Structured abstract for full paperBackgroundAfter recovery from COVID-19, most patients have anti-SARS-CoV-2 neutralizing antibodies. Their convalescent plasma could be an inexpensive and widely available treatment for COVID-19.MethodsThe Convalescent-plasma-for-COVID (ConCOVID) study was a randomized trial comparing convalescent plasma with standard of care therapy in patients hospitalized for COVID-19 in the Netherlands. Patients were randomized 1:1 and received 300ml of plasma with anti-SARS-CoV-2 neutralizing antibody titers of at least 1:80. The primary endpoint was day-60 mortality and key secondary endpoints were hospital stay and WHO 8-point disease severity scale improvement on day 15.ResultsThe trial was halted prematurely after 86 patients were enrolled. Although symptomatic for only 10 days (IQR 6-15) at the time of inclusion, 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline. A SARS-CoV-2 plaque reduction neutralization test showed neutralizing antibodies in 44 of the 56 (79%) patients tested with median titers comparable to the 115 donors (1:160 vs 1:160, p=0.40). These observations caused concerns about the potential benefit of convalescent plasma in the study population and after discussion with the data safety monitoring board, the study was discontinued. No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care.ConclusionMost COVID-19 patients already have high neutralizing antibody titers at hospital admission. Screening for antibodies and prioritizing convalescent plasma to risk groups with recent symptom onset will be key to identify patients that may benefit from convalescent plasma. Clinicaltrials.gov: NCT04342182

In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.

Exposure (AUC(0-6 h)) to rifampicin was 53% lower in Indonesian patients with TB and DM, compared with patients with TB only. Patients with TB and DM who have a higher body weight may need a higher dose of rifampicin.

As patients with diabetes mellitus are at increased risk of developing tuberculosis, we hypothesized that this susceptibility to mycobacterial infection is due to a defective Th1-cytokine response. To explore this hypothesis, we examined four groups of subjects in Indonesia: 23 patients with tuberculosis, 34 patients with tuberculosis and diabetes, 32 patients with diabetes only and 36 healthy controls. Ex-vivo production of interferon (IFN)gamma, tumour necrosis factor-alpha and interleukin (IL)-1beta, 6, 10, -12 and -4 was measured following stimulation with Mycobacterium tuberculosis, Escherichia coli lipopolysaccharide and phytohaemagglutinin. Patients with active tuberculosis were found to have lower IFNgamma levels and a higher production of other pro-inflammatory cytokines and IL-4, both in the presence and absence of diabetes. Diabetes patients without tuberculosis, however, showed strongly reduced non-specific IFNgamma production, which is essential for inhibition of the initial growth of M. tuberculosis. Our data suggest that a defective non-specific immune response in diabetes may contribute to an increased susceptibility to develop tuberculosis.