Prevention of severe COVID-19 in the elderly by early high-titer plasma

Abstract

BackgroundTherapies to interrupt progression of early COVID-19 remain elusive. Among them, convalescent plasma in hospitalized patients was unsuccessful, perhaps because antibody should be administered earlier. We advanced plasma infusions to the first 72 hours of symptoms to arrest COVID-19 progression.MethodsA randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV2 in elderly subjects within 72 hours of mild COVID-19 symptoms. The primary endpoint was severe respiratory disease defined as a respiratory rate ≥30 and/or an O2 sat<93% in room air. The study was interrupted at 76% of its projected sample size, because cases in the region decreased considerably and steady enrollment of study subjects became virtually impossible.Results160 patients underwent randomization. In the intention-to-treat analysis (ITT), 13/80(16.2%) patients receiving plasma vs. 25/80(31.2%) receiving placebo experienced severe respiratory disease [RR(95%CI)= 0.52(0.29,0.94); p=0.026)] with an RRR=48%.A modified ITT analysis, excluding six subjects who experienced the primary endpoint before infusion, showed a larger effect size [RR(95%CI) = 0.40(0.20, 0.81), p=0.007]. High- and low-titer donor analyses, based on a median IgG titer=1:3,200, evidenced a dose-dependent response with an RRR=73.3% for recipients of high-titer plasma (p=0.016) and a number needed to treat (NNT)=4.4. All secondary endpoints exhibited trends towards protection. No solicited adverse events were observed.ConclusionsEarly administration of high-titer convalescent plasma against SARS-CoV2 to mildly ill infected seniors reduced COVID-19 progression. This safe, inexpensive, outpatient intervention facilitates access to treatment from industrialized to LMIC, can decompress demands on hospitals, and may contribute to save lives.Funded by The Bill & Melinda Gates Foundation and The Fundación INFANT Pandemic Fund. Registered in the Dirección de Sangre y Medicina Transfusional del Ministerio de Salud (PAEPCC19), Plataforma PRIISA (1421), and clinicaltrials.gov (NCT04479163).All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; RL, GPM, DW and FPP are investigators in a phase 3 SARS CoV2 trial from Pfizer; no other relationships or activities that could appear to have influenced the submitted work.

Treatment of Severe COVID-19 with Convalescent Plasma in the Bronx, NYC

“…In the ConPlas-19 RCT (26), in which 49% of the patients had positive SARS-CoV-2 IgG at enrollment, CCP did not confer benefit, but there was a trend towards reduced mortality. Nonetheless, in our study as in others (27, 66), antibody titers and symptom duration associated with disease severity and a lack of evidence of CCP efficacy. This underscores the longstanding principle that convalescent antibody therapy is most likely to be effective early in the course of viral respiratory diseases (14) as shown for COVID-19 in propensity score matched studies (23, 49) and a recently published outpatient RCT (66).…”

“…Although our data suggest possible effects of age, disease severity, and corticosteroid use on CCP efficacy, prospective, randomized, controlled trials are needed to establish CCP efficacy and the effect of these and other covariates. Antibody-based therapies, including CCP have now shown promise in outpatients with mild to moderate COVID-19 (66, 75). However, nearly a year into the pandemic, effective therapies for hospitalized patients are still urgently needed, particularly for those who are elderly and at high risk for mortality.…”

Severe covid-19 pneumonia: pathogenesis and clinical management

“…One RCT evaluated convalescent plasma with high anti-SARS-CoV2 IgG titers in older patients within 72 hours of mild covid-19 symptoms. In the convalescent plasma arm, 16.2% (13/80) progressed to severe respiratory diseases (respiratory rate ≥30 or O 2 sat<93%) 186 compared with 31.2% (25/80), in a preplanned interim analysis. Early administration of high titer convalescent plasma may play a role in mild to moderate disease, but we need more data to • Seen in up to 80% after any critical illness and includes loss of muscle mass, neuromuscular weakness, fatigue, dyspnea, decreased exercise tolerance, joint contractures, and sexual dysfunction.…”

The use of observational research to inform clinical practice

“…Trials were slow to be mounted in the early days of the pandemic, and all trials so far published have been small and statistically inconclusive for mortality. Six of the seven trials now in the public domain (none from the US) showed non-significantly lower mortality in the treated arms, averaging about 50%, but significant clinical improvements in other parameters were noted in some of the trials (12). Much larger trials are now on the verge of reporting, and by the time this Viewpoint is published, we may not have to rely on observational data to draw conclusions, but as of now, the most informative data we have is from observational studies.…”