IRF2BP2 mutation with autoimmune enteropathy, immune deficiency, and respiratory failure

Case history: We present the case of a 31-year-old Hispanic male with history of recurrent bronchiectasis, invasive aspergillosis, and severe persistent asthma, who is now status post lung transplant for end-stage lung disease. He initially presented at 7 years of age with diarrhea, failure to thrive, and nearly absent immunoglobulin levels (IgG < 33 mg/dL, IgA < 7 mg/dL, IgM = 11 mg/dL, IgE = 4 IU/dL) necessitating IVIG treatment. Small intestinal biopsy showed villous atrophy consistent with autoimmune enteropathy. Sweat chloride was reported as indeterminate (44 me/dL). Initial WBC, platelet, and T- and NK-cell counts were within normal range, and B-cell count and percentage were borderline low. Most recently, he was found to have increased immature B-cell count (CD21low), decreased memory B-cells, and poor pneumococcal vaccine antibody response. Patient has been hospitalized numerous times with increasingly severe bronchiectasis, pneumonitis, and COVID-19 infections twice despite vaccination, leading to respiratory failure and lung transplantation. Family history is negative for immune deficiency and lung diseases. Discussion(s): Of these 3 VUSs (see the table), the one in IRF2BP2 has the most pathogenic potential due to its autosomal dominant inheritance, its location in a conserved domain (Ring), and previous case reports of pathogenic variants at the same or adjacent alleles 1-3. Baxter et al reported a de novo truncating mutation in IRF2BP2 at codon 536 (c.1606CinsTTT), which is similar to our patient's mutation. This patient was noted to have an IPEX-like presentation, with chronic diarrhea, hypogammaglobulinemia, and recurrent infections. Variant Functional Prediction Score for our variant predicts a potentially high damage effect. There are 2 other case reports of heterozygous mutations in loci adjacent to this allele;one (c.1652G>A)2 with a similar clinical phenotype to our patient and the other (C.625-665 del)3 with primarily inflammatory features and few infections. Impact: This case highlights a variant in IRF2BP2 associated with severe hypogammaglobulinemia, recurrent pulmonary infections, and autoimmune enteropathy. [Table presented]Copyright © 2023 Elsevier Inc.

COVID-19-Related Encephalitis in a Child with PIK3CD Defect

Introduction: COVID-19 related encephalitis has been reported in pediatric patients;however, there are no reports in patients with inborn errors of immunity (IEI). Activated PI3K Delta Syndrome (APDS) is a disease of immune dysregulation with immunodeficiency, autoimmunity, and abnormal lymphoproliferation resulting from autosomal dominant gain-offunction variants in PIK3CD or PIK3R1 genes. We investigate a family with APDS, one mother and three children, one of whom developed COVID-19 related encephalitis. Method(s): Patients were consented to an IRB-approved protocol at our institution. Medical records and detailed immunophenotyping were reviewed. Family members were sequenced for IEI with a targeted gene panel. Result(s): The index case is a 10-year-old female with a known pathogenic variant in PIK3CD (c.3061 G > A, p.Glu1021Lys), who contracted SARS-COV-2 despite one COVID-19 vaccination in the series. Her disease course included COVID-related encephalitis with cerebellitis and compression of the pons, resulting in lasting truncal ataxia and cerebellar mutism. At that time, the patient was not on immunoglobulin replacement therapy (IgRT), but was receiving Sirolimus. Besides the index case, 3 family members (2 brothers, 1 mother) also share the same PIK3CD variant with variable clinical and immunological phenotypes. All children exhibited high transitional B-cells, consistent with developmental block to follicular B cell stage. Increased non-class switched IgM+ memory B cells and skewing towards CD21lo B cell subset, which is considered autoreactive-like, was observed in all patients. Of note, the patient had low plasmablasts, but normal immunoglobulins. Of her family members, only one was receiving both sirolimus and IgRT. Conclusion(s): We describe a rare case of COVID-19-related encephalitis in a patient with inborn error of immunity while not on IgRT. This may indicate infection susceptibility because of a lack of sufficient immunity to SARS-CoV-2, unlike the rest of her family with the same PIK3CD variant.Copyright © 2023 Elsevier Inc.

SPANISH NATIONAL REGISTRY OF BELIMUMAB IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

BackgroundBelimumab (BLM) is a monoclonal antibody that inhibits B-lymphocyte stimulating factor (BlyS) approved as a specific treatment for systemic lupus erythematosus (SLE) in 2011. We present the experience with BLM in a Spanish cohort with more than 460 patients.ObjectivesTo describe demographic characteristics, efficacy and safety of BLM in patients with SLE in Spanish population since its approval.MethodsDescriptive, retrospective, multicenter study in patients diagnosed with SLE according to EULAR/ACR 2019, SLICC and/or ACR 1997 diagnostic criteria. Data regarding SLE patients treated with BLM were collected from medical records (2011-2022). Demographic features, efficacy, laboratory variables, SLEDAI, renal involvement, steroid dose, administration routes and safety were assessed. To see whether a trend in BLM prescription had changed or not over time, two periods of time were analyzed: 2011-2016 (period1) and 2017-2022 (period2).ResultsBaseline characteristics of patients are summarized in Table 1.A total of 462 patients (36 hospitals) were included, 50.9% were on intravenous (IV), 34% on subcutaneous (SC) and 15.1% switched from IV to SC route. The median number of pre-BLM csDMARD use was 2.0 (2.0-3.0), being hydroxychloroquine (HCQ) the most frequently used (94.5%). Fifty-two patients were treated with IV cyclophosphamide with a median of 6 bolus received. At the time of BLM start, 443 patients were on prednisone with a median dose of 6.2 mg (5.0-10.0). Significant decreases in prednisone dose, SLEDAI and anti-DNA antibodies were observed from baseline until the last visit, whereas complement C3 and C4 values raised (Figure 1). A total of 118 patients (27.4%) had renal involvement with a median proteinuria of 1.0 g/day (0.5-2.4). Renal biopsy was done in 102 out of 118 patients, being class IV (33%), class III (21%) and class V (16%) the most frequently reported. After BLM, 73.3% of these patients improved (median proteinuria of 0.2 g/day (0.1-0.7).In period1, 100 patients started BLM compared to 362 in period2. The median time from SLE diagnosis to BLM begin was 7.1 (4.0-13.7) and 6.2 (2.1 -14.4) years in period1 and period2, respectively (p=0.454). We found a trend to use more csDMARD before BLM treatment in period1: 2.5 (2-3) vs. 2 (2-3) (p=0.088).A total of 143 (30.5%) patients discontinued treatment mostly due to inefficacy (55.9%) and infections (11.9%). In fact, 116 patients developed infections, mostly mild;2 patients died, 16 had COVID-19 and 4 patients developed tumors requiring discontinuation of the drug.ConclusionIn our cohort of SLE patients in a real-world setting, BLM has been effective, safe and seems to be a good choice to treat renal involvement.References[1]Navarra SV, Guzmán RM, Gallacher AE, et al. Lancet. 2011;377(9767):721-31.[2]Stohl W, Hiepe;rt al. Arthritis Rheum. 2012;64(7):2328-37.[3]Furie R, Rovin BH, Houssiau F, et al. N Engl J Med. 2020;383(12):1117-1128.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Managing severe warm autoimmune haemolytic anaemia after the SARS-Cov- 2 vaccine with emergency splenectomy and eculizumab

Autoimmune haemolytic anaemia (AIHA) is rare but described after the SARS-CoV- 2 Pfizer-BioNTech vaccine. We present a case of severe refractory warm AIHA after this vaccine, managed with emergency splenectomy and complement inhibition with eculizumab. A male in his teens with a history of liver transplant for biliary atresia (aged 2 years) and AIHA (aged 6 years) presented to his district general hospital with jaundice, dark urine, fatigue and chest discomfort 48 h after the first dose of SARS-CoV- 2 Pfizer-BioNTech vaccine (BNT162b2 mRNA). Investigations revealed haemoglobin (Hb) of 70 g/L and bilirubin of 98 mumol/L, which was treated as AIHA. The patient initially responded to prednisolone (1 mg/kg, 60 mg) but subsequently deteriorated and failed to respond to second-line rituximab (375 mg/m2) and two units of packed red blood cells (PRBC). By day 29 the patient had developed life-threatening anaemia culminating in a Hb of 35 g/L (after transfusion), lactate dehydrogenase (LD) of 1293 units/L and bilirubin of 228 mumol/L. This necessitated an immediate transfer to our tertiary centre for specialist support. Further investigations revealed a haptoglobin <0.1 g/L and direct antiglobulin test (DAT) strongly positive for IgG (4+) and negative for C3d. The peripheral blood film showed severe anaemia, nucleated red cells, anisocytosis and spherocytes with no autoagglutination, schistocytes or platelet clumps. Thrombocytopaenia (platelets 49 +/- 109/L) was present. Differentials were ruled out, such as paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopaenia. HIV and hepatitis serology were negative, as were adenovirus, cytomegalovirus and Epstein-Barr virus PCR assays. A CT showed splenomegaly of 15.5 cm. Urinalysis found urobilinogen and bilirubin at high concentrations and negative urinary haemosiderin. Together, the investigations were consistent with warm AIHA. On day 29, four units of PRBC were transfused alongside 100 mg methylprednisolone and 1 g/kg IVIG. On day 30 the patient deteriorated despite the escalated treatment: Hb had only increased to 54 g/L, bilirubin was 200 mumol/L and LD was rising. Considering this life-threatening fulminant haemolysis, an emergency splenectomy was performed. This slowed haemolysis but did not completely ameliorate it: by day 33 the patient had received 15 units of PRBC. Thus, eculizumab, a terminal complement pathway inhibitor, was trialled to arrest intravascular haemolysis, alongside rituximab, repeat IVIG 1 g/kg, prednisolone 40 mg and tacrolimus 2 mg. This showed a favourable response, requiring less frequent transfusions and settling haemolysis. This case highlights the rare complication of warm AIHA with the SARS-CoV- 2 Pfizer-BioNTech vaccine, the use of emergency splenectomy for disease control, and the potential of eculizumab for refractory cases.

Exploration of potential mechanism of SARS-CoV-2 induced immune inflammatory response leading to progression of atherosclerosis and prediction of traditional Chinese medicine for preventing and treating based on bioinformatics.

Objective To explore the core targets and important pathways of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induced atherosclerosis (AS) progression from the perspective of immune inflammation, so as to predict the potential prevention and treatment of traditional Chinese medicine (TCM). Methods Microarray data were obtained from the Gene Expression Omnibus (GEO) database for coronavirus disease 2019 (COVID-19) patients and AS patients, and the "limmar" and "Venn" packages were used to screen out the common differentially expressed genes (DEGs) genes in both diseases. The gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed on the common DEGs to annotate their functions and important pathways. The two gene sets were scored for immune cells and immune function to assess the level of immune cell infiltration. The protein-protein interaction (PPI) network was constructed by STRING database, and the CytoHubba plug-in of Cytoscape was used to identify the hub genes. Two external validation datasets were introduced to validate the hub genes and obtain the core genes. Immuno-infiltration analysis and gene set enrichment analysis (GSEA) were performed on the core genes respectively. Finally the potential TCM regulating the core genes were predicted by Coremine Medical database. Results A total of 7898 genes related to COVID-19, 471 genes related to AS progression;And 51 common DEGs, including 32 highly expressed genes and 19 low expressed genes were obtained. GO and KEGG analysis showed that common DEGs, which were mainly localized in cypermethrin-encapsulated vesicles, platelet alpha particles, phagocytic vesicle membranes and vesicles, were involved in many biological processes such as myeloid differentiation factor 88 (MyD88)-dependent Toll-like receptor signaling pathway transduction, interleukin-8 (IL-8) production and positive regulation, IL-6 production and positive regulation to play a role in regulating nicotinamide adenine dinucleotide phosphate oxidase activity, Toll-like receptor binding and lipopeptide and glycosaminoglycan binding through many biological pathways, including Toll-like receptor signaling pathways, neutrophil extracellular trap formation, complement and coagulation cascade reactions. The results of immune infiltration analysis demonstrated the state of immune microenvironment of COVID-19 and AS. A total of 5 hub genes were obtained after screening, among which Toll-like receptor 2 (TLR2), cluster of differentiation 163 (CD163) and complement C1q subcomponent subunit B (C1QB) genes passed external validation as core genes. The core genes showed strong correlation with immune process and inflammatory response in both immune infiltration analysis and GSEA enrichment analysis. A total of 35 TCMs, including Chuanxiong (Chuanxiong Rhizoma), Taoren (Persicae Semen), Danggui (Angelicae Sinensis Radix), Huangqin (Scutellariae Radix), Pugongying (Taraxaci Herba), Taizishen (Pseudostellariae Radix), Huangjing (Polygonati Rhizoma), could be used as potential therapeutic agents. Conclusion TLR2, CD163 and C1QB were the core molecules of SARS-CoV-2-mediated immune inflammatory response promoting AS progression, and targeting predicted herbs were potential drugs to slow down AS progression in COVID-19 patients.Copyright © 2023 Editorial Office of Chinese Traditional and Herbal Drugs. All rights reserved.

Germline rare variants of lectin pathway genes predispose to asymptomatic SARS-CoV-2 infection in elderly individuals

Background/Objectives: Emerging evidence suggests that complement system infection-dependent hyperactivation may worsen COVID-19 outcome. We investigated the role of predicted high impact variants -referred as Qualifying Variants (QVs) -of complement system genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. Method(s): Exploiting Whole-Exome Sequencing (WES) data and 56 complement system genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (age >= 60 y.o.) and 56,885 European individuals from the gnomAD database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized COVID-19 patients. Result(s): We found an enrichment of QVs in three genes (MASP1, COLEC10 and COLEC11), which belong to the lectin pathway, in the asymptomatic cohort. Moreover, individuals with QVs showed lower serum levels of Masp1 and of prothrombin activity compared to controls while no differences were observed for CH50 and AH50 levels that measure the activity of classical and alternative complement pathways, respectively. Finally, integrative analyses of genome-wide association study and expression quantitative loci traits data showed a correlation between polymorphisms associated with asymptomatic COVID-19 and decreased expression of MASP1, COLEC11 and COLEC10 genes in lung tissue. Conclusion(s): This study suggests that rare genetic variants can protect from severe COVID-19 by mitigating the activation of lectin pathway and prothrombin activity.

Sambucus ebulus (Elderberry) Fruits Modulate Inflammation and Complement System Activity in Humans.

Sambucus ebulus (SE) fruits are used for immune stimulation and amelioration of gastrointestinal inflammatory conditions. Currently, there is no scientific evidence of their effects on various aspects of the immune response mechanisms in humans. The purpose of this study was to evaluate the immunomodulatory potential of SE fruit infusion intake in healthy humans. Anthocyanin content was determined with UPLC-ESI-MS/MS. Fifty-three volunteers enrolled in a 4-week SE infusion intake intervention. Blood count, serum total protein, Interleukin 1 beta (IL-1ß), Interleukin 6 (IL-6), Tumor Necrosis Factor Alpha (TNFα), High-sensitivity C-reactive protein (hs-CRP), C3, and C4 levels were measured on automatic analyzers, and Interleukin 8 (IL-8) was measured manually with an ELISA kit. Cyanidin-3-O-galactoside (48.15 mg/g DW), followed by cyaniding-3-sambubioside (43.41 ± 1.07 mg/g DW), were the most abundant anthocyanins in SE samples. A significant decrease in total protein (2.82%), IL-6 (20.15%), TNFα (5.38%), IL-8 (5.50%), C3 (4.16%), and C4 (14.29%) was established in the whole group. Total protein, IL-8, TNFα, and C4 decreased in women (3.11%, 4.76%, 5.09%, and 11.11%), and IL-6 decreased (40.61%) in men. Hb (1.20%) and hematocrit (1.55%) levels decreased in the whole group and in the women group (1.61% and 2.20%). SE fruits exert immune-modulatory activity as revealed by decreased pro-inflammatory status and complement activity markers in healthy volunteers after a 4-week intervention.

[Recent topics in the pathophysiology and treatment of immune thrombocytopenic purpura].

Increased and impaired platelet productions via immunological abnormalities are the main pathophysiological mechanisms of primary immune thrombocytopenia (ITP). Recent studies have revealed that platelet removal from circulation involves not only Fc receptor-mediated phagocytosis of immunoglobulin G autoantibodies-bound platelets but also complement-dependent mechanism and platelet glycoprotein desialylation. Understanding the molecular mechanism of ITP pathophysiology has helped develop many novel molecular targeted drugs, and recent clinical trials have shown their effectiveness. In particular, fostamatinib, which is a Syk inhibitor, inhibits macrophage and B-cell activity and is already been approved in Europe for multidrug-resistant ITP. Recently, coronavirus disease-2019 (COVID-19) vaccine-associated newly-onset or ITP exacerbation has come to attention. Whether COVID-19 vaccines induce de novo ITP remains controversial. However, close attention is necessary after COVID-19 vaccination because a certain number of patients with ITP presented exacerbation after COVID-19 vaccination.

The Role of NETosis and Complement Activation in COVID-19-Associated Coagulopathies.

Inflammation-induced coagulopathy is a common complication associated with coronavirus disease 2019 (COVID-19). We aim to evaluate the association of NETosis and complement markers with each other as well as their association with thrombogenicity and disease severity in COVID-19. The study included hospitalized patients with an acute respiratory infection: patients with SARS-CoV2 infection (COVpos, n = 47) or either pneumonia or infection-triggered acute exacerbated COPD (COVneg, n = 36). Our results show that NETosis, coagulation, and platelets, as well as complement markers, were significantly increased in COVpos patients, especially in severely ill COVpos patients. NETosis marker MPO/DNA complexes correlated with coagulation, platelet, and complement markers only in COVpos. Severely ill COVpos patients showed an association between complement C3 and SOFA (R = 0.48; p ≤ 0.028), C5 and SOFA (R = 0.46; p ≤ 0.038), and C5b-9 and SOFA (R = 0.44; p ≤ 0.046). This study provides further evidence that NETosis and the complement system are key players in COVID-19 inflammation and clinical severity. Unlike previous studies that found NETosis and complement markers to be elevated in COVID-19 patients compared to healthy controls, our findings show that this characteristic distinguishes COVID-19 from other pulmonary infectious diseases. Based on our results, we propose that COVID-19 patients at high risk for immunothrombosis could be identified via elevated complement markers such as C5.

Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): Real world data of a Greek nationwide multicenter retrospective study.

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions to PEG-containing Covid-19 vaccines: Evidence for immunogenicity of PEG.

A small fraction of recipients who receive polyethylene-glycol (PEG)-containing COVID-19 mRNA-LNP vaccines (Comirnaty and Spikevax) develop hypersensitivity reactions (HSRs) or anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet been proven in humans.We used ELISA for serial measurements of SARS-CoV-2 neutralizing Ab (anti-S) and anti-PEG IgG/IgM Ab levels before and after the first and subsequent booster vaccinations with mRNA-LNP vaccines in a total of 291 blood donors. The HSRs in 15 subjects were graded and correlated with anti-PEG IgG/IgM, just as the anti-S and anti-PEG Ab levels with each other. The impacts of gender, allergy, mastocytosis and use of cosmetics were also analyzed. Serial testing of two or more plasma samples showed substantial individual variation of anti-S Ab levels after repeated vaccinations, just as the levels of anti-PEG IgG and IgM, which were over baseline in 98-99 % of unvaccinated individuals. About 3-4 % of subjects in the strongly left-skewed distribution had 15-45-fold higher values than the median, referred to as anti-PEG Ab supercarriers. Both vaccines caused significant rises of anti-PEG IgG/IgM with >10-fold rises in about âˆ¼10 % of Comirnaty, and all Spikevax recipients. The anti-PEG IgG and/or IgM levels in the 15 vaccine reactors (3 anaphylaxis) were significantly higher compared to nonreactors. Serial testing of plasma showed significant correlation between the booster injection-induced rises of anti-S and anti-PEG IgGs, suggesting coupled anti-S and anti-PEG immunogenicity.Conclusions: The small percentage of people who have extremelevels of anti-PEG Ab in their blood may be at increased risk for HSRs/anaphylaxis to PEGylated vaccines and other PEGylated injectables. This risk might be further increased by the anti-PEG immunogenicity of these vaccines. Screening for anti-PEG Ab "supercarriers" may help predicting reactors and thus preventing these adverse phenomena.

Autoimmune pulmonary alveolar proteinosis in an adolescent girl with rapidly progressive dyspnea

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease, especially in pediatrics, but important to consider, as it may avoid unnecessary and/or invasive investigations and delayed diagnosis. This case report highlights an adolescent girl with rapid onset dyspnea but an unremarkable physical exam and initial testing. However, due to a high index of suspicion, a chest computed tomography (CT) scan was done, revealing a "crazy paving" pattern, which then prompted expedited assessment. This finding, however, is not as specific as often discussed and has a broad differential diagnosis, which will be reviewed in detail as part of this case. Furthermore, this report demonstrates a diagnostic approach for PAP that avoids lung biopsy, previously considered to be required for diagnosis of PAP, but is increasingly becoming unnecessary with more advanced blood tests and understanding of their sensitivity and specificity. Additionally, management strategies for PAP will be briefly discussed.Copyright © 2022 Canadian Thoracic Society.

SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer's Disease Risk

The COVID-19 pandemic is a global outbreak of coronavirus, an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One in five adults who have had COVID-19 in the past was still experiencing any one of the symptoms of long COVID like headache, brain fog, fatigue, and shortness of breath. Up to 30% of individuals with mild to severe infection show diverse neurological symptoms, including dementias. Hence, it is very much important to characterize the neurotropism and neurovirulence of the SARS-CoV-2 virus. This helps us understand the mechanisms involved in initiating inflammation in the brain, further leading to the development of earlyonset Alzheimer's disease and related dementias (ADRDs). In our brain gene expression analysis, we found that severe COVID-19 patients showed increased expression of innate immune response genes and genes that are implicated in AD pathogenesis. To study the infection-induced ADRDs, we used a mouse-adapted strain of the SARS-CoV-2 (MA10) virus to infect mice of different age groups (3, 6, and 20 Months). In this study, we found that aged mice showed evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferoninducible gene Ifi204, and complement genes like C4 and C5AR1. Brain histopathology also showed the AD signature including tau-phosphorylation, tau-oligomerization, and alpha-synuclein expression in aged MA10-infected mice. The results from gene expression profiling of SARS-CoV-2 infected and AD brains and studies with MA10 aged mice show that COVID-19 infection increases the risk of AD in the aged population. Furthermore, this study helps us to understand the crucial molecular markers that are regulated during COVID infection that could act as major players in developing ADRDs. Future studies will be involved in understanding the molecular mechanisms of ADRD in response to COVID infection and developing novel therapies targeting AD.

Granulomatous Hepatitis as Primary Manifestation of Disseminated Histoplasmosis in an Immunocompetent Host Diagnosed on EUS FNA and Liver Biopsy

Introduction: Disseminated histoplasmosis (DH) presents as primarily lung manifestations with extrapulmonary involvement in immunocompromised hosts. Granulomatous hepatitis as first presentation of DH in an immunocompetent host is uncommon. Case Description/Methods: 25-year-old female presented with one month of fever, fatigue, myalgias, 30-pound weight loss, cough, nausea, vomiting, and epigastric pain. She has lived in the Midwest and southwestern US. Presenting labs: TB 1.9 mg/dL, AP 161 U/L, AST 172 U/L, ALT 463 U/L. Workup was negative for COVID, viral/autoimmune hepatitis, sarcoidosis, tuberculosis, and HIV. CT scan showed suspected gallstones and 9 mm left lower lobe noncalcified nodule. EUS showed a normal common bile duct, gallbladder sludge and enlarged porta hepatis lymph nodes which underwent fine needle aspiration (FNA). She was diagnosed with biliary colic and underwent cholecystectomy, with white plaques noted on the liver surface (A). Liver biopsy/FNA showed necrotizing granulomas (B) and fungal yeast on GMS stain (C). Although histoplasmosis urine and blood antigens were negative, histoplasmosis complement fixation was >1:256. She could not tolerate itraconazole for DH, requiring amphotericin B. She then transitioned to voriconazole, discontinued after 5 weeks due to increasing AP. However, her symptoms resolved with normal transaminases. At one year follow up, she is asymptomatic with normal liver function tests. Discussion(s): DH is a systemic granulomatous disease caused by Histoplasma capsulatum endemic to Ohio, Mississippi River Valley, and southeastern US. DH more commonly affects immunocompromised hosts with AIDS, immunosuppressants, and organ transplant. Gastrointestinal involvement is common in DH (70-90%) with liver involvement in 90%. However, granulomatous hepatitis as primary manifestation of DH is rare (4% of liver biopsies). Hepatic granulomas are seen in < 20%. Patients may present with nonspecific systemic symptoms. Serum/urine antigens may be negative. Gold standard for diagnosis is identifying yeast on tissue stains. Recommended treatment is amphotericin B followed by 1 year of itraconazole. However, shorter treatment duration may be effective in immunocompetent hosts. This case is unique in that granulomatous hepatitis was the first presentation of DH in our immunocompetent patient diagnosed on EUS FNA and liver biopsy. Clinicians must have a high degree of suspicion for DH in patients with fever of unknown origin especially in endemic areas regardless of immunologic status. (Table Presented).

Complement Activation by an Anti-Dengue/Zika Antibody with Impaired Fcγ Receptor Binding Provides Strong Efficacy and Abrogates Risk of Antibody-Dependent Enhancement.

To combat infectious diseases, vaccines are considered the best prophylactic strategy for a wide range of the population, but even when vaccines are effective, the administration of therapeutic antibodies against viruses could provide further treatment options, particularly for vulnerable groups whose immunity against the viruses is compromised. Therapeutic antibodies against dengue are ideally engineered to abrogate binding to Fcγ receptors (FcγRs), which can induce antibody-dependent enhancement (ADE). However, the Fc effector functions of neutralizing antibodies against SARS-CoV-2 have recently been reported to improve post-exposure therapy, while they are dispensable when administered as prophylaxis. Hence, in this report, we investigated the influence of Fc engineering on anti-virus efficacy using the anti-dengue/Zika human antibody SIgN-3C and found it affected the viremia clearance efficacy against dengue in a mouse model. Furthermore, we demonstrated that complement activation through antibody binding to C1q could play a role in anti-dengue efficacy. We also generated a novel Fc variant, which displayed the ability for complement activation but showed very low FcγR binding and an undetectable level of the risk of ADE in a cell-based assay. This Fc engineering approach could make effective and safe anti-virus antibodies against dengue, Zika and other viruses.

Prognostic Significance of the Coagulation and Complement Systems in Critical COVID-19 Infection.

Infection with the SARS-CoV-2 virus (COVID-19 disease) can cause a wide range of clinical situations - from an asymptomatic state to fatal outcomes. In cases of serious clinical manifestations, the underlying mechanisms involve a number of immune cells and stromal cells as well as their products such as pro-inflammatory interleukin-6 and tumour necrosis factor-alpha that ultimately cause the cytokine storm. The situation of overproduction of pro-inflammatory cytokines is somewhat similar to, though in a mild form, health conditions in obesity and related metabolic disorders like type-2 diabetes, which are also considered important risk factors for severe illness in COVID-19. Interestingly, neutrophils perhaps play a significant role in this pathogenesis. On the other hand, it is thought that COVID-19-related critical illness is associated with pathological hyperactivity of the complement system and coagulopathy. Although the precise molecular interactions between the complement and coagulation systems are not clear, we observe an intimate cross-talk between these two systems in critically ill COVID-19 patients. It is believed that both of these biological systems are connected with the cytokine storm in severe COVID-19 disease and actively participate in this vicious cycle. In order to hinder the pathological progression of COVID-19, a number of anticoagulation agents and complement inhibitors have been used with varying success. Among these drugs, low molecular weight heparin enoxaparin, factor Xa inhibitor apixaban, and complement C5 inhibitor eculizumab have been commonly used in patients with COVID-19. Our overall experience might help us in the future to tackle any such conditions.

The choice of new treatments in autoimmune hemolytic anemia: how to pick from the basket?

Autoimmune hemolytic anemia (AIHA) is defined by increased erythrocyte turnover mediated by autoimmune mechanisms. While corticosteroids remain first-line therapy in most cases of warm-antibody AIHA, cold agglutinin disease is treated by targeting the underlying clonal B-cell proliferation or the classical complement activation pathway. Several new established or investigational drugs and treatment regimens have appeared during the last 1-2 decades, resulting in an improvement of therapy options but also raising challenges on how to select the best treatment in individual patients. In severe warm-antibody AIHA, there is evidence for the upfront addition of rituximab to prednisolone in the first line. Novel agents targeting B-cells, extravascular hemolysis, or removing IgG will offer further options in the acute and relapsed/refractory settings. In cold agglutinin disease, the development of complement inhibitors and B-cell targeting agents makes it possible to individualize therapy, based on the disease profile and patient characteristics. For most AIHAs, the optimal treatment remains to be found, and there is still a need for more evidence-based therapies. Therefore, prospective clinical trials should be encouraged.

Therapeutic approaches for intravascular microthrombi-induced acute respiratory distress syndrome (ARDS) in COVID-19 infection.

The COVID-19 pandemic has overwhelmed our health care capacity in an unprecedented way due to the sheer number of critically infected patients admitted to hospitals during the last two years. Endothelial injury is seen as one of the central hallmarks of COVID-19 infection that is the starting point in the generation of microthrombi and sepsis eventually leading to acute respiratory distress syndrome (ARDs) and multi-organ failure. The dramatic fall in lung function during ARDs is attributed to the microthrombi-induced coagulopathy primed by a hyperactive immune system. Due to the lack of effective antiviral agents, the line of treatment is limited to the management of two key risk factors i.e., immune activation and coagulopathy. In the present review, we describe the mechanistic role, therapeutic targets and opportunities to control immune activation and coagulopathy during the pathogenesis of COVID-19-induced ARDs.

A New Approach Towards Intuitionistic Fuzzy Multisets

In this paper, a new definition of intuitionistic fuzzy multisets (IFMS) has been introduced. Algebraic operations on these intuitionistic fuzzy multisets are defined, and their properties under these algebraic operations are studied. The author has also introduced a new notion of complement for an IFMS in which the complement of the original set is also an IFMS. The notion of distance and similarity between two IFMSs has been defined, and their properties have also been studied here. An application of IFMS in solving a medical diagnosis problem has been provided at the end. Copyright © 2022, IGI Global. Copying or distributing in print or electronic forms without written permission of IGI Global is prohibited.

Regional effects on efficacy and safety of vilobelimab in mechanically ventilated patients with severe COVID-19

Introduction: Poor outcomes in COVID-19 patients (pt) are associated with C5a-C5aR axis activation. A C5a-specific monoclonal antibody, vilobelimab (VILO), improves outcomes in critically ill COVID-19 pt in a Phase 3 randomized, double-blind, placebo (PLC)- controlled study [1]. Method(s): COVID-19 pt within 48 h of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or PLC at a 1:1 ratio on top of standard of care. Predefined subgroup analyses by region and country were performed. Result(s): Forty-six (46) hospitals on 4 continents randomized 369 pt: VILO (n = 178), PLC (n = 191). VILO significantly reduced 28- (HR 0.67;95% CI 0.48-0.96;p = 0.027) and 60-Day mortality (HR 0.67;95% CI 0.48-0.93, p = 0.0163) using a predefined, unstratified per protocol analysis. Mortality rates at 28- and 60-days and VILO treatment effects, however, differed substantially between regions: Western Europe HR for 60-day mortality 0.59 [0.37-0.95], South Africa plus Russian Federation HR 0.62 [0.28-1.38] and South America HR 0.80 [0.46-1.39] (Fig. 1). The weak signal in South America is predominately driven by Brazil (n = 74), which showed a significant age imbalance with a median 9-years younger PLC group (44.5-years-old vs 53.5-years-old) with low 60-day mortality of ~ 32.5% in the PLC group versus ~ 43.3% in Western Europe. Adjusting for age group categories (<= 30, 31-40, 41-50, 51-60, > 60;Cox regression) for 60-day mortality changed the HR in Brazil (0.96 [0.44-2.10] for continuous age-adjustment) to values near the estimate for the entire study population (HR 0.77 [0.35-1.69] for age in categories), suggesting a by chance imbalance and not a statistically evident weaker effect in Brazil. Conclusion(s): Regional efficacy differences between the rest of the world and South America were driven by age imbalances between treatment groups, which do not diminish the robust efficacy signal for VILO in severe COVID-19.