Interferon-α2 Auto-antibodies in Convalescent Plasma Therapy for COVID-19

Purpose To study the effect of interferon-α2 auto-antibodies (IFN-α2 Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α2 Abs transfer during convalescent plasma treatment. Methods Sera from healthy controls, cases of COVID-19, and other respiratory illness were tested for IFN-α2 Abs by ELISA and a pseudo virus–based neutralization assay. The effects of disease severity, sex, and age on the risk of having neutralizing IFN-α2 Abs were determined. Longitudinal analyses were performed to determine association between IFN-α2 Abs and survival and viral load and whether serum IFN-α2 Abs appeared after convalescent plasma transfusion. Results IFN-α2 neutralizing sera were found only in COVID-19 patients, with proportions increasing with disease severity and age. In the acute stage of COVID-19, all sera from patients with ELISA-detected IFN-α2 Abs (13/164, 7.9%) neutralized levels of IFN-α2 exceeding physiological concentrations found in human plasma and this was associated with delayed viral clearance. Convalescent plasma donors that were anti-IFN-α2 ELISA positive (3/118, 2.5%) did not neutralize the same levels of IFN-α2. Neutralizing serum IFN-α2 Abs were associated with delayed viral clearance from the respiratory tract. Conclusions IFN-α2 Abs were detected by ELISA and neutralization assay in COVID-19 patients, but not in ICU patients with other respiratory illnesses. The presence of neutralizing IFN-α2 Abs in critically ill COVID-19 is associated with delayed viral clearance. IFN-α2 Abs in COVID-19 convalescent plasma donors were not neutralizing in the conditions tested.

Virological measures and factors associated with outcomes, and missing outcome data in HIV clinical trials: a methodological study

BackgroundTo evaluate the definition of HIV virological outcomes in the literature and factors associated with outcomes and missing outcome data.MethodsWe conducted a methodological review of HIV RCTs using a search (2009–2019) of PubMed, Embase and the Cochrane Central Register of Controlled Trials.Only full-text, peer-reviewed, randomised controlled trials (RCTs) that measured virological outcomes in people living with HIV, and published in English were included.We extracted study details and outcomes. We used logistic regression to identify factors associated with a viral threshold ≤50 copies/mL and linear regression to identify factors associated with missing outcome data.ResultsOur search yielded 5847 articles; 180 were included. A virological outcome was the primary outcome in 73.5% of studies. 89 studies (49.4%) used virological success. The remaining used change in viral load (VL) (33 studies, 18.3%); virological failure (59 studies, 32.8%); or virological rebound (9 studies, 5.0%). 96 studies (53.3%) set the threshold at ≤50 copies/mL; and 33.1% used multiple measures.Compared with government and privately funded studies, RCTs with industry funding (adjusted OR 6.39; 95% CI 2.15 to 19.00; p<0.01) were significantly associated with higher odds of using a VL threshold of ≤50 copies/mL. Publication year, intervention type, income level and number of patients were not associated with a threshold of ≤50 copies/mL. Trials with pharmacological interventions had less missing data (β=−11.04; 95% CI −20.02 to −1.87; p=0.02).DiscussionCountry source of funding was associated with VL threshold choice and studies with pharmacological interventions had less missing data, which may in part explain heterogeneous virological outcomes across studies. Multiple measures of VL were not associated with missing data. The development of formal guidelines on virological outcome reporting in RCTs is needed.

Pneumonia-targeted lopinavir/ritonavir-based treatment for patients with COVID-19: an early-period retrospective single center observational study

Background Robust evidenced treatment strategy for Coronavirus disease 2019 (COVID-19) has not been established yet. Early, targeted, comprehensive management approach can be essential. Methods A lopinavir/ritonavir (LPV/r)-based antiviral treatment was administered to the patients with computed tomography (CT)-documented pneumonia. Medical records of patients with COVID-19, previously discharged or hospitalized for ≥ 21 days at the Seoul Medical Center from January 29 to April 15, 2020 were reviewed to analyze clinical and virological outcomes. Patients were divided into two groups (PCR-Negative conversion group vs. Non-negative conversion group and requiring oxygen group vs. Non-requiring oxygen group). Results In total, 136 patients with a mean age of 41.8 ± 18.2 years were included with median 3-day delay of hospitalization after illness. Thirteen (9.56%) were initially asymptomatic, and 5 (3.67%) were persistently asymptomatic. Eighty-five (62.5%) had CT-documented pneumonia, 94% of whom received LPV/r treatments. A total of 53 patients (38.97%) had negative polymerase chain reaction (PCR) results within 28 days. Eight (9.4%) out of 85 pneumonic patients received oxygen supplementation. Patients with initial lower respiratory symptoms showed significant delay in PCR negative conversion (> 28 days) (odds ratio [OR] 0.166; 95% confidence interval [CI] 0.067–0.477; P < 0.001). However, antiviral treatment for pneumonic patients was significantly related with early conversion within 28 days (OR 3.049; 95% CI 1.128–8.243; P = 0.028). Increasing age increased the likelihood of oxygen supplementation requirement in the pneumonic patient group (OR 1.108; 95% CI 1.021–1.202; P = 0.014). Conclusions Early, pneumonia targeted LPV/r-based antiviral therapy resulted in a significantly higher probability of negative conversion of PCR within 28 days compared to symptomatic treatment.

Interferon-α Auto-Antibodies in Convalescent Plasma Therapy for COVID-19

Purpose: To study the effect of Interferon-α auto-antibodies (IFN-α Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α Abs transfer during convalescent plasma treatment.Methods: Sera from cases of COVID-19 and other respiratory illness were tested for IFN-αAbs by ELISA and bioassay. IFN-α Abslevels were compared between critically, severely and moderately ill groups in both acute and convalescent stages. Longitudinal analyses were performed to determine whether IFN-α Abs levels change after convalescent plasma transfusion.Results: Critically ill COVID-19 caseshad significantly higher IFN-α Abs detection rate and levels compared tonon-COVID-19 controls.Neutralizing IFN-α Abs levels were found in 1 out of 118plasma donors.Plasma from 2 positive donors was administered to 5 patients, with no subsequent elevation of IFN-α Abs levels in the recipients. Neutralizing levels of IFN-α Abswere associated with delayed viral clearance from the respiratory tract.Conclusions: IFN-α Abs can be detected by ELISA in critical, severe, moderate and mild COVID-19 cases in both the acute and convalescent stages of disease. The presence of neutralizing IFN-α Abs in critically ill COVID-19 is associated with delayed viral clearance. Levels of IFN-α Abs inCOVID-19 convalescent plasma donorsare likely too low to be clinically relevant to the recipients.

Dual Antiretroviral Therapy—All Quiet Beneath the Surface?

Infection with the human immunodeficiency virus (HIV) is characterized by progressive depletion of CD4+ lymphocytes cells as a result of chronic immune activation. Next to the decreases in the number of CD4+ cells which leads to opportunistic infections, HIV-related immune activation is associated with several prevalent comorbidities in the HIV-positive population such as cardiovascular and bone disease. Traditionally, combination antiretroviral therapy (cART) consists of three drugs with activity against HIV and is highly effective in diminishing the degree of immune activation. Over the years, questions were raised whether virological suppression could also be achieved with fewer antiretroviral drugs, i.e., dual- or even monotherapy. This is an intriguing question considering the fact that antiretroviral drugs should be used lifelong and their use could also induce cardiovascular and bone disease. Therefore, the equilibrium between drug-induced toxicity and immune activation related comorbidity is delicate. Recently, two large clinical trials evaluating two-drug cART showed non-inferiority with respect to virological outcomes when compared to triple-drug regimens. This led to adoption of dual antiretroviral therapy in current HIV treatment guidelines. However, it is largely unknown whether dual therapy is also able to suppress immune activation to the same degree as triple therapy. This poses a risk for an imbalance in the delicate equilibrium. This mini review gives an overview of the current available evidence concerning immune activation in the setting of cART with less than three antiretroviral drugs.

Transmitted Donor Immunology Not Infection: Common Persistence of Donor Hepatitis C Antibody Production in Aviremic Lung Transplant Recipients

Since 2018 The American Society of Transplant has recommended that Hepatitis C Virus seropositive positive, non-viremic donors (HCVAb+/NAT-) be considered non-infectious and safe for transplantation. This report describes clinical outcomes and HCV serological and virological outcomes following lung transplantation (LTx) utilizing such donors. This retrospective cohort study describes seven HCVAb+/NAT- donors used for bilateral LTx. Donor information was sourced from the national organ donation service and recipient information from the institutional LTx database. Seven deceased donors (three female, median age 53, range 37-63 years) acquired HCV from injecting drug use (n=4), blood products (n=1), unknown (n=1). Four donors had been previously treated and cleared of HCV (sustained virological response at 24 weeks) before death. Seven recipients (2 female, median age 56, range 51-71 years), with pulmonary fibrosis (n=4), re-do LTx (n=3), were waitlisted a median of 87 days (range 8-362). At post-LTx follow up, six of seven are alive with excellent graft function at a median 1625 days (range 779-2582). No patient developed clinical, biochemical or virological evidence of HCV infection, however five recipients demonstrated persistent HCVAb+ (all consistently NAT-) for a median 414 days (range 332-872) post-LTx. Two patients HCVAb sero-reverted at d731 and d1461. Two other recipients remained HCVAb- at d1621 and d1398 on repeat testing. There was no evidence of HCV transmission to seven LTx recipients from HCVAb+/NAT- life-saving lung donors, however persistent HCV Ab positivity was seen in 5 LTx recipients with two demonstrating remote sero-reversion. We postulate this may be a form of Passenger Lymphocyte Syndrome.