Evaluation of Genetic or Cellular Impairments in Type I IFN Immunity in a Cohort of Young Adults with Critical COVID-19.

Several genetic and immunological risk factors for severe COVID-19 have been identified, with monogenic conditions relating to 13 genes of type I interferon (IFN) immunity proposed to explain 4.8% of critical cases. However, previous cohorts have been clinically heterogeneous and were not subjected to thorough genetic and immunological analyses. We therefore aimed to systematically investigate the prevalence of rare genetic variants causing inborn errors of immunity (IEI) and functionally interrogate the type I IFN pathway in young adults that suffered from critical COVID-19 yet lacked comorbidities. We selected and clinically characterized a cohort of 38 previously healthy individuals under 50 years of age who were treated in intensive care units due to critical COVID-19. Blood samples were collected after convalescence. Two patients had IFN-α autoantibodies. Genome sequencing revealed very rare variants in the type I IFN pathway in 31.6% of the patients, which was similar to controls. Analyses of cryopreserved leukocytes did not indicate any defect in plasmacytoid dendritic cell sensing of TLR7 and TLR9 agonists in patients carrying variants in these pathways. However, lymphocyte STAT phosphorylation and protein upregulation upon IFN-α stimulation revealed three possible cases of impaired type I IFN signaling in carriers of rare variants. Together, our results suggest a strategy of functional screening followed by genome analyses and biochemical validation to uncover undiagnosed causes of critical COVID-19.

Allogeneic stem cell transplantation: low immunoglobulin levels associated with decreased survival.

The aim of this study was to evaluate the effects and kinetics of IgG levels after allogeneic stem cell transplantation (SCT). This study retrospectively examines 179 consecutive patients undergoing SCT between 1995 and 2002. Diagnoses included acute and chronic leukemia (n=136), solid tumors (n=11), other malignancies (n=16) and non-malignant diseases (n=16). Standard myeloablative conditioning was given to 146 patients, and 33 patients received reduced intensity conditioning. Serum samples for measurement of IgG levels were collected 3, 6 and 12 months after SCT, and then yearly. IgG levels increased after SCT throughout the study period. Factors that were associated with low IgG levels after SCT were acute graft-versus-host disease (GVHD), patient age < or =30 years, female donor-to-male recipient, not receiving anti-thymocyte globulin and type of GVHD prophylaxis. Compared to patients with moderately low or normal levels as measured twice during the first year after transplantation, patients with low IgG levels (<4 g/l) showed a decreased survival rate (54 vs 71%, P=0.04) and an increased incidence of transplant-related mortality (27 vs 9%, P<0.01). IgG levels generally increase after SCT. Persistent low levels of IgG are a risk factor for death after SCT.