An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex

BACKGROUND: Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. OBJECTIVE: This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). METHODS: Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. RESULTS: We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of gamma-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Salpha and Emu regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. CONCLUSION: INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis

Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

Background Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]–R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. Objectives We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. Conclusion APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

195sinoneBackground: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value &lt; 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.nonePagano L.; Salmanton-Garcia J.; Marchesi F.; Busca A.; Corradini P.; Hoenigl M.; Klimko N.; Koehler P.; Pagliuca A.; Passamonti F.; Verga L.; Visek B.; Ilhan O.; Nadali G.; Weinbergerova B.; Cordoba-Mascunano R.; Marchetti M.; Collins G.P.; Farina F.; Cattaneo C.; Cabirta A.; Gomes-Silva M.; Itri F.; van Doesum J.; Ledoux M.-P.; Cernan M.; Jaksic O.; Duarte R.F.; Magliano G.; Omrani A.S.; Fracchiolla N.S.; Kulasekararaj A.; Valkovic T.; Poulsen C.B.; Machado M.; Glenthoj A.; Stoma I.; Racil Z.; Piukovics K.; Navratil M.; Emarah Z.; Sili U.; Maertens J.; Blennow O.; Bergantim R.; Garcia-Vidal C.; Prezioso L.; Guidetti A.; del Principe M.I.; Popova M.; de Jonge N.; Ormazabal-Velez I.; Fernandez N.; Falces-Romero I.; Cuccaro A.; Meers S.; Buquicchio C.; Antic D.; Al-Khabori M.; Garcia-Sanz R.; Biernat M.M.; Tisi M.C.; Sal E.; Rahimli L.; Colovic N.; Schonlein M.; Calbacho M.; Tascini C.; Miranda-Castillo C.; Khanna N.; Mendez G.-A.; Petzer V.; Novak J.; Besson C.; Dulery R.; Lamure S.; Nucci M.; Zambrotta G.; Zak P.; Seval G.C.; Bonuomo V.; Mayer J.; Lopez-Garcia A.; Sacchi M.V.; Booth S.; Ciceri F.; Oberti M.; Salvini M.; Izuzquiza M.; Nunes-Rodrigues R.; Ammatuna E.; Obr A.; Herbrecht R.; Nunez-Martin-Buitrago L.; Mancini V.; Shwaylia H.; Sciume M.; Essame J.; Nygaard M.; Batinic J.; Gonzaga Y.; Regalado-Artamendi I.; Karlsson L.K.; Shapetska M.; Hanakova M.; El-Ashwah S.; Borbenyi Z.; Colak G.M.; Nordlander A.; Dragonetti G.; Maraglino A.M.E.; Rinaldi A.; De Ramon-Sanchez C.; Cornely O.A.; Finizio O.; Fazzi R.; Sapienza G.; Chauchet A.; Van Praet J.; Prattes J.; Dargenio M.; Rossi C.; Shirinova A.; Malak S.; Tafuri A.; Ommen H.-B.; Bologna S.; Khedr R.A.; Choquet S.; Joly B.; Ceesay M.M.; Philippe L.; Kho C.S.; Desole M.; Tsirigotis P.; Otasevic V.; Borducchi D.M.M.; Antoniadou A.; Gaziev J.; Almaslamani M.A.; Garcia-Pouton N.; Paterno G.; Torres-Lopez A.; Tarantini G.; Mellinghoff S.; Grafe S.; Borschel N.; Passweg J.; Merelli M.; Barac A.; Wolf D.; Shaikh M.U.; Thieblemont C.; Bernard S.; Funke V.A.M.; Daguindau E.; Khostelidi S.; Nucci F.M.; Martin-Gonzalez J.-A.; Landau M.; Soussain C.; Laureana C.; Lacombe K.; Kohn M.; Aliyeva G.; Piedimonte M.; Fouquet G.; Rego M.; Hoell-Neugebauer B.; Cartron G.; Pinto F.; Alburquerque A.M.; Passos J.; Yilmaz A.F.; Redondo-Izal A.-M.; Altuntas F.; Heath C.; Kolditz M.; Schalk E.; Guolo F.; Karthaus M.; Della Pepa R.; Vinh D.; Noel N.; Deau Fischer B.; Drenou B.; Mitra M.E.; Meletiadis J.; Bilgin Y.M.; Jindra P.; Espigado I.; Drgona L.; Serris A.; Di Blasi R.; Ali N.Pagano, L.; Salmanton-Garcia, J.; Marchesi, F.; Busca, A.; Corradini, P.; Hoenigl, M.; Klimko, N.; Koehler, P.; Pagliuca, A.; Passamonti, F.; Verga, L.; Visek, B.; Ilhan, O.; Nadali, G.; Weinbergerova, B.; Cordoba-Mascunano, R.; Marchetti, M.; Collins, G. P.; Farina, F.; Cattaneo, C.; Cabirta, A.; Gomes-Silva, M.; Itri, F.; van Doesum, J.; Ledoux, M. -P.; Cernan, M.; Jaksic, O.; Duarte, R. F.; Magliano, G.; Omrani, A. S.; Fracchiolla, N. S.; Kulasekararaj, A.; Valkovic, T.; Poulsen, C. B.; Machado, M.; Glenthoj, A.; Stoma, I.; Racil, Z.; Piukovics, K.; Navratil, M.; Emarah, Z.; Sili, U.; Maertens, J.; Blennow, O.; Bergantim, R.; Garcia-Vidal, C.; Prezioso, L.; Guidetti, A.; del Principe, M. I.; Popova, M.; de Jonge, N.; Ormazabal-Velez, I.; Fernandez, N.; Falces-Romero, I.; Cuccaro, A.; Meers, S.; Buquicchio, C.; Antic, D.; Al-Khabori, M.; Garcia-Sanz, R.; Biernat, M. M.; Tisi, M. C.; Sal, E.; Rahimli, L.; Colovic, N.; Schonlein, M.; Calbacho, M.; Tascini, C.; Miranda-Castillo, C.; Khanna, N.; Mendez, G. -A.; Petzer, V.; Novak, J.; Besson, C.; Dulery, R.; Lamure, S.; Nucci, M.; Zambrotta, G.; Zak, P.; Seval, G. C.; Bonuomo, V.; Mayer, J.; Lopez-Garcia, A.; Sacchi, M. V.; Booth, S.; Ciceri, F.; Oberti, M.; Salvini, M.; Izuzquiza, M.; Nunes-Rodrigues, R.; Ammatuna, E.; Obr, A.; Herbrecht, R.; Nunez-Martin-Buitrago, L.; Mancini, V.; Shwaylia, H.; Sciume, M.; Essame, J.; Nygaard, M.; Batinic, J.; Gonzaga, Y.; Regalado-Artamendi, I.; Karlsson, L. K.; Shapetska, M.; Hanakova, M.; El-Ashwah, S.; Borbenyi, Z.; Colak, G. M.; Nordlander, A.; Dragonetti, G.; Maraglino, A. M. E.; Rinaldi, A.; De Ramon-Sanchez, C.; Cornely, O. A.; Finizio, O.; Fazzi, R.; Sapienza, G.; Chauchet, A.; Van Praet, J.; Prattes, J.; Dargenio, M.; Rossi, C.; Shirinova, A.; Malak, S.; Tafuri, A.; Ommen, H. -B.; Bologna, S.; Khedr, R. A.; Choquet, S.; Joly, B.; Ceesay, M. M.; Philippe, L.; Kho, C. S.; Desole, M.; Tsirigotis, P.; Otasevic, V.; Borducchi, D. M. M.; Antoniadou, A.; Gaziev, J.; Almaslamani, M. A.; Garcia-Pouton, N.; Paterno, G.; Torres-Lopez, A.; Tarantini, G.; Mellinghoff, S.; Grafe, S.; Borschel, N.; Passweg, J.; Merelli, M.; Barac, A.; Wolf, D.; Shaikh, M. U.; Thieblemont, C.; Bernard, S.; Funke, V. A. M.; Daguindau, E.; Khostelidi, S.; Nucci, F. M.; Martin-Gonzalez, J. -A.; Landau, M.; Soussain, C.; Laureana, C.; Lacombe, K.; Kohn, M.; Aliyeva, G.; Piedimonte, M.; Fouquet, G.; Rego, M.; Hoell-Neugebauer, B.; Cartron, G.; Pinto, F.; Alburquerque, A. M.; Passos, J.; Yilmaz, A. F.; Redondo-Izal, A. -M.; Altuntas, F.; Heath, C.; Kolditz, M.; Schalk, E.; Guolo, F.; Karthaus, M.; Della Pepa, R.; Vinh, D.; Noel, N.; Deau Fischer, B.; Drenou, B.; Mitra, M. E.; Meletiadis, J.; Bilgin, Y. M.; Jindra, P.; Espigado, I.; Drgona, L.; Serris, A.; Di Blasi, R.; Ali, N

Treatment and management of primary antibody deficiency: German interdisciplinary evidence‐based consensus guideline

This evidence‐based clinical guideline provides consensus‐recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus‐based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non‐infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG‐replacement therapy. Summary and consensus‐recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG‐replacement therapy. Special aspects of concomitant impaired T‐cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA‐4‐, and LRBA‐deficiency)