Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 36
Filter
1.
Cell Rep Med ; 3(11): 100811, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2150820

ABSTRACT

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents.


Subject(s)
COVID-19 , Humans , COVID-19/therapy , SARS-CoV-2 , Immunization, Passive/methods , Antibodies, Viral/therapeutic use , Nucleocapsid
2.
N Engl J Med ; 387(10): 955, 2022 09 08.
Article in English | MEDLINE | ID: covidwho-2106611
3.
Transfus Apher Sci ; : 103521, 2022 Aug 04.
Article in English | MEDLINE | ID: covidwho-1977877
4.
BMC Infect Dis ; 22(1): 645, 2022 Jul 27.
Article in English | MEDLINE | ID: covidwho-1962761

ABSTRACT

BACKGROUND: Monoclonal antibodies (mAb) prevent COVID-19 progression when administered early. We compared mAb treatment outcomes among vaccinated and unvaccinated patients during Delta wave and assessed the feasibility of implementing stricter eligibility criteria in the event of mAb scarcity. METHODS: We conducted a retrospective observational study of casirivimab/imdevimab recipients with mild-to-moderate COVID-19 infection in an emergency department or outpatient infusion center (July 1-August 20, 2021). Primary outcome was all-cause hospital admission within 30 days post-treatment between vaccinated vs. unvaccinated patients during Delta surge in the Bronx, NY. RESULTS: A total of 250 patients received casirivimab/imdevimab (162 unvaccinated vs. 88 vaccinated). The median age was 39 years for unvaccinated patients, and 52 years for vaccinated patients (p < 0.0001). The median number of EUA criteria met was 1 for unvaccinated and 2 for vaccinated patients (p < 0.0001). Overall, 6% (15/250) of patients were admitted within 30 days post-treatment. Eleven unvaccinated patients (7%) were admitted within 30-days compared to 4 (5%) vaccinated patients (p = 0.48). CONCLUSIONS: All-cause 30-day admission was not statistically different between vaccinated and unvaccinated patients. When federal allocation of therapies is limited, programs must prioritize patients at highest risk of hospitalization and death regardless of vaccination status.


Subject(s)
COVID-19 , Adult , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , COVID-19/prevention & control , Humans , Retrospective Studies
5.
BMC Infectious Diseases ; 22(1):1-8, 2022.
Article in English | BioMed Central | ID: covidwho-1958000

ABSTRACT

Monoclonal antibodies (mAb) prevent COVID-19 progression when administered early. We compared mAb treatment outcomes among vaccinated and unvaccinated patients during Delta wave and assessed the feasibility of implementing stricter eligibility criteria in the event of mAb scarcity. We conducted a retrospective observational study of casirivimab/imdevimab recipients with mild-to-moderate COVID-19 infection in an emergency department or outpatient infusion center (July 1–August 20, 2021). Primary outcome was all-cause hospital admission within 30 days post-treatment between vaccinated vs. unvaccinated patients during Delta surge in the Bronx, NY. A total of 250 patients received casirivimab/imdevimab (162 unvaccinated vs. 88 vaccinated). The median age was 39 years for unvaccinated patients, and 52 years for vaccinated patients (p < 0.0001). The median number of EUA criteria met was 1 for unvaccinated and 2 for vaccinated patients (p < 0.0001). Overall, 6% (15/250) of patients were admitted within 30 days post-treatment. Eleven unvaccinated patients (7%) were admitted within 30-days compared to 4 (5%) vaccinated patients (p = 0.48). All-cause 30-day admission was not statistically different between vaccinated and unvaccinated patients. When federal allocation of therapies is limited, programs must prioritize patients at highest risk of hospitalization and death regardless of vaccination status.

7.
Diagn Microbiol Infect Dis ; 103(4): 115721, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1819473

ABSTRACT

Our objectives were to evaluate the role of procalcitonin in identifying bacterial co-infections in hospitalized COVID-19 patients and quantify antibiotic prescribing during the 2020 pandemic surge. Hospitalized COVID-19 patients with both a procalcitonin test and blood or respiratory culture sent on admission were included in this retrospective study. Confirmed co-infection was determined by an infectious diseases specialist. In total, 819 patients were included; 335 (41%) had an elevated procalcitonin (>0.5 ng/mL) and of these, 42 (13%) had an initial bacterial co-infection. Positive predictive value of elevated procalcitonin for co-infection was 13% while the negative predictive value was 94%. Ninety-six percent of patients with an elevated procalcitonin received antibiotics (median 6 days of therapy), compared to 82% with low procalcitonin (median 4 days of therapy) (adjusted OR:3.3, P < 0.001). We observed elevated initial procalcitonin in many COVID patients without concurrent bacterial co-infections which potentially contributed to antibiotic over-prescribing.


Subject(s)
Bacterial Infections , COVID-19 , Coinfection , Procalcitonin , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/diagnosis , Bacterial Infections/drug therapy , Biomarkers , COVID-19/complications , Calcitonin , Calcitonin Gene-Related Peptide , Coinfection/epidemiology , Humans , Procalcitonin/analysis , Retrospective Studies
8.
Clin Microbiol Rev ; 35(3): e0020021, 2022 09 21.
Article in English | MEDLINE | ID: covidwho-1736023

ABSTRACT

Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light on the mechanisms of action, safety, and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCTs) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. We analyzed variables associated with efficacy, such as clinical settings, disease severity, CCP SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement, or mortality), CCP provenance and time for collection, and criteria for efficacy. The conflicting trial results, along with both recent WHO guidelines discouraging CCP usage and the recent expansion of the FDA emergency use authorization (EUA) to include outpatient use of CCP, create confusion for both clinicians and patients about the appropriate use of CCP. A review of 30 available RCTs demonstrated that signals of efficacy (including reductions in mortality) were more likely if the CCP neutralizing titer was >160 and the time to randomization was less than 9 days. The emergence of the Omicron variant also reminds us of the benefits of polyclonal antibody therapies, especially as a bridge to the development and availability of more specific therapies.


Subject(s)
COVID-19 , COVID-19/therapy , Humans , Immunization, Passive , Observational Studies as Topic , Randomized Controlled Trials as Topic
11.
JAMA Netw Open ; 5(1): e2147375, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1648976

ABSTRACT

Importance: Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact. Objective: To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics. Design, Setting, and Participants: This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants). Exposure: Receipt of CCP. Main Outcomes and Measures: World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI. Results: A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs. Conclusions and Relevance: The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.


Subject(s)
COVID-19/therapy , Hospitalization , Patient Selection , Plasma , Therapeutic Index , Aged , Blood Grouping and Crossmatching , Comorbidity , Female , Humans , Immunization, Passive , Male , Middle Aged , Odds Ratio , Pandemics , Respiration, Artificial , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome , World Health Organization
12.
JAMA Netw Open ; 5(1): e2147331, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1648384

ABSTRACT

Importance: COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing. Objective: To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP. Data Sources: From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly. Study Selection: Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally. Data Extraction and Synthesis: A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board. Main Outcomes and Measures: Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization. Results: Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. Conclusions and Relevance: This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.


Subject(s)
COVID-19/therapy , Hospitalization , Pandemics , Patient Selection , Plasma , Aged , Bayes Theorem , Female , Humans , Immunization, Passive , Male , Middle Aged , Respiration, Artificial , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome , World Health Organization
13.
JAMA Intern Med ; 182(2): 115-126, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1567885

ABSTRACT

Importance: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. Objective: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. Design, Setting, and Participants: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. Interventions: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). Main Outcomes and Measures: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. Results: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06). Conclusions and Relevance: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. Trial Registration: ClinicalTrials.gov Identifier: NCT04364737.


Subject(s)
Blood Component Transfusion , COVID-19/therapy , Critical Illness/therapy , Adult , Aged , Double-Blind Method , Female , Hospitalization/statistics & numerical data , Humans , Immunization, Passive , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , Treatment Outcome , United States
14.
Rev Med Virol ; 32(4): e2314, 2022 07.
Article in English | MEDLINE | ID: covidwho-1549282

ABSTRACT

Viral clearance is likely the best way to assess the efficacy of antibody-based therapies. Although antibodies can mediate a variety of effects that include modulation of inflammation, the demonstration of viral clearance provides an accessible and measurable parameter that can be used to evaluate efficacy and determine dosing. Therefore, it is important to ascertain the ability of monoclonal antibodies and convalescent plasma to effect viral clearance. For COVID-19, which is caused by the respiratory virus SARS-CoV-2, the most common assay to assess viral clearance is via a nasopharyngeal swab (NPS). However, assessment of antibody efficacy by sampling this site may be misleading because it may not be as accessible to serum antibodies as respiratory secretions or circulating blood. Adding to the complexity of assessing the efficacy of administered antibody, particularly in randomised controlled trials (RCTs) that enroled patients at different times after the onset of COVID-19 symptoms, viral clearance may also be mediated by endogenous antibody. In this article we critically review available data on viral clearance in RCTs, matched control studies, case series and case reports of antibody therapies in an attempt to identify variables that contribute to antibody efficacy and suggest optimal strategies for future studies.


Subject(s)
Antibodies, Neutralizing , COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral , Biomarkers , COVID-19/diagnosis , COVID-19/therapy , Humans , Immunization, Passive , Nasopharynx/virology , Treatment Outcome
15.
Nat Commun ; 12(1): 6853, 2021 11 25.
Article in English | MEDLINE | ID: covidwho-1537313

ABSTRACT

Transfer of convalescent plasma (CP) had been proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS-CoV-2-specific antibody titer, Fc-receptor binding, and Fc-mediated functional assays in CP units, as well as in plasma from hospitalized COVID-19 patients before and after CP administration. The profiling results show that, although all recipients exhibit expanded SARS-CoV-2-specific humoral immune responses, CP units contain more functional antibodies than recipient plasma. Meanwhile, CP functional profiles influence the evolution of recipient humoral immunity in conjuncture with the recipient's pre-existing SARS-CoV2-specific antibody titers: CP-derived SARS-CoV-2 nucleocapsid-specific antibody functions are associated with muted humoral immune evolution in patients with high titer anti-spike IgG. Our data thus provide insights into the unexpected impact of CP-derived functional anti-spike and anti-nucleocapsid antibodies on the evolution of SARS-CoV-2-specific response following severe infection.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/therapy , Immunity , Immunization, Passive/methods , Plasma/immunology , Antibodies, Neutralizing/immunology , Blood Donors , Humans , Immunity, Humoral , Nucleocapsid/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
18.
Open Forum Infect Dis ; 8(8): ofab313, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1377978

ABSTRACT

We partnered with the US Department of Health and Human Services to treat high-risk, nonadmitted coronavirus disease 2019 (COVID-19) patients with bamlanivimab in the Bronx, New York per Emergency Use Authorization criteria. Increasing posttreatment hospitalizations were observed monthly between December 2020 and March 2021 in parallel to the emergence of severe acute respiratory syndrome coronavirus 2 variants in New York City.

19.
Viruses ; 13(8)2021 08 11.
Article in English | MEDLINE | ID: covidwho-1355048

ABSTRACT

COVID-19 convalescent plasma (CCP) is currently under investigation for both treatment and post-exposure prophylaxis. The active component of CCP mediating improved outcome is commonly reported as specific antibodies, particularly neutralizing antibodies, with clinical efficacy characterized according to the level or antibody affinity. In this review, we highlight the potential role of additional factors in CCP that can be either beneficial (e.g., AT-III, alpha-1 AT, ACE2+ extracellular vesicles) or detrimental (e.g., anti-ADAMTS13, anti-MDA5 or anti-interferon autoantibodies, pro-coagulant extracellular vesicles). Variations in these factors in CCP may contribute to varied outcomes in patients with COVID-19 and undergoing CCP therapy. We advise careful, retrospective investigation of such co-factors in randomized clinical trials that use fresh frozen plasma in control arms. Nevertheless, it might be difficult to establish a causal link between these components and outcome, given that CCP is generally safe and neutralizing antibody effects may predominate.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/therapy , SARS-CoV-2/immunology , Anti-Inflammatory Agents/blood , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Autoantibodies/blood , Blood Coagulation Factor Inhibitors/blood , Blood Coagulation Factors/analysis , Cross Reactions , Extracellular Vesicles , Humans , Immunization, Passive/adverse effects , Immunologic Factors/blood , Immunosuppressive Agents/blood
SELECTION OF CITATIONS
SEARCH DETAIL