A Rare Cause of Enteritis in an Adult Male

Introduction: IgA vasculitis is more commonly seen in the pediatric population than in adults. Rarely IgA vasculitis is associated with malignancy, most commonly solid tumor malignancies, although there are case reports of association with hematologic malignancies. We report a case of large B-cell lymphoma mimicking IgA vasculitis in a 33-year-old immunosuppressed male with a prior history of IgA vasculitis. Case Description/Methods: A 33-year-old Caucasian male post renal transplant from reflux nephropathy on chronic immunosuppression was hospitalized for postprandial epigastric abdominal pain, nausea, vomiting and diarrhea. Two years prior, he was admitted for the same symptoms, palpable purpura of the lower extremities and elevated serum IgA. Enteroscopy had shown duodenal and jejunal ulceration with biopsies staining positive for IgA, confirming IgA vasculitis. He had complete resolution with a steroid taper. His current presentation had resulted in multiple hospital admissions, but empiric trial of steroids failed to alleviate symptoms. Vitals were normal and exam was notable for epigastric tenderness. Labs were notable for WBC 19.00 x103/cmm with normal differential, hemoglobin 9.2 gm/dL (prior 11.0 gm/dL), CRP 20.7 mg/L, serum creatinine 2.7 mg/dL (prior 1.5 mg/dL), and urinalysis with proteinuria, sterile pyuria, and hematuria. CTA abdomen/pelvis revealed thickening of the duodenum with shotty mesenteric lymph nodes without ischemia. Enteroscopy revealed an erythematous duodenum and jejunum (figure A). Jejunal biopsy (figure B) revealed CD20 positive cells consistent with DLCBL (figure C). He was seen by oncology and treated with R-CHOP but later unfortunately expired due to COVID-19 complications. Discussion(s): Non small cell lung cancer and renal cell carcinoma are most commonly associated with IgA vasculitis. It may also be seen in both Hodgkin and Non-Hodgkin lymphomas in adult patients. If IgA vasculitis occurs after a malignancy is diagnosed, it may indicate that metastasis has occurred. Malignancy associated IgA vasculitis is more likely to have an incomplete response to steroids and requires treatment of the underlying malignancy to achieve remission. Our case illustrates posterior probability error and premature closure cognitive biases. We should consider alternative diagnoses rather than anchor on prior diagnoses even when presentations are similar. Our case also highlights the importance of considering occult malignancy in adults with diagnosis of IgA vasculitis.

Triple combination therapy with two antivirals and monoclonal antibodies for persistent or relapsed SARS-CoV-2 infection in immunocompromised patients.

INTRODUCTION: Severely immunocompromised patients are at risk for prolonged or relapsed COVID-19 leading to increased morbidity and mortality. We aimed to evaluate efficacy and safety of combination treatment in immunocompromised COVID-19 patients. METHODS: We included all immunocompromised patients with prolonged/relapsed COVID-19 treated with combination therapy with two antivirals (remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure) plus, if available, anti-spike monoclonal antibodies (Mabs), between February and October 2022. The main outcomes were virological response at day 14 (negative SARS-CoV-2 swab) and virological and clinical response (alive, asymptomatic, with negative SARS-CoV-2 swab) at day 30 and the last follow-up. RESULTS: Overall, 22 patients (Omicron variant in 17/18) were included: 18 received full combination of two antivirals and Mabs and 4 received two antivirals only; in 20/22 (91%) two antivirals were nirmatrelvir/ritonavir plus remdesivir. Nineteen (86%) patients had hematological malignancy, 15 (68%) had received anti-CD20 therapy. All were symptomatic; 8 (36%) required oxygen. Four patients received second course of combination treatment. Response rate at day 14, 30 and last follow-up was, respectively, 75% (15/20 evaluable), 73% (16/22) and 82% (18/22). Day 14 and 30 response rates were significantly higher when combination therapy included Mabs. Higher number of vaccine doses was associated with better final outcome. Two patients (9%) developed severe side effects: bradycardia leading to remdesivir discontinuation and myocardial infarction. CONCLUSION: Combination therapy including two antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and Mabs was associated with high rate of virological and clinical response in immunocompromised patients with prolonged/relapsed COVID-19.

Long-Term Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory (R/R) Marginal Zone Lymphoma (MZL): Final Analysis of the Magnolia (BGB-3111-214) Trial

Introduction: Advanced MZL is generally incurable, with periods of remission and relapse. Zanubrutinib (BGB-3111), a potent and highly specific next-generation Bruton tyrosine kinase (BTK) inhibitor, was approved in the US and Canada for R/R MZL based on the MAGNOLIA primary analysis (BGB- 3111-214;NCT03846427);here, the final MAGNOLIA analysis is presented. Method(s): This was a phase 2, multicenter, single-arm study of adult patients (pts) with R/R MZL (>=1 prior CD20-directed therapy). Zanubrutinib (160 mg twice daily) was given until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) per Lugano classification. Secondary endpoints were investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Efficacy was assessed by positron emission tomography (PET)-based Lugano criteria for IRC-confirmed fluorodeoxyglucose (FDG)-avid disease at baseline;non-avid disease was assessed by computed tomography (CT)-based criteria. Result(s): As of May 4, 2022, 68 pts were treated (median age=70 y [range 37-95];>=75 y=27.9%). MZL subtypes included extranodal (38.2%), nodal (38.2%), splenic (17.6%), and unknown (5.9%). The median number of prior therapies was 2 (range 1-6);32.4% of pts had disease refractory to last therapy, most (89.7%) had prior chemoimmunotherapy, and 7 (10.3%) had rituximab monotherapy as their only prior treatment. Sixty-one pts (89.7%) had FDG-avid disease. After a median follow-up of 28.0 mos (range 1.6-32.9) and a median treatment duration of 24.2 mos (range 0.9-32.9), 66 pts were efficacy- evaluable. IRC-assessed ORR (complete response [CR]+partial response [PR]) was 68.2% (CR=25.8%). By subtype, (Figure Presented)(Figure Presented)ORR/CR rates were 64.0%/40.0% (extranodal), 76.0%/20.0% (nodal), 66.7%/8.3% (splenic), and 50.0%/25.0% (unknown). Median DOR, PFS, and OS were not reached. Over 70.0% of pts were alive or progression-free after 2 years (Figure). Sensitivity analysis using only CT-based criteria (n=66) showed an ORR of 66.7% and CR of 24.2%. The most common treatment-emergent AEs were bruising (23.5%), diarrhea (22.1%), and constipation (17.6%). Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common Grade >=3 AEs. Five pts (7.4%) died due to unrelated AEs: COVID-19 pneumonia=2, acute myeloid leukemia=1, myocardial infarction=1, septic encephalopathy=1. Hypertension occurred in 3 pts (4.4%), atrial fibrillation and atrial flutter in 1 pt (1.5%) each;none led to treatment withdrawal. One pt (1.5%) had a Grade 3 gastrointestinal hemorrhage while receiving rivaroxaban. None of the pts required dose reduction. Conclusion(s): In this final analysis with over 2 years of median follow-up, zanubrutinib continues to demonstrate durable disease control and was generally well tolerated, with no new safety signals observedCopyright © 2023 American Society for Transplantation and Cellular Therapy

Restoration of Humoral Response to Covid-19 Vaccination in Rituximab-Treated Patients

Background: Previous studies had demonstrated that patients with hematologic malignancies had suboptimal antibody response after receiving COVID-19 vaccines, especially among those having previously treated with anti- CD20 monoclonal antibodies. Method(s): Adult patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia (CLL) were enrolled before receiving the second dose of SARS-CoV-2 vaccine. Determinations of anti-SARS-CoV-2 spike and nucleocapsid IgG titers were performed every 1-3 months, after they received the second and the third dose of SARS-CoV-2 vaccine, respectively. Patients were excluded from analysis if they were diagnosed with COVID-19. All serum samples were tested for anti-nucleocapsid antibody and those tested positive were excluded from subsequent analyses. Result(s): A total of 85 participants were enrolled, including 42 (49.4%) with diffused large B-cell lymphoma, and 13 (15.3) with follicular lymphoma and 9 with CLL. 72 (84.7%) participants had received anti-CD20 monoclonal antibodies, with a median interval of 24 months between last anti-CD20 treatment and the second dose of vaccine, and 21 (24.7%) had HIV infection. Factors associated with failure to achieve an anti-spike IgG titer >141 BAU/ mL within 12 weeks after the second dose of vaccine included HIV infection (adjusted odds ratio [aOR], 0.14;95% CI, 0.04-0.51), active hematologic disease (aOR, 5.50;95% CI 1.42-21.32), receipt of anti-CD20 monoclonal antibodies (aOR, 6.65;95% CI 1.52-29.07), and receipt of two doses of homologous mRNA vaccination (aOR, 0.17;95% CI 0.05-0.56). In the participants having previously treated with anti-CD20 regimen, only 8.6% achieved an antibody response ( >141 BAU/mL) in the first year, while 78.3% achieved anti-spike IgG titer > 141 BAU/mL after two years post B-cell depleting treatment. After the third dose of SARS-CoV-2 vaccine, 53.6% achieved an antispike IgG titer > 141 BAU/mL in the first year post anti-CD20 treatment. Conclusion(s): Our study demonstrated that previous treatment with anti-CD20 monoclonal antibodies was associated a lower antibody response among patients with lymphoproliferative disorders receiving two doses of SARS-CoV-2 vaccine. While two doses of SARS-CoV-2 vaccines might not be sufficient even one year apart from the last dose of rituximab, a third dose of vaccine may boost anti-spike IgG particularly in the subset of recent exposure to rituximab. Anti-spike IgG determined 1-3 months after the second (A) / third (B) dose of COVID-19 vaccine, stratified by the interval between last anti-CD20 regimen and the second / third dose of COVID-19 vaccine. (Figure Presented).

Sarcoidosis-Associated Immune Thrombocytopenic Purpura and Focal Segmental Glomerulosclerosis

Purpose of study A 32-years old male with known multi-system sarcoidosis in remission for 5 years off treatment presented to the emergency room with complaints of generalized weakness, hematemesis, epistaxis, and bruises. Physical examination was notable for petechiae, ecchymosis along with papules and plaques suggestive of active sarcoid skin lesions on his extremities. Laboratory workup was significant for thrombocytopenia 3000/uL, acute kidney injury with sub-nephrotic proteinuria. Peripheral blood smear did not show evidence of hemolysis and direct Coombs test was negative. Infectious workup including COVID-19, HIV, and hepatitis serologies were negative. Computed Tomography (CT) of chest, abdomen, and pelvis showed mild splenomegaly and an increased number of sub-centimeter hilar and mediastinal lymph nodes. The patient was treated with dexamethasone 40 mg daily for 4 days and intravenousimmunoglobulins (IVIG-2 gm/kg) for possible Immune Thrombocytopenic Purpura (ITP) with improvement in platelet count to 42000/uL by day 3. His workup for AKI and sub-nephrotic proteinuria was negative apart from a positive ANA (1: 160) with low complements. The anti-phospholipid antibody panel was negative. The ACE level was markedly elevated (>80U/L). The patient could not get a renal biopsy due to severe thrombocytopenia. He was discharged but was re-admitted in 15 days for severe thrombocytopenia of 1000/uL, epistaxis, and bruising. We continued high dose steroids along with IVIG 1 gm/kg for refractory ITP with minimal response and started anti-CD20 agent (Rituximab) 375 mg/m2 weekly with thrombopoietin-receptor agonist (Eltrombopag). His platelets count improved in response to treatment and subsequent renal biopsy showed focal and segmental glomerulosclerosis along with mild interstitial fibrosis, tubular atrophy thought to be from long standing sarcoidosis. There was also evidence of focal arteriosclerosis with no evidence of granulomas, immune complex, complement, or IgG4 deposition. Given skin lesions, thrombocytopenia, extensive lymphadenopathy, and renal involvement with markedly elevated ACE levels the overall picture was consistent with active multi-system sarcoidosis. His platelet count increased to 177,000/uL at the time of discharge. Currently, the patient is on slow steroid taper along with Eltrombopag 25 mg every other day without any recurrence of his symptoms so far. Methods used We described one case of sarcoidosis with hematologic and renal involvement. Summary of results Our patient developed hematologic and renal complications approximately 6 years after being diagnosed with sarcoidosis. Initially, he did not demonstrate sufficient clinical response to IVIG and high dose steroids. However, after a course of anti-CD20 agent (Rituximab) and with the addition of thrombopoietin-receptor agonist (Eltrombopag) he showed improvement of platelet count and stabilization of the renal function. Currently, the patient is receiving maintenance therapy with Prednisone 7.5 mg daily along with Eltrombopag 25 mg twice weekly with no recurrence of ITP and stable renal function. A further decision on whether the patient needs another cycle of Rituximab will be determined by the patient's clinical course. Conclusions Highly variable manifestations of Sarcoidosis can pose a significant diagnostic and therapeutic challenge as can be seen from our case. ITP is a rare hematological manifestation of sarcoidosis and addition of anti-CD20 agents should be considered in refractory cases.

CO7.1 - Anti-CD20 et severite de la COVID-19 chez les patients vivants avec une sclerose en plaques dans la cohorte COVISEP: un impact different selon la forme progressive ou recurrente-remittente de la sclerose en plaques.

[Formula presented] [Formula presented] Fig. 1. Impact des anti-CD20 sur le risque de COVID-19 severeCopyright © 2023

Evaluation of lung cell populations in severe COVID-19 pneumonia

Introduction/Aim: Coronavirus disease 2019 (COVID-19) is a novel viral infection that can cause severe pneumonia and acute respiratory failure;however, the mechanism of disease progression is still unclear. The aim of this study is to evaluate inflammatory cells in the lung by analysing cell populations of bronchial aspirates of COVID-19 pneumonia. Method(s): Eligible cases were diagnosed as COVID-19, confirmed by SARS-CoV-2 PCR. All cases had developed severe COVID-19 pneumonia and undergone invasive positive pressure ventilation for the treatment of respiratory failure. Bronchial aspirates were collected during endotracheal intubation, and SARS-CoV-2 PCR was done. The populations of obtained cells from bronchial aspirates were examined by Giemsa staining and immunohistochemical staining of CD3, CD4, CD8, CD20 and CD68 antigens. Bronchial aspirates were cultured to confirm respiratory bacterial co-infections. Result(s): A total of 14 cases (median age 70;eleven male and three female) were enrolled in this study. Their bronchial aspirates were all positive for SARS-CoV-2 PCR. Bacterial co-infections were developed in 10 cases, including 6 cases of pneumonia/respiratory tract infection, 2 cases of sepsis, and 2 cases of urinary tract infection. Cell populations of bronchial aspirates with or without bacterial co-infections were as follows: neutrophils 33.0% vs. 21.5%;CD3+ mononuclear cells (MNCs) 2.5% vs. 5.8%;CD4+ MNCs 4.6% vs. 3.4%;CD8+ MNCs 3.5% vs. 5.2%;CD20+ MNCs 0.2% vs. 0.1%;CD68+ MNCs 39.7% vs. 38.8%, respectively. Conclusion(s): CD68 antigen is mainly expressed in monocytes/macrophages. CD68+ MNCs were dominant in bronchial aspirates of the cases with severe COVID-19 pneumonia. Our data suggests that CD68+ MNCs, presumably macrophages, would play an essential role during the innate immune response to acute SARS-CoV-2 infection in the lung.

Cellular and humoral responses after second and third SARS-CoV-2 vaccinations in patients with autoimmune diseases treated with rituximab: specific T cell immunity remains longer and plays a protective role against SARS-CoV-2 reinfections.

Background: Humoral and cellular immune responses are known to be crucial for patients to recover from COVID-19 and to protect them against SARS-CoV-2 reinfection once infected or vaccinated. Objectives: This study aimed to investigate humoral and T cell responses to SARS-CoV-2 vaccination in patients with autoimmune diseases after the second and third vaccine doses while on rituximab and their potential protective role against reinfection. Methods: Ten COVID-19-naïve patients were included. Three time points were used for monitoring cellular and humoral responses: pre-vaccine to exclude virus exposure (time point 1) and post-second and post-third vaccine (time points 2 and 3). Specific IgG antibodies were monitored by Luminex and T cells against SARS-CoV-2 spike-protein by ELISpot and CoVITEST. All episodes of symptomatic COVID-19 were recorded. Results: Nine patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and one with an undifferentiated autoimmune disease were included. Nine patients received mRNA vaccines. The last rituximab infusion was administered for a mean (SD) of 15 (10) weeks before the first vaccine and six patients were CD19-B cell-depleted. After a mean (SD) of 19 (10) and 16 (2) days from the second and third vaccine dose, IgG anti-SARS-CoV-2 antibodies were detected in six (60%) and eight (80%) patients, respectively. All patients developed specific T cell responses by ELISpot and CoVITEST in time points 2 and 3. Previous B cell depletion correlated with anti-SARS-CoV-2 IgG levels. Nine (90%) patients developed mild COVID-19 after a median of 7 months of the third dose. Conclusion: Rituximab in patients with autoimmune diseases reduces humoral responses but does not avoid the development of T cell responses to SARS-CoV-2 vaccination, which remain present after a booster dose. A steady cellular immunity appears to be protective against subsequent reinfections.

Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

BACKGROUND AND PURPOSE: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. METHODS: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. RESULTS: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs. CONCLUSIONS: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.

Hypogammaglobulinemia after Rituximab Treatment in an Italian Real-Life Cohort of Iim

Background. Rituximab (RTX) is a chimeric monoclonal antibody that binds the CD20 molecule on the surface of B cells and leads to B cell depletion. RTX is recommended by the European League Against Rheumatism (EULAR) as off-label in patients affected by idiopathic inflammatory myopathies (IIM). The real-world experience has shown that hypogammaglobulinemia occurring early after anti-CD20 treatment can be multifactorial (active disease, effect of other drugs) and usually transient, with a minimal increase in the risk of infections. The present study aimed to analyse the differences in the rate of RTX-associated hypogammaglobulinemia in a cohort of IIM patients in clinical practice, as well as the onset of major infections and its correlation with hypogammaglobulinemia. Methods. Patients followed at Rheumatology Unit of Siena University Hospital from January 2020 to September 2021 were retrospectively enrolled. Inclusion criteria were as follows: fulfilment of disease-specific classification criteria 2017 EULAR criteria and /or Peter and Bohan criteria for dermatomyositis (DM) and polymyositis (PM), positivity of anti-synthetase antibody and typical clinical features for anti-synthetase syndrome (ASS) and the measurement of serum Ig levels at the time of RTX administration (maximum 2 weeks before) (T0) and 6 (T1) to 12 (T2) months later, consistently with previous studies. Ig serum levels, measured by standard nephelometry (normal ranges: IgG 700-1600 mg/dL, IgM 40-240 mg/dL, IgA 70-400 mg/dL) were assessed as part of routine clinical care. Hypogammaglobulinemia was defined as moderate (serum IgG <600 mg/dL) and severe (IgG <400 mg/dL), as previously reported. Results. Seven patients (mean+/-SD, 57.3+/-19.7 years;7 female) were enrolled. Three of them had diagnosis of DM, three ASS and one PM. Two patients showed MDA5-positivity, two JO1-positivity, one TIF1-gamma-positivity, one PL7-positivity and the other one PM/Scl-positivity. All patients had at least two organs involved, and 4 out of 7 (57%) suffered from interstitial lung disease. Before starting RTX treatment, three and four patients underwent at least one and two synthetic immunosuppressants. All patients underwent low dosage of corticosteroids, and four patients underwent concomitant synthetic immunosuppressants (2 hydroxychloroquine and 2 MTX). IgG concentrations were statically lower at T2 compared to those at baseline (p=0.0391). None of them showed severe hypogammaglobulinemia. Similarly, IgM concentration significantly decreased at T2 compared to those at baseline (p=0.0078). Two patients showed major infections and two patients had paucisymptomatic COVID-19 (one of them had twice). Corticosteroids dosages were inversely correlated with IgG T2 concentrations (p=0.040, r=-0.919). Conclusion. Hypogammaglobulinemia following RTX is uncommon in IIM and is more likely in patients with high glucocorticoids, immunosuppressants and CYC exposure. IgG monitoring at least 6 months after RTX treatment may be useful in stratifying patients to identify those who require closer monitoring. These results shine a spotlight for increased awareness of the role of immunoglobulin measurement before maintenance doses of RTX.

Effectiveness and Safety of Nirmatrelvir/ Ritonavir in Real Life Setting

Background and Importance On March 28th 2022, nirmatrelvir/ ritonavir was marketed in Spain. The Spanish Agency for Medicines and Medical Devices (AEMPS) established criteria to prioritise its administration in patients at high risk of progression to severe COVID. Data regarding the effectiveness and safety of nirmatrelvir in preventing severe coronavirus disease outcomes are limited. Aim and Objectives To assess the effectiveness and safety of nirmatrelvir/ritonavir in patients at high risk for severe COVID-19. Material and Methods Prospective descriptive study from April to August 2022 of patients treated with nirmatrelvir/ritonavir. Sociodemographic variables, vaccination status, hospital admission, high risk factors for progression and concomitant treatment were recorded. Readmissions were recorded within 30 days of the end of antiviral treatment. Results 53 patients were included with a mean age of 64 years, 51% women and 49% men. 57% were vaccinated with 3 doses, 17% with 2 doses, 9% with 4 doses, 6% with 1 dose and 11% were not vaccinated. 34% (18/53) were hospitalised at the time of initiation of treatment. The most prevalent high-risk criteria were: 24% active treatment with myelotoxic chemotherapy, 21% treatment in the previous 6 months with anti-CD20 drugs, 14% over 80 years vaccinated with some risk factor for progression, 7% patients with onco-haematological treatment and 7% in treatment in the previous 3 months with inhibitors of the proteinkinase. 3 treatments were performed off-label for persistent covid. The mean number of days from the onset of symptoms to the start of treatment was 1.6 days. 23% of patients required dose adjustment due to renal impairment. 53% required adjustment of chronic treatment for interactions, mainly with metamizole, statins, fentanyl and diazepam. 2 patients received remdesivir and sotrovimab, 2 remdesivir and another two sotrovimab. 4 (7%) patients were readmitted within 30 days after the end of treatment with nirmatrelvir ritonavir, 1 of them with persistent covid. One patient stopped treatment for hives. Conclusion and Relevance Nirmatrelvir ritonavir has been shown to be a safe and effective drug in high-risk patients of progression to severe covid.

Disease-Modifying Therapies, Outcomes, Risk Factors and Severity of COVID-19 in Multiple Sclerosis: A MENACTRIMS Registry Based Study

Background: Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use;however, there is little data in our Middle East and North Africa region (MENA) identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Material(s) and Method(s): This a nationwide, multicenter, retrospective cohort study conducted between March 2020 and February 2021 and included MS patients with a suspected or confirmed COVID-19. Using data collected from the MENACTRIMS registry and local COVID-19 registries, the association of patient demographics, MS disease characteristics, and use of disease-modifying therapies with outcomes and severity of COVID-19 illness were evaluated by multivariate logistic models. Result(s): A total of 600 MS patients with suspected (n=58) or confirmed (n=542) COVID-19 (mean age: 36.4 +/- 10.16 years;414 (69%) females;mean disease duration: 8.3+/- 6.6 years) were analyzed. Seventy-three patients (12.2%) had a COVID-19 severity score of 3 or more, and 15 patients (2.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 559 patients (93.2%) were receiving disease-modifying therapy (DMT). There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients treated with DMTs relative to untreated patients (82.9% vs 17.1%;P < .001), from whom the majority (n=117;19.7%) were maintained on anti-CD20 therapies such as ocrelizumab and rituximab. Comorbidities mainly hypertension and cardiovascular diseases, progressive MS, disease duration, and EDSS were associated with severe or worse COVID-19 disease outcome. Multivariate logistic regression analysis showed that older age (odds ratio per 10 years, 1.5 [95%CI, 1.1-2.0]), male gender (OR, 2.1 [95%CI. 1.2-3.8]), obesity (OR, 2.8 [95%CI, 1.3-5.8]), and treatment ocrelizumab/rituximab (OR for ocrelizumab, 4.6 [95%CI. 1.2-17.7], OR for rituximab, 14.1 [95%CI, 4.8-41.3]) or off-label immunosuppressive medications such as azathioprine or mycophenolate mofetil (OR, 8.8 [95%CI. 1.7-44.0]) were risk factors for moderate to severe COVID-19 requiring hospitalization. Surprisingly, smoking and diabetes were not identified as risk factors for severe COVID-19 disease in our cohort. Conclusion(s): In this registry-based cohort study of patients with MS, age, sex, EDSS, obesity, progressive MS were independent risk factors for severe COVID-19. Moreover, there was an association found between exposure to anti-CD20 DMTs and COVID-19 severity. Knowledge of these risk factors may help improve the clinical management of MS patients with COVID-19 infection.Copyright © 2022

Hairy Cell Leukemia in a Filipino Male during the COVID-19 Pandemic - Report of a Rare Case

Hairy cell leukemia (HCL) is a rare, chronic, mature B-cell lymphoproliferative disorder accounting for 2% of all leukemias. In this paper, we would like to present our experience in the management of HCL in a financially limited setting where other diagnostic tests and chemotherapy are unavailable. The case report aims to emphasize the recognition of the distinctive morphology of hairy cells in the peripheral blood in the consideration of the initial diagnosis. A 60-year-old Filipino male was incidentally found to have anemia, thrombocytopenia and an absolute neutrophilic count below 1,000 in a pre-operative clearance for elective herniorrhaphy. Blood smear revealed atypical lymphocytes with hair like cytoplasmic projections. CT-scan of the abdomen showed splenomegaly and prominent paraaortic nodes. Flow cytometry of the bone marrow aspirate was consistent with an involvement of a Mature B cell neoplasm markers CD19, CD20, CD22 and surface immunoglobulin lambda and hairy cell leukemia markers CD11c, CD103 and CD25. He responded to six-weekly sessions of Cladribine with remission of the bone marrow and hematologic parameters. HCL is a rare type of a mature B cell neoplasm characterized by pancytopenia, splenomegaly, bone marrow fibrosis and the presence of atypical lymphoid cells with hairy projections in blood, bone marrow and spleen. Immunophenotyping express CD11c, CD103, CD123, and CD25. BRAF V600E mutation is the disease defining genetic event. Cladribine and Pentostatin are the first line of treatment. Cases of leukemia can be easily overlooked because of the mild derangement in the complete blood count. A meticulous differential review of the atypical lymphocyte, is the first step in the diagnosis of this rare disease.Copyright © 2022, Philippine College of Physicians. All rights reserved.

Persistent SARS-CoV-2 infection with multiple clinical relapses in two patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab.

PURPOSE: People with hematologic malignancies have a significantly higher risk of developing severe and protracted forms of SARS-CoV-2 infection compared to immunocompetent patients, regardless of vaccination status. RESULTS: We describe two cases of prolonged SARS-CoV-2 infection with multiple relapses of COVID-19 pneumonia in patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab. The aim is to highlight the complexity of SARS-CoV-2 infection in this fragile group of patients and the necessity of evidence-based strategies to treat them properly. CONCLUSIONS: Patients with hematological malignancies treated with bendamustine and anti-CD20 antibodies had a significant risk of prolonged and relapsing course of COVID-19. Specific preventive and therapeutic strategies should be developed for this group of patients.

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

Anti-CD20 antibodies and bendamustine attenuate humoral immunity to COVID-19 vaccination in patients with B-cell non-Hodgkin lymphoma.

Serologic responses of COVID-19 vaccine are impaired in patients with B-cell lymphoma, especially those who had recently been treated with anti-CD20 monoclonal antibodies. However, it is still unclear whether those patients develop an immune response following vaccination. We investigated the efficacy of vaccination against SARS-CoV-2 in 171 patients with B-cell non-Hodgkin lymphoma (B-NHL) who received two doses of an mRNA-based COVID-19 vaccine and we compared the efficacy of vaccination to that in 166 healthy controls. Antibody titers were measured 3 months after administration of the second vaccine dose. Patients with B-NHL showed a significantly lower seroconversion rate and a lower median antibody titer than those in healthy controls. The antibody titers showed correlations with the period from the last anti-CD20 antibody treatment to vaccination, the period from the last bendamustine treatment to vaccination and serum IgM level. The serologic response rates and median antibody titers were significantly different between diffuse large B-cell lymphoma (DLBCL) patients in whom anti-CD20 antibody treatment was completed within 9 months before vaccination and follicular lymphoma (FL) patients in whom anti-CD20 antibody treatment was completed within 15 months before vaccination. Moreover, the serologic response rates and median antibody titers were significantly different among FL patients in whom bendamustine treatment was completed within 33 months before vaccination. We demonstrated that B-NHL patients who were recently treated with anti-CD20 antibodies and bendamustine had a diminished humoral response to COVID-19 vaccination. UMIN 000,045,267.

Seroconversion following COVID-19 vaccination: can we optimize protective response in CD20-treated individuals?

Although there is an ever-increasing number of disease-modifying treatments for relapsing multiple sclerosis (MS), few appear to influence coronavirus disease 2019 (COVID-19) severity. There is concern about the use of anti-CD20-depleting monoclonal antibodies, due to the apparent increased risk of severe disease following severe acute respiratory syndrome corona virus two (SARS-CoV-2) infection and inhibition of protective anti-COVID-19 vaccine responses. These antibodies are given as maintenance infusions/injections and cause persistent depletion of CD20+ B cells, notably memory B-cell populations that may be instrumental in the control of relapsing MS. However, they also continuously deplete immature and mature/naïve B cells that form the precursors for infection-protective antibody responses, thus blunting vaccine responses. Seroconversion and maintained SARS-CoV-2 neutralizing antibody levels provide protection from COVID-19. However, it is evident that poor seroconversion occurs in the majority of individuals following initial and booster COVID-19 vaccinations, based on standard 6 monthly dosing intervals. Seroconversion may be optimized in the anti-CD20-treated population by vaccinating prior to treatment onset or using extended/delayed interval dosing (3-6 month extension to dosing interval) in those established on therapy, with B-cell monitoring until (1-3%) B-cell repopulation occurs prior to vaccination. Some people will take more than a year to replete and therefore protection may depend on either the vaccine-induced T-cell responses that typically occur or may require prophylactic, or rapid post-infection therapeutic, antibody or small-molecule antiviral treatment to optimize protection against COVID-19. Further studies are warranted to demonstrate the safety and efficacy of such approaches and whether or not immunity wanes prematurely as has been observed in the other populations.

Risk factors and outcomes of COVID-19 in adult patients with hematological malignancies: A single-center study showing lower than expected rates of hospitalization and mortality.

BACKGROUND: Studies addressing coronavirus disease 2019 (COVID-19) in patients with hematological malignancies have reported mortality rates of up to 40%; however, included predominantly hospitalized patients. METHODS: During the first year of the pandemic, we followed adult patients with hematological malignancies treated at a tertiary center in Jerusalem, Israel, who contracted COVID-19, with the aim of studying risk factors for adverse COVID-19-related outcomes. We used remote communication to track patients managed at home-isolation, and patient questioning to assess the source of COVID-19 infection, community versus nosocomial. RESULTS: Our series included 183 patients, median age was 62.5 years, 72% had at least one comorbidity and 39% were receiving active antineoplastic treatment. Hospitalization, critical COVID-19, and mortality rates were 32%, 12.6%, and 9.8%, respectively, remarkably lower than previously reported. Age, multiple comorbidities, and active antineoplastic treatment were significantly associated with hospitalization due to COVID-19. Treatment with monoclonal antibodies was strongly associated with both hospitalization and critical COVID-19. In older (≥60) patients not receiving active antineoplastic treatment, mortality, and severe COVID-19 rates were comparable to those of the general Israeli population. We did not detect patients that contracted COVID-19 within the Hematology Division. CONCLUSION: These findings are relevant for the future management of patients with hematological malignancies in COVID-19-affected regions.

Immunopathogenetic Aspects and Effectiveness of Combination Therapy for Influenza A (H1N1)pdm2009 in Children.

Introduction. The continuing circulation of influenza A (H1N1)pdm2009 virus poses a threat of a new epidemic rise. It is known that influenza A (H1N1)pdm2009 is characterized by a severe course, development of life-threatening complications, and high mortality, which is associated not only with the biological features of the pathogen, but also with the induction of deep immunosuppression, especially the interferon system and the cellular-type immune response. The role of influenza in the development of severe forms of the new coronavirus infection COVID-19 has been revealed. The increase of the number of virus strains resistant to various classes of antiviral drugs is of unfavorable importance. This requires the development of new approaches to the treatment of influenza A (H1N1)pdm2009 with the combined use of drugs with complex antiviral and immunocorrective activity. Purpose. To substantiate the combination therapy of influenza A (H1N1)pdm2009 in children using oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon). Materials and methods. Clinical and laboratory examination of 85 children aged from 3 to 5 years with moderate (43) and severe forms (42) of influenza A (H1N1)pdm2009 was carried out. Results and discussion. In patients with severe forms of A(H1N1)pdm2009 influenza, a higher frequency of anamnestic risk groups (85.7%), frequent development of febrile fever (100%), severe intoxication symptoms (100%), symptoms of laryngitis (28.6%), tracheitis (57.1%), bronchitis (76.2%), dyspeptic (42.9%) and cerebral syndromes (62.9%), other complications (80.9%) were revealed. In these patients, more significant changes of the indicators of the cellular type of the immune response were found - the decrease of CD3, CD4, CD8, the humoral type of immune response - the increase of CD20, IgM, circulating immune complexes, the decrease of IgA and IgG, innate immunity factors - the decrease of the metabolic activity of neutrophils, moderate increase of CD16. The combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (tamiflu) compared with oseltamivir (tamiflu) monotherapy reduced the duration of fever (Me 2, IQI 1-4 days and Me 3, IQI 2-4 days), intoxication (Me 3, IQI 2-4.5 days and Me 4.5, IQI 3-7 days), symptoms of rhinitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), pharyngitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), tracheitis (Me 2, IQI 1-3 days and Me 3.5, IQI 2-4 days), bronchitis (Me 3, IQI 2-5 days and Me 5, IQI 4-6 days). In this group, the complications developed less frequently (4.5% and 33.3%);there was the decrease of hospitalization time (Me 5, IQI 4-7 days and Me 6.5, IQI 5-7 days). There was the increase of the number of children, who (after 10 days from the start of therapy) had sanitation of the nasopharynx from the virus (90.9% and 61.9%). Conclusion. The high frequency of anamnestic risk groups and the induction of deep immunosuppression, especially the cellular component of immunity, are the cause of the formation of severe forms of influenza A (H1N1)pdm2009. This justified the appointment of combination therapy using the neuraminidase inhibitor oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon), which not only inhibits virus replication, but also has immunocorrective activity against the interferon system and cellular immunity. The high efficiency of the combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (Tamiflu) lets to recommend the inclusion of these drugs in the treatment of severe forms of influenza A(H1N1)pdm2009 in children.Copyright © 2020, Professionalnye Izdaniya. All rights reserved.

Immunopathogenetic Aspects and Effectiveness of Combination Therapy for Influenza A (H1N1)pdm2009 in Children.

Introduction. The continuing circulation of influenza A (H1N1)pdm2009 virus poses a threat of a new epidemic rise. It is known that influenza A (H1N1)pdm2009 is characterized by a severe course, development of life-threatening complications, and high mortality, which is associated not only with the biological features of the pathogen, but also with the induction of deep immunosuppression, especially the interferon system and the cellular-type immune response. The role of influenza in the development of severe forms of the new coronavirus infection COVID-19 has been revealed. The increase of the number of virus strains resistant to various classes of antiviral drugs is of unfavorable importance. This requires the development of new approaches to the treatment of influenza A (H1N1)pdm2009 with the combined use of drugs with complex antiviral and immunocorrective activity. Purpose. To substantiate the combination therapy of influenza A (H1N1)pdm2009 in children using oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon). Materials and methods. Clinical and laboratory examination of 85 children aged from 3 to 5 years with moderate (43) and severe forms (42) of influenza A (H1N1)pdm2009 was carried out. Results and discussion. In patients with severe forms of A(H1N1)pdm2009 influenza, a higher frequency of anamnestic risk groups (85.7%), frequent development of febrile fever (100%), severe intoxication symptoms (100%), symptoms of laryngitis (28.6%), tracheitis (57.1%), bronchitis (76.2%), dyspeptic (42.9%) and cerebral syndromes (62.9%), other complications (80.9%) were revealed. In these patients, more significant changes of the indicators of the cellular type of the immune response were found - the decrease of CD3, CD4, CD8, the humoral type of immune response - the increase of CD20, IgM, circulating immune complexes, the decrease of IgA and IgG, innate immunity factors - the decrease of the metabolic activity of neutrophils, moderate increase of CD16. The combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (tamiflu) compared with oseltamivir (tamiflu) monotherapy reduced the duration of fever (Me 2, IQI 1-4 days and Me 3, IQI 2-4 days), intoxication (Me 3, IQI 2-4.5 days and Me 4.5, IQI 3-7 days), symptoms of rhinitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), pharyngitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), tracheitis (Me 2, IQI 1-3 days and Me 3.5, IQI 2-4 days), bronchitis (Me 3, IQI 2-5 days and Me 5, IQI 4-6 days). In this group, the complications developed less frequently (4.5% and 33.3%);there was the decrease of hospitalization time (Me 5, IQI 4-7 days and Me 6.5, IQI 5-7 days). There was the increase of the number of children, who (after 10 days from the start of therapy) had sanitation of the nasopharynx from the virus (90.9% and 61.9%). Conclusion. The high frequency of anamnestic risk groups and the induction of deep immunosuppression, especially the cellular component of immunity, are the cause of the formation of severe forms of influenza A (H1N1)pdm2009. This justified the appointment of combination therapy using the neuraminidase inhibitor oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon), which not only inhibits virus replication, but also has immunocorrective activity against the interferon system and cellular immunity. The high efficiency of the combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (Tamiflu) lets to recommend the inclusion of these drugs in the treatment of severe forms of influenza A(H1N1)pdm2009 in children.Copyright © 2020, Professionalnye Izdaniya. All rights reserved.