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Background: X-Linked Moesin-Associated Immune Deficiency (X-MAID) is a rare severe combined immunodeficiency (SCID) subtype that can present at any age due to its variability. Depending on severity, patients demonstrate failure to thrive, recurrent bacterial and viral infections, and increased susceptibility to varicella zoster. It has been characterized by marked lymphopenia with hypogammaglobulinemia and impaired T-cell migration and proliferation. Case Presentation: This is a report of a Cuban 7-year-old male with poor weight gain and facial dysmorphia. He had a history of recurrent bacterial gastrointestinal infections and pneumonia beginning at 4 months of age. He additionally had 4-6 upper respiratory tract and ear infections annually. While still living in Cuba, he was admitted for a profound EBV infection in the setting of significant leukopenia. A bone marrow biopsy confirmed no malignancy. After he moved to the United States, his laboratory work-up revealed marked leukopenia with low absolute neutrophil and lymphocyte count with low T and B cells, very low immunoglobulin levels IgG, IgA, and IgM, and poor vaccination responses to streptococcus pneumonia, varicella zoster, and SARS-CoV-2. Genetic testing revealed a missense pathogenic variant c.511C>T (p.Arg171Trp) in the moesin (MSN) gene associated with X-MAID. He was managed with Bactrim and acyclovir prophylaxis, and immunoglobulin replacement therapy, and considered for hematopoietic stem cell transplantation. Discussion(s): Diagnosis of X-MAID should be considered in patients with recurrent infections and profound lymphopenia. As with SCID, early diagnosis and intervention is of utmost importance to prevent morbidity and mortality. This case demonstrates the importance of genetic testing in identifying this disease as it may prompt an immunologist to consider HSCT if conservative management is suboptimal. In the current literature, HSCT appears promising, but the long-term outcomes have yet to be described.Copyright © 2023 Elsevier Inc.
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Bivalent COVID-19 vaccines that contain two mRNAs encoding Wuhan-1 and Omicron BA.4/5 spike proteins are successful in preventing infection from the original strain and Omicron variants, but the quality of adaptive immune responses is still not well documented. This study aims at characterizing adaptive immune responses to the bivalent booster vaccination in 46 healthy participants. Plasma and PBMC were collected prior and three weeks after bivalent booster. We measured anti-N, anti-S, and RBD IgM, IgA, IgG plasma titers against original, Omicron BA.1, and BA.5 variants (pending) as well as total anti-S IgG titers and surrogate Virus Neutralization capacity against the Alpha, Delta, and BA.1 variant. With spectral flow-cytometry we identified peripheral blood B-cells specific for the RBD of the S-protein of the original and BA.1 variants. T-cell-specific responses were assessed by cytokine release assay after stimulation with SARS-CoV-2 peptides from the original, BA.1, BA.4, and BA.5 variants (pending). Finally, we performed TRB and IGH repertoire studies on sorted CD4+, CD8+, CD19+ lymphocytes, to study breadth of SARS-CoV-2 specific clonotypes (pending). 27/46 participants were analyzed;9 had SARS-CoV-2 infection (COVID+), while 18 are infection naive (COVID-). In both groups, median time since last dose of SARS-CoV-2 vaccine (3rd or 4th) was 11 months. All subjects were positive for anti-S IgG prior to bivalent booster. The COVID + group displayed anti-S IgG pre-booster levels and neutralization against BA.1 higher than the COVID- group. Significant increase post-boost of total anti-S IgG and BA.1 neutralizing activity was detected in the COVID- but not in the COVID+ group;however, no difference in neutralization activity post-boost was detected between the two groups. Furthermore, the COVIDgroup showed significant increase in the frequency of CD19+ and CD27+ switched memory B-cells specific for BA.1 RBD in post-boost compared to pre-boost samples. However, post-boost frequencies of the same B-cells were higher in the COVID+ compared to the COVID- group. These preliminary findings confirm that among individual immunized with the original COVID-19 mRNAvaccine, prior COVID infection provides increased protection against SARS-CoV-2 variants. They also demonstrate that booster immunization with the bivalent vaccine induces robust adaptive immune responses against Omicron variant.[Formula presented][Formula presented]Copyright © 2023 Elsevier Inc.
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Background: Studies suggest perinatal infection with SARSCoV- 2 can induce adverse birth outcomes, but studies published to date have substantial limitations. Most have identified cases based upon their presentation for clinical care, and very few have examined pandemic-related stress which may also impact adverse birth outcomes. Objective(s): To evaluate the relationships between SARSCoV- 2 infection in pregnancy and pandemic-related stress with birth outcomes. Study Design: We conducted an observational study of 211 mother-newborn dyads in three urban cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) Program. Serology for SARS-CoV-2 was assessed in a convenience sample of prenatal maternal, cord serum or dried blood spots from births occurring between January 2020-September 2021. Specimens were assessed for IgG, IgM, and IgA antibodies to nucleocapsid, S1 spike, S2 spike, and receptor-binding domain. A Pandemic-related Traumatic Stress (PTS) scale was based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Acute Stress Disorder criteria. Result(s): 36% were positive for at least one antibody type, chiefly IgG. Self-report of infection was not significantly correlated with combined serology. There were no differences in gestational age (GA), birth weight, preterm birth (PTB), or low birth weight (LBW) among seropositive mothers. However, IgM seropositive mothers had children with lower BW (434g, 95% CI: 116- 752), BW Z score-for-GA (0.73 SD, 95% CI 0.10-1.36) and were more likely to deliver preterm (OR 8.75, 95% CI 1.22-62.4). Associations with LBW sustained in sensitivity analyses limited to pre-vaccine samples, and PTS symptoms were not associated with birth outcomes. The addition of PTS did not substantially change associations with BW, although associations with PTB attenuated to near-significance. Conclusion(s): We identified decreased birth weight and increased prematurity in mothers IgM seropositive to SARS-CoV-2, independent of PTS. Though there are limits to interpretation, the data support efforts to prevent SARS-CoV-2 infections in pregnancy.
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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.
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Case: Wiskott-Aldrich Syndrome (WAS) is a rare X-linked inborn error of immunity caused by mutations in the WAS gene. It is classically characterized by immunodeficiency, eczema, and micro-thrombocytopenia. It has been known since the 1960s that patients with WAS have an increased risk of lymphoproliferative disease though the exact incidence remains unknown in the American population. Limited case reports have discussed EBV-related lymphoproliferative disease in patients with WAS. We present a case of a 9-year-old boy with known WAS complicated by eczematous rash, thrombocytopenia, recurrent ear infections, and monoclonal gammopathy who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. Family had been offered treatment with hematopoietic stem cell transplant but declined multiple times in the past. Earlier in the year, he presented with possible MIS-C with negative SARS-CoV-2 PCR. He presented to our hospital with mastoiditis and lymphadenopathy. Physical examination showed severe eczema on hands and tender right mastoid. Laboratory evaluation showed thrombocytopenia, elevated IgG of 6290, IgA of 744, IgE of 827, low IgM of 41, and 14% response to pneumococcal titers. He was empirically treated with intravenous antibiotics. ENT performed right postauricular incision and drainage and the culture grew Hemophilus influenza. Throughout his hospital stay, his submandibular lymphadenopathy became more prominent despite treatment. Core needle biopsy of right submandibular lymph node was suggestive of EBV-associated lymphoid hyperplasia. EBV PCR and antibodies were both positive. CT chest, abdomen, and pelvis revealed multifocal pulmonary lymphadenopathy and a diffuse, bilateral nodularity as well as retroperitoneal and mesenteric lymphadenopathy. He was given four doses of weekly Rituximab, which successfully decreased EBV viremia below linear detectability. Immunoglobulin replacement therapy (IgRT) was initiated. Bronchoalveolar lavage and lung biopsy were performed and are results are currently pending. Discussion(s): We present a case of a 9-year-old boy with known WAS awaiting transplant who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. While lymphoproliferative disease is a known complication of WAS, EBV-related lymphoproliferative disease in WAS patients has only been reported as case reports and remains a rare but known complication of patient with WAS.Copyright © 2023 Elsevier Inc.
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Background: SAMD9L is a tumor suppressor involved in regulating the proliferation and maturation of cells, particularly those derived from the bone marrow, and appears to play an important role in cerebellar function. It can be activated in hematopoietic stem cells by type I and type II interferons. It has been hypothesized to act as a critical antiviral gatekeeper regulating interferon dependent demand driven hematopoiesis. Gain of function mutations can present with an immunodeficiency due to transient severe cytopenias during viral infection. Case presentation: We report a 3-year-old boy born full term with a history of severe thrombocytopenia requiring transfusions, developmental delay, ataxia, seizure disorder, and recurrent severe respiratory viral infections. His infectious history was significant for respiratory syncytial virus with shock requiring extracorporeal membrane oxygenation complicated by cerebral infarction and a group A streptococcus empyema, osteomyelitis requiring a left below the knee amputation, and infections with rhinovirus, COVID-19, and parainfluenza requiring hospitalizations for respiratory support. Initial immunologic evaluation was done during his hospitalization for parainfluenza. His full T cell subsets was significant for lymphopenia across all cell lines with CD3 934/microL, CD4 653/microL, CD8 227/microL, CD19 76/microL, and CD1656 61/microL. His mitogen stimulation assay to phytohemagglutinin and pokeweed was normal. Immunoglobulin panel showed a mildly decreased IgM of 25 mg/dL, but normal IgA and IgG. Vaccine titers demonstrated protective titers to 12/22 pneumococcus serotypes, varicella, diphtheria, mumps, rubella, and rubeola. Repeat full T cell subsets 6 weeks later revealed marked improvement in lymphocyte counts with CD3 3083/microL, CD4 2101/microL, CD8 839/microL, CD19 225/microL, and CD1656/microL. A primary immunodeficiency genetic panel was ordered and positive for a heterozygous SAMD9L c.1549T>C (p.Trp517Arg) mutation classified as a variant of unknown significance. Discussion(s): This patient's history of severe viral infections, ataxia, thrombocytopenia, and severe transient lymphopenia during infection is suggestive of a SAM9DL gain of function mutation. Protein modeling done by the laboratory suggests this missense mutation would affect protein structure. The mutation found has been observed in individuals with thrombocytopenia. This case highlights the importance of immunophenotyping both during acute illness and once recovered.Copyright © 2023 Elsevier Inc.
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BackgroundIgA vasculitis (IgAV) is a rare autoimmune disease affecting small vessels. It is well established that the incidence is higher in children (3 to 26 per 100,000 children/year,) [1] than in adults (0.1 to 1.8 per 100,000 individuals/year) [1]. However others epidemiological data and impact of the COVID-19 on IgAV remain overlooked [2].ObjectivesTo collect and analyze epidemiological data on IgAV in both adults and children in France.MethodsWe conducted an observational study using a national database called "BNDMR” [3] (Banque Nationale de Données Maladies Rares) on IgA vasculitis (code ORPHA761), which gathered patients managed in the French rare disease expert network. The incidence was estimated from the date of diagnosis, and we calculated the median annual incidence over the period 2010-2022. We specifically assessed the north/south gradient (latitude of the residence higher/lower than the median of the latitudes), the seasonality, and the impact of the COVID-19 pandemic compared to other patients reported within the same period and addressed in the same expert centers used as controls.ResultsDuring this 12-year period, 1988 patients with IgAV were reported (1498 children;490 adults). The male to female ratio was 1.57 for adults and 1.05 for children. The median IgAV annual incidence was 15 cases/year [IQR 9-30] and 82 cases/year [IQR 72-86] for adult and children cases respectively. Time to diagnosis was less than 1 month for both. Compared with other patients reported in the same expert centers, IgAV was more frequently reported in the southern part of France than in the north (OR 4.88 [95% confidence intervals: 4.17 - 5.74] in adults and OR 1.51 [1.35 - 1.68] in children). IgAV was also more frequently observed in winter than during the rest of the year in both adults (OR 1.60 [1.39 - 1.82]) and children (OR 1.22 [1.01 - 1.48]). The incidence of IgAV decreased during the COVID-19 pandemic period (from March 2020 to September 2022) in children (OR 0.62 [0.47 - 0.81]) but not in the adult population (OR 0.90 [0.76 - 1.06]).ConclusionOur study confirms the winter seasonality and sex ratio in IgAV [4,5], but suggests that the incidence or the reporting of IgAV decreased in children during the COVID19 pandemia, possibly due to barrier measures [6]. The observed north/south gradient need confirmation. The main limitation of this study is a possible IgAV under-reporting as this study rely only on cases addressed in expert centers.References[1]Audemard-Verger A, Pillebout E, Guillevin L, Thervet E, Terrier B. IgA vasculitis (Henoch-Shönlein purpura) in adults: Diagnostic and therapeutic aspects. Autoimmun Rev. 2015;14(7):579-585. doi:10.1016/j.autrev.2015.02.003[2]Deshayes S, Moulis G, Pillebout E, Aouba A, Audemard-Verger A. Positive predictive value of hospital discharge diagnosis code to identify immunoglobulin A vasculitis in France: A validation study. Eur J Intern Med. 2017;43:e18-e19. doi:10.1016/j.ejim.2017.05.025[3]Jannot AS, Messiaen C, Khatim A, Pichon T, Sandrin A, BNDMR infrastructure team. The ongoing French BaMaRa-BNDMR cohort: implementation and deployment of a nationwide information system on rare disease. J Am Med Inform Assoc. 2022;29(3):553-558. doi:10.1093/jamia/ocab237[4]Piram M, Maldini C, Biscardi S, et al. Incidence of IgA vasculitis in children estimated by four-source capture-recapture analysis: a population-based study. Rheumatology (Oxford). 2017;56(8):1358-1366. doi:10.1093/rheumatology/kex158[5]Gardner-Medwin JMM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet. 2002;360(9341):1197-1202. doi:10.1016/S0140-6736(02)11279-7[6]Kaya Akca U, Atalay E, Cuceoglu MK, et al. Impact of the COVID-19 pandemic on the frequency of the pediatric rheumatic diseases. Rheumatol Int. 2022;42(1):51-57. doi:10.1007/s00296-021-05027-7Figure.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Objective: A new generation of vaccine technology platform has been developed to combat the COVID- 19 pandemic, the mRNA vaccine. The EMA granted the Pfizer- BioNTech COVID-19 vaccine an emergency use authorization in December 2020 with limited clinical experience, especially in the pediatric population. Method(s): Here, we present a case-report of a 17-yearold girl, who was vaccinated with the mRNA-COVID vaccine in October 2021, and developed a gross hematuria and proteinuria the day after the vaccination. Result(s): The patient presented at our outpatient clinic three days after the vaccination with new-onset hematuria and proteinuria. Up to this date, she had no former known medical conditions and the family history was negative regarding kidney diseases. We excluded nephrolithiasis, autoimmune glomerulonephritis and urinary tract infection as causes. The laboratory chemistry of the kidney was within normal range. The proteinuria dissolved spontaneously, and a microhematuria persisted. One day after the second dose of Cominarty in November 2021, the gross hematuria with proteinuria relapsed. A treatment with an ACE-inhibitor did not have any effect on the proteinuria. At this point, only a few casereports of patients with a comparable clinical course, especially from Japan, were published. In suspicion of a vaccine-triggered nephritis we started a prednisolon therapy which dissolved the proteinuria and induced a regression of the haematuria to a minimal stage. Conclusion(s): Within the last year, the medical community has gained more insights concerning mRNA vaccines. There is growing evidence, that mRNA vaccines can trigger de novo or relapse IgA nephropathy. But more systematic research and long-term evaluation is desirable to elucidate the underling pathophysiology as well as the influence on kidney survival of affected patients in the future. Furthermore, patient education should incorporate the risk of hematuria and proteinuria in children when applying mRNA vaccines.
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We conducted a retrospective study in the adult primary immunodeficiency clinic at UAB examining COVID-19 infection and COVID-19 antibody response from vaccination, natural infection, and immunoglobulin replacement from February 2021 to November 2022. Our goal was to determine if nucleocapsid and spike antibodies could be found in our PID patients and if these antibodies could be derived from natural infection, vaccination, or antibody replacement exclusively or combinatory. We hypothesized that increasing antibodies would be detected in our population as the COVID period extended. Two hundred and forty-five subjects were tracked over 336 clinic visits during this period. Our PID population included subjects with CVID, XLA, thymoma, hypogammaglobulinemia, IgA deficiency, IgG subclass deficiency, specific antibody deficiency, Down syndrome, IgM deficiency, and patients with recurrent sinopulmonary infections. We had 196 females and 45 males in our study. In our patient population, 47% of our patient had known COVID-19 infection. Of those 47%, 21% of those infected patients had COVID-19 at least twice. Of those infected, three did not have COVID-19 spike antibodies and chose not to get vaccinated either. Two of those patients were not on IVIG and one was on Pangyza. Of those infected, 70% (n = 80) were on IgG infusions compared to those uninfected, 77% (n = 96) were on IgG infusions. Of interest, we had three XLA patients and all three had COVID-19 infection in the summer 2021. Two of them tested positive for nucleocapsid and spike antibodies in high titers and they were receiving Gammagard or Gamunex infusions, suggesting that these immunoglobulin preparations contain COVID-19 antibodies. We are still in the process of analyzing our data to see if diagnosis, IgG preparations, date of testing, B cell numbers, and drugs play a role in producing nucleocapsid antibodies and high spike antibody titers.Copyright © 2023 Elsevier Inc.
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Ab s t r ac t Aim: The aim of this study was to summarize different types of benefits that have been observed in the baby's development and the mother's psychological health during the postpartum period. Background(s): Breastfeeding is a natural process that plays a vital role in the physical as well as mental health of the mother and child. Breast milk is rich in contents such as proteins, fats, and vitamins, which are responsible for building the immune system of the baby. Lactation helps in decreasing the prevalence of infant mortality rate. It enhances the development of the physical health of the children. Breastfeeding protects the mother from many systemic conditions like endometrial cancer, ovarian cancer, breast cancer, etc. It has been observed that with an increase in healthy breastfeeding practices, there is a decline in the cases of maternal mental health issues reported mainly in the postpartum period. Review result: The authors have explained various types of advantages of breastfeeding on the child's and mother's health, their mechanism of action, effects on the baby, and mother-child relationship. Conclusion(s): The mother's mental health plays a crucial role in a healthy infant, and breastfeeding is key to it. The role of breastfeeding is therefore considered a boon for the mother because if there is a decrease in health issues in the child, the mother's mental condition improves automatically. Therefore, breastfeeding should be promoted at the national level. Clinical significance: Breastfeeding not only helps in reducing maternal stress and postpartum depression but also improves the physical health of the child and mother during the postpartum period. The clinicians should teach mothers about the importance and also the correct positions of breastfeeding. "Breastfeeding week" is celebrated every year from August 1 to August 7, as implemented by the Indian government.Copyright © The Author(s). 2023 Open Access.
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Introduction: Type 1 interferon (IFN) autoantibodies, such as anti-IFNalpha, have pathogenic significance in life-threatening COVID-19 pneumonia. Ten to twenty percent of severe COVID cases are associated with type I IFN autoantibodies. These autoantibodies likely pre-exist while others arise de novo relative to SARS-CoV-2 infection. It is unclear to what extent type I anti-IFN autoantibodies are induced by SARS-CoV-2 infection and contribute to COVID-19 severity. We investigated these phenomena in those with inborn errors of immunity (IEI) and rheumatic disease (RHE). Aim(s): We aim to compare the prevalence and neutralization ability of anti-IFNalpha autoantibodies in IEI and RHE patients using archived blood samples before and after the COVID-19 pandemic began. Method(s): We determined the presence of autoantibodies against IFNalpha in plasma samples by enzyme linked immunosorbent assay in 453 patients with IEI or RHE who were testing either before or after the COVID-19 pandemic began in March 2020. Using flow cytometry, we determined the function of IFNalpha autoantibodies in plasma to block CD4T cell activation by inhibiting STAT-1 phosphorylation. Result(s): We found that 25 patients with IEI or RHE were positive for anti-IFNalpha autoantibodies. 10 out of 229 patient samples collected before the pandemic (4.2%) tested positive whereas 15 out of 224 patient samples collected after the pandemic began (7.0%) were positive. Seven of the 25 patients (28%) who tested positive had neutralizing antibodies in plasma, which prevented STAT-1 phosphorylation in CD4T cells;all of these patients had partial recombination activating gene deficiency (pRD) except for one patient with autoimmunity, leukemia and selective IgA deficiency. One pRD patient had anti-IFNalpha autoantibodies with neutralization capacity before the pandemic, which persisted after hematopoietic stem cell transplantation (HSCT) with full immune reconstitution. The patient was immunized for SARS-CoV-2 before and after HSCT and acquired COVID-19 infection a year after HSCT. The patient was symptomatic but never hospitalized and fully recovered despite having anti-IFNalpha autoantibodies. Conclusion(s): Anti-IFNalpha autoantibody levels were comparable before and after the start of the COVID-19 pandemic in IEI and RHE patients but only 28% of cases were neutralizing. The clinical implications of these autoantibodies are yet to be determined.Copyright © 2023 Elsevier Inc.
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BackgroundTreatment with Rituximab (RTX) in patients with rheumatic diseases (RD) has presented a challenge during the COVID-19 pandemic, as RTX leads to markedly reduced and often undetectable antibody responses after COVID-19 vaccination (1).ObjectivesTo investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with RD who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion.MethodsFrom a RD cohort (COPANARD) vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies (abs) and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralizing abs, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. This study was funded by the Danish Rheumatism Association.ResultsPatient demographics are given in Table 1. Forty-seven percent of cases had detectable total SARS-CoV-2 abs and neutralizing abs after revaccination. However, antibody levels were significantly lower than in controls and blood donors (p<0.008), Figure 1A+B. Revaccination induced an antibody class switch in cases with a decrease in detectable IgM abs (Baseline 11/17, Followup 3/17) and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups, Figure 1C. The proportion of cases with detectable CD4+ T cells increased from 69% to 88% (p=0.25), and for CD8+ T cells, the proportion decreased from 88% to 82% (p=1.00). Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors, Figure 1D. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination, Figure 1D.Univariate logistic regression analysis was performed to analyze if active RTX treatment, the presence of B-cells, or a positive T-cell response prior to revaccination predicted seroconversion of total SARS-CoV-2-abs in the patient cohort. We did not find a significant explanatory effect of either variable in the univariate logistic models, data not shown.Table 1.DemographicsCases Revaccination, n=17Controls Boost, n=29Female sex, no(%)1482%2172%Age, median (IQR)6549 - 706762 - 72Disease duration, years1510 - 18229 - 31Rheumatoid Arthritis/SLE13/410/19None DMARD529%828%Prednisone424%13%Methotrexate741%1241%Hydroxychloroquine212%414%None biologic treatment424%931%Rituximab1271%0TNF-inhibitors16%724%JAK-inhibitors0621%IL-6-inhibitors, Abatacept, Benlysta0724%Previous rituximab treatmentAny rituximab treatment1694%13%RTX within the last 15 months, no1488%0Cumulative total dose, mg134-242Time from RTX to revaccination, months95-1249Figure 1.ConclusionIn conclusion, forty-seven percent of initial non-responders were able to seroconvert after two-dose revaccination. However, plasma concentrations of the antibodies against SARS-COV-2 and the levels of neutralizing capacity remained significantly lower than in immunocompetent blood donors. B-cell levels or T-cell responses before revaccination did not predict seroconversion. Our study suggests that patients with RDs who did not mount a detectable serological response to a COVID-19 mRNA vaccine have a T cell response similar to immunocompetent controls. Future studies should establish the antibody levels that identify RD patients without sufficient protection against SARS-CoV-2 infection.References[1]Troldborg A, et al. Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases. J Rheumatol. 2022.AcknowledgementsThe Danish Rheumatism Association [grant number R203-A7217]. We acknowledge all patients and blood donors contributing to the stud for their invaluable participation. The authors would like to thank Sif Kaas Nielsen and Mads Engelhardt Knudsen, the Laboratory of Molecular Medicine at Rigshospitalet, for their excellent technical assistance in analyzing the samples.Disclosure of InterestsNone Declared.
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Introduction: The prevalence of various infectious diseases has been changing since the COVID-19 pandemic in Japan. Hepatitis A (HA) is transmitted from food and drink contaminated with the hepatitis A virus, while hepatitis E (HE) is a known zoonotic disease. The trends of HA and HE infection during the COVID-19 pandemic are unknown in Japan. Objective(s): In this study, we investigated the incidence of HA and HE before and after the COVID-19 epidemic, and compared the differences in trends between our hospital and Japanese statistics. Method(s): We investigated the number of IgA-HEV and IgM-HAV antibodies tested and positive at our hospital between January 2015 and December 2021. We verified the patient background, blood test findings and outcome of each antibody-positive. Result(s): The number of HE diagnoses /tests (rate) was 2 /187 (1.1%) in 2015, 2 /155 (1.3%) in 2016, 7 /236 (3.0%) in 2017, 11 /234 (4.7%) in 2018 and 15/ 307 (4.9%) in 2019, which was an increasing trend, but the number of tests remained the same but the number of diagnoses decreased 6 /314 (1.9%) in 2020, 2 /296 (1.0%) in 2021. According to Japanese statistics, the number of HE diagnoses showed a gradual increase from 213 in 2015 to 490 in 2019, but a slight decrease was reported in 441 in 2020 and 447 cases in 2021, respectively. On the other hand, there was no marked change in the number of HA diagnoses/tests between 2015 and 2019. 7 cases of HIV co-infection and an epidemic among Men who have Sex with Men (MSM) were observed in 2018. The number of cases decreased markedly to 0 /362 (0%) in 2020 and 0 /339 (0%) in 2021. In Japan, the number of HA diagnoses was in the 200 s from 2015 to 2017, while 925 cases were diagnosed in 2018 and 425 cases in 2019, indicating an epidemic, but the number of HA diagnoses has decreased significantly to 118 in 2020 and 69 in 2021. Conclusion(s): The number of cases of HE, a zoonosis, was reported to have decreased slightly nationwide, even with the coronary disaster, but the number of cases decreased markedly at our facility in Tokyo, suggesting the influence of changes in the lifestyle and activity patterns of the patient population. On the other hand, the number of cases of HA, which had been prevalent in recent years as a result of sexual contact among MSM, has decreased, probably due to a decrease in the influx of cases from overseas as a result of travel restrictions.
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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.
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Junior Physician Investigator Award Recipient Purpose of study Severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Convalescent plasma obtained from recovered persons was used for previous respiratory pandemics. Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) was proposed as an option that may hold promise as treatment for COVID-19. Our aim was to retrospectively evaluate the efficacy of CCP treatment of patients with severe to life-threatening COVID-19 hospitalized at Montefiore Medical Center (MMC) in the Bronx, NY between April 13 to May 4, 2020. Methods used We administered CCP as part of the Mayo Clinic expanded access investigational new drug (IND) program for hospitalized patients. We compared the mortality and clinical outcome of 73 patients with COVID-19 who received 200 mL of CCP with a Spike protein IgG titer >=1:2,430 (median 1:47,385) within 72 hours of admission to 1:1 propensity score-matched controls. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroids, and anticoagulation use (figure 1). We additionally measured Spike protein IgG and neutralizing antibody titer in CCP and pre- and post-transfusion Spike protein IgG, IgM and IgA titer in CCP recipients. The primary outcome was all-cause mortality at day 28 post-CCP. The secondary outcomes were improvement in oxygenation status or mortality at day 28 post-CCP. Exploratory outcomes were associations between pre-CCP SARS-CoV-2 antibody titers and mortality at day 28. Summary of results There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared to matched controls, CCP recipients < 65 years had 4-fold lower mortality and 4-fold lower deterioration in oxygenation or mortality at day 28 (figure 2, 3). There was no association between CCP IgG or neutralizing antibody titer and clinical outcome. For CCP recipients, pre-transfusion Spike protein IgG, IgM and IgA titers were associated with mortality at day 28 in univariate analyses but not in multivariable analyses. Pre-transfusion Spike protein IgG titer was significantly correlated with Ddimer and detected viral load measured by cycle threshold (Ct) value of nasopharyngeal SARS-CoV-2 reverse-transcriptase- polymerase-chain-reaction (figure 4). No adverse effects of CCP were observed. Conclusions We report that CCP administration within 72 hours of hospitalization demonstrated a possible signal of reduced mortality in patients < 65 years. Pre-transfusion IgG titer may be a proxy for disease severity that may be useful in identifying those who are more likely to respond to CCP. Data from controlled trials is needed to validate this finding and establish the effect of ageing on CCP efficacy. (Figure Presented).
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Background: SARS-CoV-2 evokes vigorous humoral immune responses which includes production of virus-specific antibodies of the immunoglobulin IgM, IgG & IgA isotypes. Seroconversion & production of detectable antibodies usually occurs within 20 days of symptom onset, while the kinetics of their production is variable. IgA is the major antibody class in mucosal membranes which plays an important role in SARS-CoV-2 infections. It's response in the early stage of the disease seems to be more pronounced than IgM. Objective(s): To detect the presence of serum IgA antibody response against Spike Receptor Binding Domain & Nucleoprotein of SARSCoV- 2 in naturally infected individuals as well as vaccinated individuals. Material(s) and Method(s): Confirmed RT-PCR Covid positive serum samples were tested by in-house developed SRBD IgA ELISA & N protein IgA ELISA of SARS-CoV-2. The subjects were classified according to the post onset of disease date. Serum samples of vaccinated individuals (Covishield & Covaxin) were assessed to compare IgA response. Result(s): Our results suggest a linear trend in the level of IgA antibody response POD 8 onwards in natural infection. In vaccinated individuals Covaxin groups exhibits a prominent increase in the IgA response in comparison to Covisheld. Conclusion(s): IgA might play an important role in assessing the immune status of SARS-CoV-2 infected patients. This study suggests that IgA antibody act as a promising immunological marker for vaccine study.
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Dysbiosis, especially in the gut plays a crucial role in the pathogenesis of a wide variety of diseases, including inflammatory bowel disease, colorectal cancer, cardiovascular disease, obesity, diabetes and multiple sclerosis. At mucosal surfaces, mucosal polymeric immunoglobulin A（IgA）antibodies are known to be important to regulate the gut microbiota as well as to exclude infection induced by pathogenic bacteria or virus such as influenza and SARS-CoV-2（severe acute respiratory syndrome coronavirus 2）. Since the 1970s, oral administration of IgA or IgG antibodies has been performed against infectious enteritis caused by pathogenic Escherichia coli or Clostridioides difficile. However, none of them has been successfully developed as an antibody drug up to now. Although IgA is well known to modulate the gut commensal microbiota, the therapeutic IgA drugs to treat dysbiosis has not been developed. Here, we discuss the advantages of therapeutic IgA antibodies.Alternate :抄録Dysbiosisは、健康な微生物叢と比較した微生物組成の変化であり、腸内微生物多様性の減少および微生物分類群の変化を特徴とする。腸内のdysbiosisはまた、炎症性腸疾患、結腸直腸がん、心血管疾患、肥満、糖尿病および多発性硬化症を含むさまざまな疾患の病因において重要な役割を果たすと提唱されている。腸の多量体免疫グロブリンA（IgA）抗体は、腸内微生物叢を調節するだけではなく、病原性細菌、インフルエンザやSARS-CoV-2（重症急性呼吸器症候群コロナウイルス2）などのウイルス感染を粘膜部位から排除するのに重要であることが、多くのエビデンスから示されている。1970年代以降、治療用IgAまたはIgGの経口投与試験が、主に病原性大腸菌またはディフィシル菌によって引き起こされる感染性腸炎を治療するために行われてきた。しかし、現在まで臨床応用として開発に成功したものはない。腸内病原体に対する防御機能に加えて、IgAは腸内共生微生物叢を調節して共生に導くことがよく知られているが、dysbiosisを治療するためのIgA治療薬の開発も進んでいない。本稿では、治療用IgA抗体の利点とその開発について議論する。
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Background: People with HIV (PWH) on antiretroviral therapy (ART) appear to be at higher risk for worse COVID-19 outcomes, but the underlying mechanisms-including effects of COVID-19 and host factors on the broader humoral immune repertoire-are poorly understood. Method(s): REPRIEVE enrolled a global cohort of ART-treated PWH ages 40-75. COVID+ was defined by positive receptor binding domain IgG or IgA from annual visits 5/2020-2/2021. Antibody isotype, subclass, and Fc receptor Luminex arrays to SARS-CoV-2, CMV, EBV, HSV, HIV, influenza, pneumococcus, and RSV were assessed. Report of COVID diagnosis (collected every 4 months) was defined as mild, moderate, or severe (asymptomatic if no clinical diagnosis but IgG/ IgA+). FDR-corrected regression was used to assess effects of 1) COVID+ on non- SARS-CoV-2 repertoire in full cohort and 2) host factors on non-SARS-CoV-2 and SARS-CoV-2 repertoire in COVID- and COVID+ cohorts, respectively, adjusted for age, sex, region, nadir CD4, and HIV VL at entry. Result(s): Of 2,464 unvaccinated participants, 283 (11%) were COVID+;260 (92%) were asymptomatic. Median age was 53, 35% were women, 50% had nadir CD4 < 200, median current CD4 was 649, and 97% had HIV VL < 400. In the full cohort, COVID+ was associated with higher CMV PP65 IgG3 and FcgammaRIIA (P< 0.05);COVID severity was not associated with the non-SARS-CoV-2 repertoire. Among COVID-, older age, female sex, and lower nadir CD4 were associated with higher EBV and CMV responses;IgG1 levels were higher in women for all non-SARS-CoV-2 antigens assessed (P< 0.05). Among COVID+, higher BMI was associated with amplified SARS-CoV-2 IgG, IgA, IgM, and FcgammaRIIA responses (P< 0.05). Lower nadir CD4 was associated with a SARSCoV- 2 repertoire shift toward IgM and FcgammaRIIB (P< 0.05). Age and sex were not associated with SARS-CoV-2-related repertoire changes in COVID+. Conclusion(s): Our analysis presents a comprehensive view of host factors associated with the humoral immune repertoire among a global cohort of ART-treated PWH. COVID's association with higher CMV responses may suggest increased susceptibility to or a consequence of persistent inflammation after infection. The striking amplification of SARS-CoV-2 responses with higher BMI suggests an excessive inflammatory response. Lower nadir CD4 was related to uncontrolled extra-follicular and inhibitory SARS-CoV-2 responses, which are unlikely to be protective. These findings may suggest mechanisms underlying factors associated with worse COVID-19 outcomes among PWH. (Figure Presented).
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Background: The pathogenetic mechanisms behind the development of long- COVID (LC) are largely unknown. Because both plasma SARS-CoV-2 RNAemia and dysregulated immunity have been correlated with COVID-19 severity, we evaluated whether they are associated with LC. Method(s): We consecutively enrolled unvaccinated hospitalized COVID-19 patients during acute-COVID-19 (T0) in March-October 2020 who either developed LC at a follow-up visit 2-3 months from virologic clearance (T1) or did not. LC was defined as persistence >=2 months after recovery of >=1 symptom: anosmia, dysgeusia, fever, gastrointestinal symptoms, dyspnoea, fatigue, musculoskeletal pain, muscle weakness, brain fog. We measured: SARS-CoV-2 RNAemia (RT-qPCR, log10(copies/mL)), magnitude (ELISA, AUC) and functionality (pseudovirus neutralization, ID50;Fc-mediated functions, %ADCC) of SARS-CoV-2-specific antibodies, SARS-CoV-2-specific B and CD4-T-cells (Immunophenotype, AIM and ICS assays). Result(s): We enrolled 48 COVID-19 individuals, 38/48 (79.2%) developed LC (LC+) and 10 did not (LC-). LC+ and LC- had similar co-morbidities and symptoms in the acute phase (Fig.1A), and the majority showed a radiologically documented SARS-CoV-2 pneumonia. The SARS-CoV-2 RNAemia did not differ between groups at both time points. The levels of RBD-specific Abs, as well as their functionality, appeared to increase over time in the LC- group but not in the LC+ (Fig.1B-D). Similarly, a trend towards increased RBD-specific B-cells was observed over time in the LC- group but not in LC+ (Fig.1E). B-cell immunophenotyping showed a significant increase over time of classical memory B cells (MBCs) at the expenses of activated MBCs (Fig.1F-G) as well as an IgA class-switching in the LC- group compared to LC+ (Fig.1H-I). Furthermore, LC+ showed a faster decline of SARS-CoV-2-specific (CD69+CD137+) CD4- TEMRA and CD4-TEM (Fig.1L-M). Finally, IFN-gamma-producing TREG of LC- individuals increased over time (Fig.1N). Conclusion(s): Acutely ill, hospitalized COVID-19 patients developing LC feature a dysregulated SARS-CoV-2-specific humoral as well as B- and T-cell response, in both magnitude and functionality, suggesting a link between dysregulated SARS-CoV-2-specific adaptive immunity and LC development. The fine understanding of the factors contributing to such dysregulation in LC patients is strongly needed, that might further inform targeted therapeutic interventions. (Figure Presented).
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Background: SARS-CoV-2 is a highly contagious respiratory virus responsible for COVID-19 pandemic. To understand the role of antibodies in neutralization, our study quantified circulating levels of IgA/IgG and IgG subtypes induced at different days post onset of symptoms, in severe and non severe patients. Objective(s): To quantify circulating levels of IgA, IgG and IgG subclass in severe and non severe patients induced at different days post onset of symptoms. Material(s) and Method(s): Serum or plasma samples collected from 79 COVID-19 patients were used. Indirect SARS-CoV-2 specific IgA, IgG, and IgG subclass specific ELISAs were performed. Antibody titers between severe and non severe patients were compared at different times post onset of clinical symptoms. Titers in ELISA were correlated to neutralizing antibody titers. Results and Conclusion(s): Over 75% patients were positive for IgA and IgG antibodies in the first week. The ELISA titers did not differ during the first week of infection. However, patients with severe disease exhibited raised titers. Neutralizing antibody titers correlated with the ELISA titers in mild presentation but not in severe disease. IgA and IgG1 antibodies correlated stronger with neutralizing antibodies. The findings highlighted that IgA together with IgG play an important in SARS-CoV-2 neutralization.