COVID-19 is associated with bystander polyclonal autoreactive B cell activation as reflected by a broad autoantibody production, but none is linked to disease severity.

Coronavirus disease 2019 (COVID-19) is associated with autoimmune features and autoantibody production in a small subset of the population. Pre-existing neutralizing antitype I interferons (IFNs) autoantibodies are related to the severity of COVID-19. Plasma levels of IgG and IgM against 12 viral antigens and 103 self-antigens were evaluated using an antibody protein array in patients with severe/critical or mild/moderate COVID-19 disease and uninfected controls. Patients exhibited increased IgGs against Severe acute respiratory syndrome coronavirus-2 proteins compared to controls, but no difference was observed in the two patient groups. 78% autoreactive IgGs and 93% autoreactive IgMs were increased in patients versus controls. There was no difference in the plasma levels of anti-type I IFN autoantibodies or neutralizing anti-type I IFN activity of plasma samples from the two patient groups. Increased anti-type I IFN IgGs were correlated with higher lymphocyte accounts, suggesting a role of nonpathogenic autoantibodies. Notably, among the 115 antibodies tested, only plasma levels of IgGs against human coronavirus (HCOV)-229E and HCOV-NL63 spike proteins were associated with mild disease outcome. COVID-19 was associated with a bystander polyclonal autoreactive B cell activation, but none of the autoantibody levels were linked to disease severity. Long-term humoral immunity against HCOV-22E and HCOV-NL63 spike protein was associated with mild disease outcome. Understanding the mechanism of life-threatening COVID-19 is critical to reducing mortality and morbidity.

Complex considerations - Fever and pancytopenia after solid organ transplantation.

This case describes a 42-year-old man who underwent kidney transplantation and developed fevers, pancytopenia, and elevated liver function tests starting on post-operative day 9. An extensive microbiologic and molecular workup was performed, ultimately leading to a diagnosis of donor-derived toxoplasmosis with associated hemophagocytic lymphohistiocytosis in the recipient. This case highlights the potential for post-transplant toxoplasmosis in high-risk mismatch (D+/R-) recipients, as well as the role of Toxoplasma-targeted prophylaxis in such patients.

Early steps to kidney transplantation among persons with HIV and end-stage renal disease in ESRD network 6.

INTRODUCTION: End-stage renal disease is a significant cause of morbidity and mortality in persons with HIV (PWH). Limited data exist on access to kidney transplantation for this population. METHODS: A dataset inclusive of incident dialysis patients between 2012 and 2016 with follow-up through December 2017 that identifies PWH and the general dialysis population of Network 6 (Georgia, North Carolina, South Carolina) was created through merging the United States Renal Data System with the southeastern early transplant access registry. Early steps to kidney transplantation and patient and dialysis facility-level characteristics that serve as barriers to transplantation were described. RESULTS: Twenty-three thousand four hundred fourteen patients were identified; 469 were PWH. Compared to non-HIV individuals, PWH were younger (49 vs. 58 years, p < 0.001), predominantly Black (87% vs. 56% p < 0.001) and male (72% vs. 56% p < 0.001). PWH were less likely to be referred to kidney transplant within 1 year of starting dialysis (36% vs. 41% p < 0.001) and waitlisted within 1 year of evaluation-start (14% vs. 30%, p = 0.05). PWH (vs. non-PWH) waited longer for referral, evaluation-start, and waitlisting and in multivariable analysis; HIV positivity was associated with a lower probability of referral (hazard ratios [HR]: 0.70; 95% confidence intervals [CIs]: 0.62-0.80), evaluation (HR 0.66; 95% CI: 0.55-0.80), and waitlisting (HR 0.29; 95% CI: 0.20-0.41). CONCLUSIONS: Targeted interventions are needed to improve access to kidney transplants, particularly in waitlisting, for PWH.

Clinical characteristics and outcomes of toxoplasmosis among transplant recipients at two US academic medical centers.

Toxoplasma gondii can cause severe opportunistic infection in immunocompromised individuals, but diagnosis is often delayed. We conducted a retrospective review of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients with toxoplasmosis between 2002 and 2018 at two large US academic transplant centers. Patients were identified by ICD-9 or ICD-10 toxoplasmosis codes, positive Toxoplasma polymerase chain reaction test result, or pathologic diagnosis. Data were collected regarding transplant type, time from transplant to toxoplasmosis diagnosis, clinical and radiographic features, and mortality at 30 and 90 days. Twenty patients were identified: 10 HSCT recipients (80% allogeneic HSCT) and 10 SOT recipients (60% deceased donor renal transplants). Rejection among SOT recipients (70%) and graft-versus-host disease (GVHD) prophylaxis among HSCT recipients (50%) were frequent. Median time from transplant to toxoplasmosis diagnosis was longer for SOT than HSCT (1385 vs. 5 days, P-value .002). Clinical manifestations most commonly were encephalitis (65%), respiratory failure (40%), renal failure (40%), and distributive shock (40%). Cohort 30-day mortality was 45%, and 90-day mortality was 55%. Diagnosis was postmortem in 25% of the cohort. Further evaluation of toxoplasmosis screening is needed for noncardiac SOT recipients, HSCT recipients with GVHD, and periods of increased net immunosuppression.

Impacts of plasma microbial lipopolysaccharide translocation on B cell perturbations and anti-CD4 autoantibody production in people with HIV on suppressive antiretroviral therapy.

BACKGROUND: . Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear. METHODS: . Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG-producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro. RESULTS: . Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro. CONCLUSION: . Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.

Hepatitis C Care Continuum in a Human Immunodeficiency Virus (HIV) Positive Cohort: Data From the HIV Atlanta Veterans Affairs Cohort Study.

BACKGROUND: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection is associated with accelerated progression to cirrhosis, end-stage liver disease, and liver-associated death. It is fortunate that curative direct-acting antivirals for the treatment of HCV are widely available in the VA healthcare system. We attempted to identify, evaluate, and treat all HIV/HCV-coinfected persons at the Atlanta VA Healthcare System. METHODS: Human immunodeficiency virus/HCV-coinfected persons at Atlanta VA between 2015 and 2018 were identified using the HIV Atlanta Veterans Affairs Cohort Study and Hepatitis C VA Clinical Case Registry. Retrospective reviews of each electronic medical record were conducted by the hepatitis C clinical team for validation. The primary end point was achieving sustained virologic response. RESULTS: One hundred thirty-eight veterans with HIV and hepatitis C viremia were identified. One hundred twenty-five (90%) were evaluated for treatment and 113 (91%) were initiated on direct-acting antiviral therapy. Median age at initiation of treatment was 60 years and the majority were black race (90%). Genotype 1a was most common (70%) and 41% had compensated cirrhosis. One hundred eight completed treatment and 96% achieved sustained virologic response. Six veterans had virologic relapse; 4 had treatment-emergent resistance mutations in the NS5a gene. Mean CD4 was 580 cells/mm3 with HIV viral suppression in 82% of the cohort. In those not treated, unstable housing (25%), active substance use (31%), and psychiatric conditions (42%) were identified barriers to care. CONCLUSIONS: Through a concerted, systematic effort, over 80% of HIV/hepatitis C persons in the Atlanta VA have been initiated on treatment for hepatitis C, 96% of which have been cured.

Metabolic Syndrome in HIV/HCV Co-infected Patients.

PURPOSE OF REVIEW: We review the scope and burden of metabolic syndrome in HIV/HCV co-infected patients, risk factors and potential mechanisms driving the increased cardio-metabolic risk in this population, and discuss relevant clinical considerations for management in the era of highly effective antiretroviral therapy (ART) and curative anti-HCV direct-acting antivirals. RECENT FINDINGS: HIV/HCV co-infected patients are at elevated risk of metabolic syndrome, attributed to (1) patient-specific factors, (2) viral-mediated effects, and (3) ART exposure. Risk factors for cardio-metabolic disorders are common in this population and include poor socioeconomic conditions, substance use, cardiovascular comorbidities, and liver/kidney disease. Chronic HIV/HCV infection induces an inflammatory and immune activated state in the host leading to alterations in glucose and lipid metabolism. Selection of life-saving ART must carefully consider the differential metabolic risk associated with each drug class and agent, such as dyslipidemia, hyperglycemia and insulin resistance, weight gain and hypertension. Emerging evidence supports metabolic derangements in chronic HCV may be improved by viral eradication with direct-acting antivirals, however, additional study in HIV/HCV co-infected patients is needed. SUMMARY: Future research programs should aim to better characterize metabolic syndrome in HIV/HCV co-infected patients with the goal of improved screening, treatment and prevention.