ABSTRACT
Background: Trials on convalescent plasma (CP) for hospitalized patients with COVID-19 have not demonstrated clear benefits. However, data on outpatients with early symptoms are limited. We studied if treatment with CP reduces disease burden of outpatients treated in the first 7 days of symptoms. Methods: Two double blind randomized trials (NCT04621123, NCT04589949) were merged. Pooling of data started when <20% of their predefined sample size had been recruited. A Bayesian adaptive individual patient data meta-analysis was implemented. Analyses were done with Bayesian proportional odds and logistic models, where odds ratios(OR)<1.0 indicate a favorable outcome for CP. A DSMB monitored the accumulating data for efficacy. Patients aged ≥50, diagnosed with COVID-19 and symptomatic for ≤7days were eligible for participation. The intervention was one unit (200-300mL) of CP with a predefined minimum level of antibodies. The two primary endpoints were (a) a 5-point disease severity scale (fully recovered by day 7 or not, hospital or ICU admission and death) and (b) a composite of hospitalization or death. Secondary endpoints were efficacy in patients with ≤5days of symptoms and time to full symptom resolution. Results: Of 797 patients included, 390 received CP and 392 placebo. They had a median age of 58, 1 comorbidity, symptoms for 5 days and 93% tested negative for SARS-CoV-2 S-protein IgG antibodies. 74 patients were hospitalized, 6 required mechanical ventilation and 3 died. The OR of CP for an improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311). The OR for hospitalization or death was 0.919 (CI 0.592-1.416). The effect of CP on hospital admission or death was largest in patients with ≤5days of symptoms (OR 0.658, 95% CI 0.394-1.085). CP did not decrease the time to full symptom resolution (p=0.62). Conclusion: Treatment with CP of outpatients in the first 7 days of symptoms did not improve outcome of COVID-19. The possible beneficial effect in patients with ≤5days of symptoms requires further study.
ABSTRACT
Background: Convalescent plasma could be an inexpensive and widely available drug for COVID-19 patients. Reports on its effectiveness are inconclusive. We collected convalescent plasma with high titers of neutralizing anti-SARS-CoV-2 antibodies effectively blocking SARS-CoV-2 infection and assessed their clinical and viro-immunological responses in COVID-19 patients with severe disease. Methods: In a multicentre open-label randomized clinical trial in 14 secondary and academic hospitals in the Netherlands, included patients were admitted for COVID-19 with SARS-CoV-2 detected by PCR and not on mechanical ventilation for >96hours. Convalescent plasma donors were selected based on SARS-CoV-2 plaque reduction neutralization test (PRNT50) result of ≥1:80. Primary outcome was day 60 mortality. Secondary outcomes were disease severity, inflammatory and virological markers. Results: Included patients were 72% male, median 63 years (IQR 56-74) and with median 10 days of symptoms (IQR 6-15) at inclusion when they were randomized to convalescent plasma or standard of care. We found no significant difference in mortality at day 60 by using 300mL of convalescent plasma (median PRNT50 1:640) between the arms after adjustment (OR: 0.95, 95%CI: 0.20-4.67). Improvements in WHO COVID-19 disease severity scores at day 15 (OR: 1.30, 95%CI 0.52-3.32) and time to discharge (HR: 0.88, 95%CI: 0.49-1.60) were also comparable. The vast majority of patients already had potent neutralizing anti-SARS-CoV-2 antibodies at hospital admission and at comparable titers as the carefully selected plasma donors. No effect of convalescent plasma on viral clearance in the respiratory tract, anti- SARS-CoV-2 antibody development or changes in serum pro-inflammatory cytokine levels were observed. After the inclusion of 86 patients and per DSMB recommendation, we decided to interrupt the study for futility. Conclusion: Convalescent plasma treatment in this patient group did not improve survival or disease course, nor did it alter relevant virological and immunological parameters. Together, these data indicate that the variable effectivity observed in trials on convalescent plasma for COVID-19 may be explained by the timing of treatment and varying levels of preexisting anti-SARS-CoV-2 immunity in patients. It also substantiates that convalescent plasma should be studied as early as possible in the disease course or at least preceding the start of an autologous humoral response. (Clinicaltrials.gov: NCT04342182).
ABSTRACT
Background: After SARS-CoV-2 reached the Netherlands in February 2020, rapid interventions were taken to mitigate viral spread and optimise care for COVID-19 patients. Lockdowns and downscaling of regular healthcare practices were necessary to scale up COVID-19-related care. The effect of these interventions on HIV care are uncertain. We assessed the impact of the nationwide lockdown in March and May during the first COVID-19 wave on HIV diagnosis and linkage to care. Methods: An observational study was conducted at the Erasmus MC, a regional reference tertiary hospital in the Netherlands. All patients ≥ 18 years presenting with HIV indicator conditions (ICs) were identified in electronic patient records, using an automated identification system for ICD-10 and health insurance codes. Primary outcomes measured were the number of HIV tests performed, number of HIV ICs and corresponding HIV testing rates, and new HIV diagnoses before, during and after lockdown. Results: From January to April, all newly registered diagnoses decreased by 35%, and in patients referred for HIV ICs by 69% (figure 1). The proportion of patients presenting with HIV ICs that were adequately tested for HIV remained relatively stable, especially where HIV testing is standardised, even during lockdown in March, April and May when a cumulative 328 proven or suspected COVID-19 patients were admitted. The absolute number of HIV tests performed during the first half year of 2020 was 13% lower than the same period in 2019, and new HIV patient referrals dropped 67%. The number of HIV IC, HIV testing rates and HIV referrals showed recovery after the lockdown. Conclusion: The first two pillars of the HIV care continuum were affected by the lockdown during the COVID-19 pandemic. Standardisation of HIV testing could prevent diagnostic delays to a certain extent. With an eye on subsequent COVID-19 waves, these data indicate that maintaining focus on adequate identification and testing of patients with undiagnosed HIV is essential to prevent unwanted declines affecting the 95-95-95 goals.
ABSTRACT
Background: Anti-CD 20 therapy is widely used in the treatment of autoimmune and hematological diseases. An absent antibody response to COVID-19 puts patients at high risk for a poor outcome or a protracted disease course. These patients may benefit from antibody-based therapy. We describe our experience with convalescent plasma (ConvP) as a source of antibody-based therapy in 5 consecutive B-cell depleted patients admitted with COVID-19. Methods: B-cell depleted patients with PCR confirmed COVID-19, symptomatic for at least 12 days were informed about the possibility of ConvP therapy. ConvP was selected based on virus neutralizing antibody titers (PRNT50 using a whole SARS-CoV-2 neutralization assay) of 1:160 or higher. 300 or 600mL was transfused and in non-responders 600ml ConvP was repeated when no clinical response was observed. SARS-CoV-2 antibodies (Wantai ELISA detecting SARS-CoV-2 RBD antibodies and PRNT50) were measured preceding and after transfusion. Results: 5 B-cell depleted patients were admitted to a general COVID-19 ward. B-cell depletion was the result of rituximab (n=4) and blinatumomab (n=1) for lymphoma, auto-immune disease or Acute Lymphoblastic Leukemia. They had been sick with COVID-19 for a median of 33 days (Range 13-84 days). All had a serum PRNT50 titer <1:20 and were without detectable antibodies against RBD by a Wantai ELISA on the day of transfusion. 1 patient received 300mL and 4 patients received 600mL of ConvP on day 1 with a median PRNT50 titer in donor plasma of 1:640 (Range 1:160-1:1280). All patients showed obvious clinical improvement after the first transfusion. All patients also showed pulmonary improved on a chest CT-scan. All patients seroconverted with a median PRNT50 24 hours after transfusion of 1:40 (Range 1:20-1:80) and a median positive Wantai total Ig OD ratio of 12.63 (range 3,55-18,39) (Figure 1). PCR became negative in all patients within 16 days after transfusion and isolation could be lifted at that time. Conclusion: We observed prompt clinical and virological recovery after therapy with ConvP of B-cell depleted patients with a very protracted COVID-19 disease course. Our observation provide a proof of concept that in carefully selected patients, antibody-based therapy can be very effective. 24 hours after the transfusion of 600mL of ConvP, all patients had seroconverted to a PRNT50 titer of 1:20 to 1:80. We therefore suggest an initial dose of 600mL of ConvP with a PRNT50 of at least 1:320.
ABSTRACT
Background: Anti-CD20 therapy is used to treat autoimmune and hematological diseases. An absent or delayed antibody response against SARS-CoV-2 puts patients at risk for a protracted and severe disease course. These patients may benefit from antibody-based therapy of which convalescent plasma (ConvP) is the most broadly available source. Methods: ConvP from donors with SARS-CoV-2 antibody titers was used when their plaque reduction neutralization test (PRNT50) showed a PRNT50 titer of at least 1:160. When PRNT50 results were not yet available, an in-house RBD ELISA was used to select the donors with the 10% highest titers. Preceding and following transfusion, SARS-CoV-2 antibodies were measured (Wantai Ig SARSCoV-2 RBD antibodies and PRNT50). All but 6 patients received 2 units of 300mL of ConvP. Two non-responders received a second 2x300ml transfusion while 5 patients were successfully treated with only 300ml ConvP. Results: 22 B-cell depleted patients admitted with COVID-19 were treated with ConvP. B-cell depletion was the result of Rituximab (n=19), Obinutuzumab (n=1), XLA (n=1) or Blinatumomab (n=1) for lymphoma, auto-immune disease or ALL. Patients had been sick for a median of 26 days (IQR 18-34.5 days) and all were SARS-CoV-2 RBD antibody negative on the day of transfusion. The plasma units had a median PRNT50 titer of 1:640 (IQR 1:160-1:1280). 19 of 22 patients showed clear clinical improvement after transfusion and could be discharged from the hospital. 3 patients died of which 1 had treatment refractory extensive idiopathic pulmonary fibrosis preceding COVID-19. All patients seroconverted to a median total Wantai Ig OD ratio of 18.39 (IQR 11.245-18.41), Figure 1. PRNT50 titers increased from <1:20 preceding transfusion to 1:40 (IQR 1:20-1:80) after transfusion. One patient quickly recovered clinically after transfusion but it took 10 weeks to become PCR negative. Conclusion: Prompt clinical and virological recovery after ConvP transfusion was observed in the large majority of B-cell depleted antibody negative patients admitted with COVID-19. Our observation shows that for carefully selected patients, antibody-based therapy can be effective. After transfusion of 600mL of ConvP, all patients had seroconverted to high anti-RBD antibody titers and detectable PRNT50 titers of 1:20 or higher. Based on these observations, we suggest an initial dose of 600mL of ConvP.