Early administration of remdesivir plus convalescent plasma therapy is effective to treat COVID-19 pneumonia in B-cell depleted patients with hematological malignancies

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Abstract

Patients with hematological malignancies (HMs) are at a higher risk of developing severe form and protracted course of COVID-19 disease. We investigated whether the combination of viral replication inhibition with remdesivir and administration of anti-SARS-CoV-2 immunoglobulins with convalescent plasma (CP) therapy might be sufficient to treat B-cell-depleted patients with COVID-19. We enrolled 20 consecutive patients with various HMs with profound B-cell lymphopenia and COVID-19 pneumonia between December 2020 and May 2021. All patients demonstrated undetectable baseline anti-SARS-CoV-2 immunoglobulin levels before CP. Each patient received at least a complete course of remdesivir and at least one unit of CP. Previous anti-CD20 therapy resulted in a more prolonged SARS-CoV-2 PCR positivity compared to other causes of B-cell lymphopenia ( p = 0.004). Timing of CP therapy showed a significant impact on the clinical outcome. Simultaneous use of remdesivir and CP reduced time period for oxygen weaning after diagnosis ( p = 0.017), length of hospital stay ( p = 0.007), and PCR positivity ( p = 0.012) compared to patients who received remdesivir and CP consecutively. In addition, time from the diagnosis to CP therapy affected the length of oxygen dependency ( p < 0.001) and hospital stay ( p < 0.0001). In those cases where there were at least 10 days from the diagnosis to plasma administration, oxygen dependency was prolonged vs. patients with shorter interval ( p = 0.006). In conclusion, the combination of inhibition of viral replication with passive immunization was proved to be efficient and safe. Our results suggest the clear benefit of early, combined administration of remdesivir and CP to avoid protracted COVID-19 disease among patients with HMs and B-cell lymphopenia.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00277-022-04924-6.

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Remdesivir for the Treatment of Covid-19 — Final Report

John H. Beigel, Kay Tomashek, Lori Dodd … (2022)

Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)

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A minimal common outcome measure set for COVID-19 clinical research

John C Marshall, Srinivas Murthy, Janet V. Diaz … (2020)

Summary Clinical research is necessary for an effective response to an emerging infectious disease outbreak. However, research efforts are often hastily organised and done using various research tools, with the result that pooling data across studies is challenging. In response to the needs of the rapidly evolving COVID-19 outbreak, the Clinical Characterisation and Management Working Group of the WHO Research and Development Blueprint programme, the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium have developed a minimum set of common outcome measures for studies of COVID-19. This set includes three elements: a measure of viral burden (quantitative PCR or cycle threshold), a measure of patient survival (mortality at hospital discharge or at 60 days), and a measure of patient progression through the health-care system by use of the WHO Clinical Progression Scale, which reflects patient trajectory and resource use over the course of clinical illness. We urge investigators to include these key data elements in ongoing and future studies to expedite the pooling of data during this immediate threat, and to hone a tool for future needs.

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Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19

F. Ibarrondo, Jennifer A. Fulcher, David Goodman-Meza … (2020)

To the Editor: A recent article suggested the rapid decay of anti–SARS-CoV-2 IgG in early infection, 1 but the rate was not described in detail. We evaluated persons who had recovered from Covid-19 and referred themselves to our institution for observational research. Written informed consent was obtained from all the participants, with approval by the institutional review board. Blood samples were analyzed by enzyme-linked immunosorbent assay (ELISA) to detect anti–SARS-CoV-2 spike receptor-binding domain IgG. 2 The ELISA was further modified to precisely quantify serum anti–receptor-binding domain activity in terms of equivalence to the concentration of a control anti–receptor-binding domain monoclonal IgG (CR3022, Creative Biolabs). Infection had been confirmed by polymerase-chain-reaction assay in 30 of the 34 participants. The other 4 participants had had symptoms compatible with Covid-19 and had cohabitated with persons who were known to have Covid-19 but were not tested because of mild illness and the limited availability of testing. Most of the participants had mild illness; 2 received low-flow supplemental oxygen and leronlimab (a CCR5 antagonist), but they did not receive remdesivir. There were 20 women and 14 men. The mean age was 43 years (range, 21 to 68) (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). A total of 31 of the 34 participants had two serial measurements of IgG levels, and the remaining 3 participants had three serial measurements. The first measurement was obtained at a mean of 37 days after the onset of symptoms (range, 18 to 65), and the last measurement was obtained at a mean of 86 days after the onset of symptoms (range, 44 to 119). The initial mean IgG level was 3.48 log10 ng per milliliter (range, 2.52 to 4.41). On the basis of a linear regression model that included the participants’ age and sex, the days from symptom onset to the first measurement, and the first log10 antibody level, the estimated mean change (slope) was −0.0083 log10 ng per milliliter per day (range, −0.0352 to 0.0062), which corresponds to a half-life of approximately 36 days over the observation period (Figure 1A). The 95% confidence interval for the slope was −0.0115 to −0.0050 log10 ng per milliliter per day (half-life, 26 to 60 days) (Figure 1B). The protective role of antibodies against SARS-CoV-2 is unknown, but these antibodies are usually a reasonable correlate of antiviral immunity, and anti–receptor-binding domain antibody levels correspond to plasma viral neutralizing activity. Given that early antibody decay after acute viral antigenic exposure is approximately exponential, 3 we found antibody loss that was quicker than that reported for SARS-CoV-1, 4,5 and our findings were more consistent with those of Long et al. 1 Our findings raise concern that humoral immunity against SARS-CoV-2 may not be long lasting in persons with mild illness, who compose the majority of persons with Covid-19. It is difficult to extrapolate beyond our observation period of approximately 90 days because it is likely that the decay will decelerate. 3 Still, the results call for caution regarding antibody-based “immunity passports,” herd immunity, and perhaps vaccine durability, especially in light of short-lived immunity against common human coronaviruses. Further studies will be needed to define a quantitative protection threshold and rate of decline of antiviral antibodies beyond 90 days.

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Author and article information

Contributors

László Imre Pinczés:

ORCID: http://orcid.org/0000-0003-0453-1709

pinczes.laszlo.imre@med.unideb.hu

Journal

Journal ID (nlm-ta): Ann Hematol

Journal ID (iso-abbrev): Ann Hematol

Title: Annals of Hematology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0939-5555

ISSN (Electronic): 1432-0584

Publication date (Electronic): 14 July 2022

Publication date PMC-release: 14 July 2022

Pages: 1-9

Affiliations

[1 ]GRID grid.7122.6, ISNI 0000 0001 1088 8582, Division of Hematology, Department of Internal Medicine, Faculty of Medicine, , University of Debrecen, ; Debrecen, Hungary

[2 ]GRID grid.7122.6, ISNI 0000 0001 1088 8582, Doctoral School of Clinical Medicine, , University of Debrecen, ; Debrecen, Hungary

[3 ]GRID grid.7122.6, ISNI 0000 0001 1088 8582, Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, , University of Debrecen, ; Debrecen, Hungary

[4 ]GRID grid.7122.6, ISNI 0000 0001 1088 8582, Department of Radiology, Faculty of Medicine, , University of Debrecen, ; Debrecen, Hungary

[5 ]GRID grid.7122.6, ISNI 0000 0001 1088 8582, Department of Emergency Medicine, Faculty of Medicine, , University of Debrecen, ; Debrecen, Hungary

[6 ]GRID grid.7122.6, ISNI 0000 0001 1088 8582, Department of Laboratory Medicine, Faculty of Medicine, , University of Debrecen, ; Debrecen, Hungary

Author information

László Imre Pinczés http://orcid.org/0000-0003-0453-1709

Article

Publisher ID: 4924

DOI: 10.1007/s00277-022-04924-6

PMC ID: 9282831

PubMed ID: 35836007

SO-VID: 75520230-8f4e-4cea-8bd2-91f3a4bb7db8

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 2 February 2022

Date accepted : 6 July 2022

Funding

Funded by: University of Debrecen

Open Access :

Open access funding provided by University of Debrecen.

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Early administration of remdesivir plus convalescent plasma therapy is effective to treat COVID-19 pneumonia in B-cell depleted patients with hematological malignancies

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Novel Coronavirus Disease COVID-19

Most cited references 31

Remdesivir for the Treatment of Covid-19 — Final Report

A minimal common outcome measure set for COVID-19 clinical research

Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19

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Cited by 10

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