A Retrospective Review of Secondary Hemophagocytic Lymphohistiocytosis (HLH) and Dengue-associated HLH from a Teaching Hospital in Singapore.

Real-world data on the outcome of Asian patients with secondary hemophagocytic lymphohistiocytosis (HLH), especially on dengue-associated HLH, are limited to small case series. This is a retrospective records review of adult patients with secondary HLH between 2015 and 2020. Thirty-two adult patients were followed up for a median of 6.6 months (range 0.1 - 75 months). 15 had underlying lymphomas, and 12 had viral infections. Hemophagocytosis was seen in 28 of 29 patients with a bone marrow biopsy. 100% and 76.5% of patients with and without an underlying malignancy required HLH-directed therapy and blood product transfusion. 12 of 15 patients with lymphomas were treated with additional chemotherapy. Patients with malignancy-associated HLH had poorer survival than non-malignancy-associated HLH (median overall survival (OS) 1.5 months versus not reached, p-value 0.003). The 1-year survival rates of patients with malignancy-associated HLH, HLH with unknown etiologies, and infection-associated HLH were 0.133 (95% CI: 0.036 - 0.484), 0.400 (95% CI: 0.137 - 1.000) and 0.833 (95% CI: 0.647 - 1.000), respectively. Malignancy significantly increased the risk of death compared to infection-associated HLH (HR 9.37, p-value 0.003). Eight patients were diagnosed with dengue-associated HLH with a median HSCORE of 240 (98-99% probability of HLH). Their mean ferritin was 34,740 ng/mL. Three patients required blood product transfusion, 5 required corticosteroids and/or etoposide, with a median duration of treatment of 31 days. Their overall survival rate was 87.5%. Our study highlights the stark contrast in the survival of secondary HLH patients with and without an underlying malignancy. We also present one of the world's most extensive case series of dengue-associated HLH.

Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody.

Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enriched Ackr1 expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.

Direct oral anticoagulants in atrial fibrillation following cardiac surgery: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) have been increasingly used as anticoagulation therapy in the postoperative period. However, their effectiveness in post-cardiac surgical atrial fibrillation is yet to be determined. METHODS: We conducted a meta-analysis, searching three international databases from 1 January 2003 to 26 January 2022 for studies reporting on DOACs in at least 10 adult patients (>18 yr of age) with post-cardiac surgical atrial fibrillation. The primary outcomes were major neurological events and bleeding; secondary outcomes were mortality, hospital and ICU length of stay, cost, and other complications from therapy. We included studies of any design, including RCTs, cohort studies with and without propensity score matching methods, and single-armed case series. RESULTS: Twelve studies (8587 DOACs; 8315 warfarin) were included in this meta-analysis. The incidences of postoperative bleeding and major neurological events with DOACs were 7.3% (95% confidence interval [CI]: 3.4-14.7%) and 2.2% (95% CI: 0.9-4.9%), respectively. The incidence of major neurological events was lower in high-risk patients, including those with hypertension and higher CHA2DS2-VASc score, whereas patients with prior transient ischaemic attack or stroke had higher incidence of bleeding. Trial sequential analysis revealed that the cumulative Z-curve crossed the conventional boundary of benefit. Compared with warfarin, DOACs reduced the risk of bleeding (relative risk [RR] 0.74; 95% CI: 0.62-0.89; P=0.0011) and major neurological events (RR 0.63; 95% CI: 0.48-0.83; P=0.0012) but not mortality (RR 1.02; 95% CI: 0.77-1.35; P=0.090). CONCLUSIONS: DOACs reduced bleeding and major neurological events in patients with post-cardiac surgical atrial fibrillation, appearing safer than warfarin in this context. However, which specific DOAC provides the most effective anticoagulation in this patient population needs further investigation. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42021282777.