Background Genetic predisposition to COVID-19 may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. Aim To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. Methods This retrospective case control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the United States, Hungary, and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. Results In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls (11% vs. 19%, OR: 0.54 [0.41, 0.72], p < 0.0001). Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR: 2.87 [1.42, 5.78], p = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, p < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, p = 0.01) and maximum CRP (r = 0.16, p = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. Conclusions In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7  MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of host genetics in different stages of COVID-19 infection.

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Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4 + T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4 + T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19 + B-cells, switched memory B-cells, naïve CD8 + T-cells, and a higher frequency of EM CD8 + T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.

PURPOSE Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer. METHODS Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC. RESULTS In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively. CONCLUSION Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.

Results: From 2000-2015 a total of 57 cases of tularemia were reported in Armenia. Of these, 84.2% were male and 78.9% were from rural areas. Distribution of age groups were: ≤18-24.6%, 19-30-54.4%, 31-44-14.01%, ≥45-7.0%. The most common symptoms include: fatigue (n=52, 91%), fever (n=45, 78.9%), pharyngitis (n=40, 70.2%), headache (n=27, 47.4%), hepatomegaly (n=5, 8.8%), and splenomegaly (n=2, 3.5%). The average hospitalization stay was 35.7 days. The most frequent clinical forms were bubonic (n=28, 49.1%), oropharyngeal (n=21, 36.9%) and oculoglandular (n=8, 14%). In all patients enlargement of the lymph nodes was reported, most frequently the cervical ones (n=52, 91.2%). Ultrasound imaging showed hepatosplenomegaly in three cases (5.2%). Antibiotics were given prior to admission for 26 (45.6%) patients and during hospitalization for 54 (94.8%). Twenty-three (40.4%) received monotherapy while 31 (54.4%) received combined therapy. Diagnosis was based on agglutination reaction in most cases (n=50, 87.7%). For seven patients, diagnosis was made based on only clinical-epidemiological history without laboratory confirmation (n=7, 12.3%). Surgical treatment was used for 8.8% patients. Presence of rodents at household was mentioned by 14 (24.6%), while four (7%) noted a vector bite and three (5.3%) had contact with rodents. Over half (56.2%) had centralized water. Conclusion:Most of the patients were male and from rural areas. People from 19-30 years of age were more likely to contract tularemia. Approximately half of the patients had the bubonic form, mainly cervical. Other potential risk factors that might explain a long hospitalization (e.g. suppressed immune system, treatment failure etc.), should be a topic for future investigations.