key: cord-0792399-9eigxugh authors: Ma, T.; Wiggins, C. C.; Kornatowski, B. M.; Hailat, R. S.; Clayburn, A. C.; Guo, W.; Johnson, P. W.; Senefeld, J. W.; Klassen, S. A.; Baker, S. E.; Bruno, K. A.; Fairweather, D.; Wright, R. S.; Carter, R. E.; Li, C.; Joyner, M. J.; Paneth, N. title: The Role of Disease Severity and Demographics in the Clinical Course of COVID-19 Patients Treated with Convalescent Plasma date: 2021-01-20 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2021.01.19.21249678 sha: 3eea2283717a7794351f203bbfbbb2d181c4ecd9 doc_id: 792399 cord_uid: 9eigxugh Treatment of patients with COVID-19 using convalescent plasma from recently recovered patients has been shown to be safe, but the time course of change in clinical status following plasma transfusion in relation to baseline disease severity has not yet been described. We analyzed short, descriptive daily reports of patient status in 7,180 hospitalized recipients of COVID-19 convalescent plasma in the Mayo Clinic Expanded Access Program. We assessed, from the day following transfusion, whether the patient was categorized by his or her physician as better, worse or unchanged compared to the day before, and whether, on the reporting day, the patient received mechanical ventilation, was in the ICU, had died or had been discharged. Most patients improved following transfusion, but clinical improvement was most notable in mild to moderately ill patients. Patients classified as severely ill upon enrollment improved, but not as rapidly, while patients classified as critically ill/end-stage and patients on ventilators showed worsening of disease status even after treatment with convalescent plasma. Patients age 80 and over showed little or no clinical improvement following transfusion. Clinical status at enrollment and age appear to be the primary factors in determining the therapeutic effectiveness of COVID-19 convalescent plasma among hospitalized patients. The number of deaths from COVID-19 in the United States surpassed 350,000 19 on January 3, 2021 1 , just ten months after the first confirmed case of novel coronavirus 20 (SARS-CoV-2) in the US, demonstrating the urgent need to find safe and effective 21 treatment options. Convalescent plasma, rich in antibodies from recently recovered 22 patients, was used successfully in the 1918 influenza pandemic 2 , SARS-1 3 and Ebola 4 23 epidemics. Recognizing that a vaccine would not be widely available for several months 24 to a year, and facing a paucity of treatment options, the United States Federal 25 Government, in collaboration with the Mayo Clinic and the national blood banking 26 community, developed the Expanded Access Program (EAP) for COVID-19 27 convalescent plasma as a national registry to examine the safety and as much as 28 possible the efficacy of convalescent plasma treatment in hospitalized patients. The 29 inclusion criteria of the EAP required that enrolled patients 1) have a diagnosis of 30 SARS-CoV-2, 2) be severely ill or at high risk for becoming severely ill from COVID- 19, 31 and 3) be admitted to an acute care facility for COVID-19 complications. 32 Evidence of efficacy has emerged from retrospective comparisons of treated and 33 untreated patients 4 , and from several small randomized trials [5] [6] [7] [8] [9] [10] [11] [12] . However, only one of 34 these trials 13 and one retrospective treatment-control analysis 14 in hospitalized patients 35 stratified patients based on disease severity at time of treatment to examine efficacy 36 accordingly. Analyses of the EAP have shown that COVID-19 convalescent plasma is 37 safe 15, 16 and likely to be effective in treating COVID-19 17 . Based on the historical 38 literature, we hypothesized that patients treated with convalescent plasma earlier in the 39 course of the disease (who were not on mechanical ventilation or in the intensive care 40 unit (ICU)) or who had less severe disease at the time of transfusion, would show more rapid and better improvement than convalescent plasma recipients receiving 42 mechanical ventilation or in the ICU at the time of treatment. 43 44 The EAP was developed primarily as a registry to investigate the safety of 45 convalescent plasma as a treatment for COVID-19 during an ongoing pandemic. It was 46 implemented at a time when health systems were overwhelmed and clinical research 47 resources were limited because of hospitals restricting patient access to essential 48 personnel and the frequent reassignment of research staff to clinical duties. We 49 therefore developed the REP as an optional reporting tool requiring minimal time and 50 effort on the part of the treating physician, but that would nonetheless provide useful 51 information as to whether improvement or worsening was noted following treatment with 52 convalescent plasma, and how this varied by category of patient. 53 We offered all physicians enrolling patients in the EAP the opportunity to 54 participate in the Rapid Evaluation Project (REP) by providing brief, daily updates of the 55 status of their patients until death or discharge from the hospital. Physicians or their 56 designees, after providing the baseline status of each participant on the day of 57 enrollment, described each participant's status compared to the previous day -better, 58 the same, or worse -and also noted whether the patient had been discharged from 59 hospital or died that day, and whether the patient was in an ICU or had required 60 mechanical ventilation. 61 This simple system was inspired by the study by Waller and Lawther who asked 62 London patients with chronic obstructive pulmonary disease to record their daily status 63 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 82 We constructed ordinal scales of clinical outcome from the physicians' reports 83 ranging from -2 to +2. Death was scored as -2, clinical worsening as -1, no change as 0, 84 clinical improvement as +1, and hospital discharge as +2. Figure 1 displays the 85 trajectories of mean ordinal scale scores for all patients ( Figure 1A ) and for several 86 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. For all patients in the REP ( Figure 1A ), the mean daily score increased rapidly 91 from one day after CP infusion (mean=0.16, 95% CI: 0.14 -0.19) to day 8 (mean=0.82, 92 95% CI:0.78 -0.87). Thereafter, the mean scores stabilized between 0.82 to 0.91. 93 When stratified by age group ( Figure 1B ), only the elderly (80+ years old) did not length of stay following transfusion was 6 days (IQR= 4-11 days), and among patients 109 who died, median length of stay following transfusion was 8 days (IQR= 4-13 days). 110 The leveling off of improvement after day 9 in the overall patient population 111 ( Figure 1A ) appears to be attributable to patients still being hospitalized after that time Table 2 shows the day of the segment breakpoint for several sub-groups of the study 123 population. The largest factor determining both direction of the trajectory and the 124 rapidity of stabilization was ventilator status, with unventilated patients stabilizing, after 125 improvement, after 7-8 days, while ventilated patients did not begin to stabilize from 126 their downhill course until 12-13 days. To assess the individual and combined contributions of the factors described 129 above (age, gender, ICU status, ventilator status at the time of transfusion, and a 130 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Table 2) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. infusion. 156 We found that most patients who received COVID-19 convalescent plasma (which was not certified by peer review) 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 January 20, 2021. ; https://doi.org/10.1101/2021.01.19.21249678 doi: medRxiv preprint transfusion were associated with condition change following convalescent plasma 177 treatment including patients' level of severity; ventilator use, ICU presence, and 178 advanced age. We also observed that baseline severity is also related to the slope of 179 the change in trajectory, suggesting that critically ill patients do improve following 180 treatment with convalescent plasma, albeit at a much slower rate. 181 Overall, the data from our analysis provide a framework for best case use when 182 considering administering convalescent plasma to treat COVID-19. These data offer a 183 qualitative supplement to more quantitative analyses from our group 17 (which was not certified by peer review) 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 January 20, 2021. (which was not certified by peer review) 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 January 20, 2021. ; Participant enrollment in the REP was open to any patient (patient 213 inclusion/exclusion criteria for EAP described previously 15, 16 ) in the EAP whose 214 physician or designee were willing to provide daily updates. 215 Data Analysis. 216 To define each patient's overall level of improvement or worsening on each day 217 of observation, we calculated the total number of "condition worsened" and "condition 218 improved" responses for each patient for the days preceding the day of observation. If a 219 participant had more "condition worsened" than "condition improved" responses, but To more fully assess the trajectories, we performed a linear segmented analysis to 234 identify the changes of scores overtime in each patient group [21] [22] [23] . This method allowed us to 235 test for significantly increasing or decreasing linear trends in clinical outcomes after transfusion. 236 The program examined the data to identify one breakpoint for each segmented regression 237 model in which the trajectory changed The R package "segmented" was used for the data 238 analysis[citation 19 20] and P < 0.001 was considered statistically significant. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 3 -0.043* All regression models were analyzed with 2 segments to assess changes and trends of the clinical outcome of each day. * indicates P < 0.001 for that segment of the trajectory. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Adjusted GEE model was used to estimate the odds of being in a higher category (net improvement) of the ordinal clinical outcomes. *Initial status of severity and time interaction term were added in the model as time-varying covariate. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 January 20, 2021. ; https://doi.org/10.1101/2021.01.19.21249678 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 January 20, 2021. all patients, B) by age, C) by sex, D) by initial clinical status, E) by ICU status prior to transfusion, and F) by ventilator status prior to transfusion. Net patient scores of 0= no net change, +1= net improvement but still hospitalized, -1= net worsened and still hospitalized, +2= discharged from hospital, and -2= patient expiration. Points are the mean score for each day, and gray bands indicate the 95% confidence interval for each data set. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 January 20, 2021. ; https://doi.org/10.1101/2021.01.19.21249678 doi: medRxiv preprint Department of Health & Human Services Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis Evaluation of convalescent plasma for Ebola virus disease in Guinea Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial Convalescent Plasma for COVID-19. A randomized clinical trial. medRxiv (2020) Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial The therapeutic potential of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG Early safety indicators of COVID-19 convalescent plasma in 5,000 patients Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. medRxiv Air pollution and exacerbations of bronchitis Some observations on London fog Covid-19 in critically ill patients in the Seattle region-case series Segmented: an R package to fit regression models with broken-line relationships Segmented regression analysis of interrupted time series studies in medication use research R package multgee: A generalized estimating equations solver for multinomial responses Gee for longitudinal ordinal data: Comparing R-geepack, R-multgee, R-repolr, SAS-genmod, SPSSgenlin 7%) West 1,487 (20.1%) 6,983 (13.9%) 085 (55.2%) 28,479 (56.5%) 80 or older 850 (11.5%) 5,745 (11.4%) Gender Female 2,974 (40.3%) 20,280 (40.4%) Male