Variant of Concern-Matched COVID-19 Convalescent Plasma Usage in Seronegative Hospitalized Patients.

COVID-19 convalescent plasma (CCP) has been the only specific anti-viral therapy against SARS-CoV-2 available for more than one year. Following the negative results from most randomized controlled trials on its efficacy in COVID-19 hospitalized patients and the availability of anti-spike monoclonal antibodies (mAbs), the use of CCP has subsequently rapidly faded. However, the continuous appearance of new variants of concern (VOCs), most of which escape mAbs and vaccine-elicited neutralizing antibodies (nAbs), has renewed the interest towards CCP, at least in seronegative immunocompetent patients, and in immunocompromised patients not able to mount a protective immune response. We report here the experience of a single Italian hospital in collecting and transfusing CCP in immunocompromised patients hospitalized for severe COVID-19 between October 2021 and March 2022. During this 6-month period, we collected CCP from 32 vaccinated and convalescent regular blood donors, and infused high nAb-titer CCP units (titered against the specific VOC affecting the recipient) to 21 hospitalized patients with severe COVID-19, all of them seronegative at the time of CCP transfusion. Patients' median age was 66 years (IQR 50-74 years) and approximately half of them (47.6%, 10/21) were immunocompromised. Two patients were rescued after previous failure of mAbs. No adverse reactions following CCP transfusion were recorded. A 28-day mortality rate of 14.3 percent (3/21) was reported, with age, advanced disease stage and late CCP transfusion associated with a worse outcome. This real-life experience also supports the use of CCP in seronegative hospitalized COVID-19 patients during the Delta and Omicron waves.

Neutralizing antibody levels against SARS-CoV-2 variants of concern Delta and Omicron in vaccine breakthrough-infected blood donors.

BACKGROUND: Novel SARS-CoV-2 variants of concern (VOC) Delta and Omicron are able to escape some monoclonal antibody therapies, making again COVID-19 convalescent plasma (CCP) a potential frontline treatment. STUDY DESIGN/METHODS: In this study, we investigated the kinetics of anti-SARS-CoV-2 neutralizing antibodies (nAbs) against VOCs Delta and Omicron in vaccine breakthrough infected plasma donors. Serum samples from 19 donors were collected at the time of plasma donation and tested for anti-SARS-CoV-2 nAbs (using live authentic VOC viral neutralization test) and IgG (Liaison® SARS-CoV-2 S1/S2 and Liaison® SARS-CoV-2 TrimericS IgG assays, DiaSorin). Measures were correlated with different variables, including the time between last vaccine dose and CCP donation, and time between SARS-COV-2 infection and CCP donation. RESULTS: nAb titers against VOC Delta and Omicron were directly related to the time interval since last vaccine dose to CCP donation, but inversely related to time since COVID19 breakthrough infection. DISCUSSION: SARS-CoV-2 breakthrough infection in vaccinated in donors boosts nAb titers against VOCs Delta and Omicron, but such titers decay shortly after infection. Therefore, CCP must be collected early after vaccine breakthrough infection.

Convalescent Plasma for Hospitalized COVID-19 Patients: A Single-Center Experience.

In Winter 2020, Italy, and in particular the Lombardy region, was the first country in the Western hemisphere to be hit by the COVID-19 pandemic. Plasma from individuals recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first therapeutic tool adopted to counteract the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this retrospective cohort study, we report the experience of the city hospital of Mantua, Lombardy region, on the compassionate use of CCP in patients hospitalized for severe COVID-19. Between April 2020 and April 2021, 405 consecutive COVID-19 patients received 657 CCP units with a median anti-SARS-CoV-2 neutralizing antibody (nAb) titer of 160 (interquartile range (IQR), 80-320). Their median age was 68 years (IQR, 56-78 years), and 62% were males. At enrollment, 55% of patients had an increased body mass index (BMI), and 25.6% had at least three comorbidities. The 28-day crude mortality rate was 12.6% (51/405). Young age (<68 years), mild disease (admission to low-intensity departments) and early treatment (<7 days from symptoms onset) with high nAb titer (≥320) CCP were found as independently associated with a favorable response to CCP treatment. No safety concerns were recorded, with a rate of CCP-related adverse reactions (all of mild intensity) of 1.3%. In our real-life experience, the first in the western world, early administration of high-titer CCP was a safe and effective treatment for hospitalized COVID-19 patients.

Convalescent Plasma for Pregnant Women with COVID-19: A Systematic Literature Review.

The treatment of COVID-19 is particularly critical in pregnant women, considering the potential teratogenic effects of antiviral agents and the immune-depression related with pregnancy. The aim of this review is to systematically examine the current evidence on the clinical use of convalescent plasma during pregnancy. The electronic databases Medline PubMed Advanced Search Builder, Scopus, Web Of Science and Google Scholar were searched (until 1 January 2021). Inclusion criteria were pregnant women with COVID-19 (or SARS-CoV-2 infection), in whom convalescent plasma (or hyperimmune plasma) was used as treatment. We searched clinical trial registries (censored 5 January 2021) for eligible studies under way. After elimination of duplications, the initial search yielded 79 potentially relevant records, of which 67 were subsequently excluded. The 12 remaining records were case reports involving 12 pregnancies. Six of the mothers were reported to be well, two were reported to have preeclampsia, and in one case each the maternal outcome was described as survival, clinical improvement, discharged with oxygen and rehabilitation. With regard to the neonates, two were declared to be well, four had transient morbidity, two were critically ill and one died; normal ongoing pregnancies, but no post-delivery information, were reported for the remaining three cases. Clinical trials under way or planned to investigate the use of convalescent plasma for COVID-19 during pregnancy are lacking. This is the first systematic review of the literature regarding the treatment of COVID-19 in pregnancy. The published literature data seem to indicate that convalescent plasma administered to pregnant women with severe COVID-19 provides benefits for both the mother and the fetus. The quality of the available studies is, however, very limited since they are all case reports and thus suffer from relevant reporting bias.

The Three Pillars of COVID-19 Convalescent Plasma Therapy.

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly around the world in the last year causing the coronavirus disease 2019 (COVID-19), which still is a severe threat for public health. The therapeutic management of COVID-19 is challenging as, up until now, no specific and efficient pharmacological therapy has been validated. Translating the experience from previous viral epidemics, passive immunotherapy by means of plasma from individuals recovered from COVID-19 has been intensively investigated since the beginning of the pandemic. In this narrative review, we critically analyze the three factors, named "pillars", that play a key role in determining the clinical effectiveness of this biologic therapy: the convalescent plasma, the disease (COVID-19), and the patients.

Potential mechanisms of action of convalescent plasma in COVID-19.

The COVID-19 pandemic will be remembered as one of the worst catastrophic events in human history. Unfortunately, no universally recognized effective therapeutic agents are currently available for the treatment of severe SARS-CoV-2 infection. In this context, the use of convalescent plasma from recovered COVID-19 patients has gained increasing interest thanks to the initially positive clinical reports. A number of mechanisms of action have been proposed for convalescent plasma, including direct neutralization and suppression of viremia, anti-inflammatory and immunomodulation effects and mitigation of the COVID-19-associated hypercoagulable state. These immune and non-immune mechanisms will be critically discussed in this narrative review.

Safety and Efficacy of Convalescent Plasma in Elderly COVID-19 Patients: The RESCUE Trial.

OBJECTIVE: To assess the safety and efficacy of convalescent plasma (CP) transfusion in elderly people with moderate to severe coronavirus disease 2019 (COVID-19) living in a long-term care facility (LTCF). PATIENTS AND METHODS: Twenty-two consecutive elderly patients with COVID-19 infection living in an LTCF in Lombardy, Italy, who were given CP during May 15 to July 31, 2020, were enrolled in a prospective cohort study. Their clinical, instrumental, and laboratory parameters were assessed following the CP treatment. The overall mortality rate in this group was compared with that recorded in other LTCFs in Lombardy during the 3-month period from March to May 2020. RESULTS: Of the 22 patients enrolled, 68.2% (n=15) received 1 CP unit, 27.3% (n=6) received 2 units, and 4.5% (n=1) received 3 units. Of the CP units transfused, 76.7% (23/30) had a neutralizing antibody titer of 1:160 or greater. No adverse reactions were recorded during or after CP administration. Improvements in clinical, functional, radiologic, and laboratory parameters during the 14 days after CP transfusion were observed in all 19 patients who survived. Viral clearance was achieved in all patients by the end of follow-up (median, 66 days; interquartile range, 48-80 days). The overall mortality rate was 13.6% (3/22), which compared favorably with that in the control group (38.3% [281/733]; P=.02) and corresponded to a 65% reduction in mortality risk. CONCLUSION: Early administration of CP with an adequate anti-severe acute respiratory syndrome coronavirus 2 antibody titer to elderly symptomatic patients with COVID-19 infection in an LTCF was safe and effective in eliminating the virus, restoring patients' immunity, and blocking the progression of COVID-19 infection, thereby improving patients' survival. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04569188.

A retrospective study assessing the characteristics of COVID-19 convalescent plasma donors and donations.

BACKGROUND: Although many trials are currently investigating the safety and efficacy of convalescent plasma (CP) in critically ill COVID-19 patients, there is a paucity of ongoing and published studies evaluating the CP donors' side. This retrospective study reports the first Italian experience on CP donors' selection and donations. METHODS: Patients aged 18-68 years who had recovered from COVID-19 at least 2 weeks previously were recruited between March 18 and June 30, 2020 in a study protocol at the Italian hospitals of Pavia and Mantova. RESULTS: During the study period, 494 of 512 donors recruited were judged eligible and underwent 504 plasmapheresis procedures. Eighty-five percent (437/512) of the CP donors were males. The average time between symptom recovery and CP donation was 36.6 (±20.0) days. Four hundred and eighty-eight plasmapheresis procedures (96.8%) were concluded and each unit was divided into two subunits (total 976) with an average volume of 316.2 (±22.7) mL. Ninety-three percent (460/494) of CP donors at the time of plasma donation had a neutralizing IgG titer ≥1:80. Plasmapheresis-related adverse reactions occurred in 2.6% (13/504) of cases; all the reactions were mild and none required therapeutic intervention. Donors' age and COVID-19 severity were positively associated with greater antibody responses. CONCLUSION: This study demonstrates the feasibility and safety of a pilot CP program conducted in Italy. The identification of factors (ie, age and severity of COVID-19) positively associated with higher neutralizing antibody titers at the time of donation may help to optimize the selection of CP donors.

Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial.

Hyperimmune plasma from Covid-19 convalescent is a potential treatment for severe Covid-19. We conducted a multicenter one arm proof of concept interventional study. Patients with Covid-19 disease with moderate-to-severe Acute Respiratory Distress Syndrome, elevated C-reactive Protein and need for mechanical ventilation and/or CPAP were enrolled. One to three 250-300 ml unit of hyperimmune plasma (neutralizing antibodies titer ≥1:160) were administered. Primary outcome was 7-days hospital mortality. Secondary outcomes were PaO2/FiO2, laboratory and radiologic changes, as well as weaning from mechanical ventilation and safety. The study observed 46 patients from March, 25 to April, 21 2020. Patients were aged 63, 61% male, of them, 30 were on CPAP and 7 intubated. PaO2/FiO2 was 128 (SD 47). Bilateral infiltrates on chest X-ray was present in 36 patients (84%). Symptoms and ARDS duration were 14 (SD 7) and 6 days (SD 3). Three patients (6.5%) died within 7 days as compared to an expected 15% from the National Statistics and 30% from a small concurrent cohort of 23 patients. The upper one-sided 90%CI was 13.9%, allowing to reject the null hypothesis of a 15% mortality. PaO2/FiO2 increased by 112 units (95%CI 82 to142) in survivors, the chest radiogram severity decreased in 23% (95%CI 5% to 42%); CRP, Ferritin and LDH decreased by 60, 36 and 20% respectively. Weaning from CPAP was obtained in 26/30 patients and 3/7 were extubated. Five serious adverse events occurred in 4 patients (2 likely, 2 possible treatment related). In conclusion, Hyperimmune plasma in Covid-19 shows promising benefits, to be confirmed in a randomized controlled trial. This proof of concept study could open to future developments including hyperimmune plasma banking, development of standardized pharmaceutical products and monoclonal antibodies.