk of severe 216 COVID-19 outcomes compared to treated patients in the current study, notably a higher proportion with 217 elevated BMI. Although mAb treatment remained significantly associated with a decreased risk of 218 hospitalization or E.D. visit after adjusting for pre-existing conditions (82% reduction; 95% CI: 66%, 219 94%), the baseline differences between the treated and untreated groups suggest a potential difference in 220 accessibility of mAb treatment. For example, patients with fewer co-morbidities may have more easily 221 been able to avail themselves of treatment. The continued U.S. government efforts to increase access to 222 mAbs are intended to ensure that COVID-19 therapeutics are equally available to all patients -an 223 important national health equity consideration. 224 225 To receive mAb infusions, patients must seek out treatment within 10 days of a positive SARS-CoV-2 226 antigen test result. This can be burdensome and stresses the importance of widespread availability of 227 testing. Evidence also suggests that patients with more significant or severe co-morbidities are likely to 228 have more complete health records [26, 27] . This effect may have overrepresented patients with more 229 severe chronic conditions into the untreated group based on the application of mAb eligibility criteria for 230 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 10, 2021. ; https://doi.org/10.1101/2021.04.08.21254705 doi: medRxiv preprint inclusion in the analysis. Additionally, without active follow-up of patient outcomes, misclassification of 231 the medical visit outcome was possible as patients could seek follow-up care at any facility. These 232 considerations and the differences between the study groups suggest confounders remain that were 233 unmeasured in this analysis. These limitations could be further evaluated in a larger, prospective, 234 observational study. 235 236 While individuals at increased risk of SARS-CoV-2 infection and severe disease are prioritized for 237 vaccination in most U.S. states, therapeutic options such as mAb infusions remain a necessity for those 238 who remain unvaccinated due to contraindications or vaccine hesitancy [28, 29] . Although viral variants 239 are being discovered that are poorly neutralized by several mAbs in laboratory studies [30, 31] , suggesting 240 reduced effectiveness in patient populations, relatively minor adjustments to the currently available mAb 241 products can counter these changes. Additionally, the FDA has issued guidance encouraging use of 242 existing formulations, platforms, and clinical protocols to facilitate expedited review and rapid 243 introduction of these modified mAb products to general public [32] . 244

In summary, we demonstrated that mAb treatment with bamlanivimab was associated with an 246 approximately 80% reduction in the risk of medical visits among a diverse COVID-19 patient population 247 under real-world conditions. Increasing availability and utilization of novel COVID-19 therapeutics may 248 improve patient outcomes, reduce burden on the health system, and contribute to increased health equity 249 in the United States. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted April 10, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 10, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 10, 2021. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 10, 2021. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 10, 2021. ; https://doi.org/10.1101/2021.04.08.21254705 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It 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)

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. CC-BY-NC-ND 4.0 International license It 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)

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Undiagnosed pneumonia -China (Hubei) Request for Information

Characteristics of and Important Lessons From the Coronavirus Disease 268 2019 (COVID-19) Outbreak in China

COVID-19 positive persons and their transmission potential: A systematic review and meta-272 analysis

Abbreviations: CI, confidence interval; mAb, monoclonal