Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations.

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

The histopathological spectrum of myocardial inflammation in relation to circumstance of death: a retrospective cohort study in clinical and forensic autopsies.

Interpreting a myocardial inflammation as causal, contributory or as of no significance at all in the cause of death can be challenging, especially in cases where other pathologic and/or medico-legal findings are also present. To further evaluate the significance of myocardial inflammation as a cause of death we performed a retrospective cohort study of forensic and clinical autopsy cases. We revised the spectrum of histological inflammatory parameters in the myocardium of 79 adult autopsy cases and related these to the reported cause of death. Myocardial slides were reviewed for the distribution and intensity of inflammatory cell infiltrations, the predominant inflammatory cell type, and the presence of inflammation-associated myocyte injury, fibrosis, edema and hemorrhage. Next, the cases were divided over three groups, based on the reported cause of death. Group 1 (n = 27) consisted of all individuals with an obvious unnatural cause of death. Group 2 (n = 29) included all individuals in which myocarditis was interpreted to be one out of more possible causes of death. Group 3 (n = 23) consisted of all individuals in which myocarditis was reported to be the only significant finding at autopsy, and no other cause of death was found. Systematic application of our histological parameters showed that only a diffuse increase of inflammatory cells could discriminate between an incidental presence of inflammation (Group 1) or a potentially significant one (Groups 2 and 3). No other histological parameter showed significant differences between the groups. Our results suggest that generally used histological parameters are often insufficient to differentiate an incidental myocarditis from a (potentially) significant one.

Tissues attached to retrieved leadless pacemakers: Histopathological evaluation of tissue composition in relation to implantation time and complications.

BACKGROUND: Leadless pacemakers (LPs) have proven safe and effective, but device revisions remain necessary. Either replacing the LP or implanting a new adjacent LP is feasible. Replacement seems more appealing, but encapsulation and tissue adhesions may hamper the safety and efficacy of LP retrieval. OBJECTIVE: We determined the incidence and cellular characteristics of tissue adherent to retrieved LPs and the potential implications for end-of-life strategy. METHODS: All 15 consecutive successful Nanostim LP retrievals in a tertiary center were included. We assessed the histopathology of adherent tissue and obtained clinical characteristics. RESULTS: Adherent tissue was present in 14 of 15 retrievals (93%; median implantation duration 36 months; range 0-96 months). The tissue consisted of fibrosis (n = 2), fibrosis and thrombus (n = 9), or thrombus only (n = 3). In short-term retrievals (<1 year), mostly fresh thrombi without fibrosis were seen. In later retrievals, the tissue consisted of fibrosis often with organizing or lytic thrombi. Fibrosis showed different stages of organization, notably early fibrocellular and later fibrosclerotic tissue. Inflammatory cells were seen (n = 4) without signs of infection. Tricuspid valve material was retrieved in 1 patient after 36 months, resulting in increased tricuspid regurgitation. CONCLUSION: Our results suggest that fibrosis and thrombus adherent to LPs are common and encapsulate the LP as seen in transvenous pacemakers. LPs may adhere to the tricuspid valve or subvalvular apparatus affecting retrieval safety. The end-of-life strategy should be optimized by incorporating risk stratification for excessive fibrotic encapsulation and adhesions.

Proven Fatal Invasive Aspergillosis in a Patient with COVID-19 and Staphylococcus aureus Pneumonia.

There is increasing attention for opportunistic pathogens such as Aspergillus fumigatus complicating SARS-CoV-2 infections in the critically ill. For invasive fungal disease, establishing a clear diagnosis can be challenging due to the invasiveness of diagnostic procedures required for a proven case. Here we present one of the first proven cases of COVID-19-associated pulmonary aspergillosis by positive culture of post-mortem lung biopsy.

Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy. METHODS: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course. FINDINGS: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41-78). Median disease course (time from onset of symptoms to death) was 22 days (range 5-44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5-44]; ten patients with neutrophilic plugs, 21 days [5-44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets.. INTERPRETATION: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19. FUNDING: Amsterdam UMC Corona Research Fund.