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3. Charge-exchange-dependent energy loss of H and He in freestanding monolayers of graphene and MoS2

Author

Niggas, A., Fischer, L., (0000-0002-5098-5763) Kretschmer, S., Werl, M., Biber, H., Speckmann, C., McEvoy, N., Kotakoski, J., Aumayr, F., (0000-0003-0074-7588) Krasheninnikov, A., Wilhelm, R. A., Niggas, A., Fischer, L., (0000-0002-5098-5763) Kretschmer, S., Werl, M., Biber, H., Speckmann, C., McEvoy, N., Kotakoski, J., Aumayr, F., (0000-0003-0074-7588) Krasheninnikov, A., and Wilhelm, R. A.

Abstract

We study the energy loss of helium and hydrogen ions after transmission through monolayers of graphene and MoS2 and compare experimental results with different computational approaches. We find a systematically higher energy loss in experiments compared to simulations by up to a factor of 2. Additionally, our results show that neutralization processes of the particles increase the kinetic energy loss, a contribution generally not included in any computational approach.

Published
2023

5. Ion-Induced Surface Charge Dynamics in Freestanding Monolayers of Graphene and MoS2 Probed by the Emission of Electrons

Author

Niggas, A., Schwestka, J., Balzer, K., Weichselbaum, D., Schlünzen, N., Heller, R., Sascha, C., Inani, H., Tripathi, M., Speckmann, C., McEvoy, N., Susi, T., Kotakoski, J., Gan, Z., George, A., Turchanin, A., Bonitz, M., Aumayr, F., Wilhelm, R. A., Niggas, A., Schwestka, J., Balzer, K., Weichselbaum, D., Schlünzen, N., Heller, R., Sascha, C., Inani, H., Tripathi, M., Speckmann, C., McEvoy, N., Susi, T., Kotakoski, J., Gan, Z., George, A., Turchanin, A., Bonitz, M., Aumayr, F., and Wilhelm, R. A.

Abstract

We compare the ion-induced electron emission from freestanding monolayers of graphene and MoS2 to find a sixfold higher number of emitted electrons for graphene even though both materials have similar work functions. An effective single-band Hubbard model explains this finding by a charge-up in MoS2 that prevents low energy electrons from escaping the surface within a period of a few femtoseconds after ion impact. We support these results by measuring the electron energy distribution for correlated pairs of electrons and transmitted ions. The majority of emitted primary electrons have an energy below 10 eVand are therefore subject to the dynamic charge-up effects at surfaces.

Published
2022

6. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Author

Albert, M. H., Sirait, T., Eikema, D. -J., Bakunina, K., Wehr, C., Suarez, F., Fox, M. L., Mahlaoui, N., Gennery, A. R., Lankester, A. C., Beier, R., Bernardo, M. E., Bigley, V., Lindemans, C. A., Burns, S. O., Carpenter, B., Dybko, J., Gungor, T., Hauck, F., Lum, S. H., Balashov, D., Meisel, R., Moshous, D., Schulz, A., Speckmann, C., Slatter, M. A., Strahm, B., Uckan-Cetinkaya, D., Meyts, I., Vallee, T. C., Wynn, R., Neven, B., Morris, E. C., Aiuti, A., Maschan, A., Aljurf, M., Gedde-Dahl, T., Gurman, G., Bordon, V., Krivan, G., Locatelli, Franco, Porta, F., Valcarcel, D., Beguin, Y., Faraci, M., Kroger, N., Kulagin, A., Shaw, P. J., Veelken, J. H., Diaz de Heredia, C., Fagioli, F., Felber, M., Gruhn, B., Holter, W., Rossig, C., Sedlacek, P., Apperley, J., Ayas, M., Bodova, I., Choi, G., Cornelissen, J. J., Sirvent, A., Khan, A., Kupesiz, A., Lenhoff, S., Ozdogu, H., von der Weid, N., Rovira, M., Schots, R., Vinh, D. C., Locatelli F. (ORCID:0000-0002-7976-3654), Albert, M. H., Sirait, T., Eikema, D. -J., Bakunina, K., Wehr, C., Suarez, F., Fox, M. L., Mahlaoui, N., Gennery, A. R., Lankester, A. C., Beier, R., Bernardo, M. E., Bigley, V., Lindemans, C. A., Burns, S. O., Carpenter, B., Dybko, J., Gungor, T., Hauck, F., Lum, S. H., Balashov, D., Meisel, R., Moshous, D., Schulz, A., Speckmann, C., Slatter, M. A., Strahm, B., Uckan-Cetinkaya, D., Meyts, I., Vallee, T. C., Wynn, R., Neven, B., Morris, E. C., Aiuti, A., Maschan, A., Aljurf, M., Gedde-Dahl, T., Gurman, G., Bordon, V., Krivan, G., Locatelli, Franco, Porta, F., Valcarcel, D., Beguin, Y., Faraci, M., Kroger, N., Kulagin, A., Shaw, P. J., Veelken, J. H., Diaz de Heredia, C., Fagioli, F., Felber, M., Gruhn, B., Holter, W., Rossig, C., Sedlacek, P., Apperley, J., Ayas, M., Bodova, I., Choi, G., Cornelissen, J. J., Sirvent, A., Khan, A., Kupesiz, A., Lenhoff, S., Ozdogu, H., von der Weid, N., Rovira, M., Schots, R., Vinh, D. C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.

Published
2022

7. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Author

Albert MH, Sirait T, Eikema DJ, Bakunina K, Wehr C, Suarez F, Fox ML, Mahlaoui N, Gennery AR, Lankester AJ, Beier R, Bernardo ME, Bigley V, Lindemans CA, OBurns S, Carpenter B, Dybko J, Gungor T, Hauck F, Lum SH, Balashov D, Meisel R, Moshous D, Schulz A, Speckmann C, Slatter MA, Strahm B, Uckan-Cetinkaya D, Meyts I, Vallee TC, Wynn R, Neven B, Morris EC, EBMT IEWP, ESID

Published
2022
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10. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency

Author

Rensing-Ehl, A., Warnatz, K., Fuchs, S., Schlesier, M., Salzer, U., Draeger, R., Bondzio, I., Joos, Y., Janda, A., Gomes, M., Abinun, M., Hambleton, S., Cant, A., Shackley, F., Flood, T., Waruiru, C., Beutel, K., Siepermann, K., Dueckers, G., Niehues, T., Wiesel, T., Schuster, V., Seidel, M.G., Minkov, M., Sirkiä, K., Kopp, M.V., Korhonen, M., Schwarz, K., Ehl, S., and Speckmann, C.

Published
2010
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14. Hematopoietic stem cell transplantation for CD40 ligand deficiency : Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

Author

Ferrua, F., Galimberti, S., Courteille, V., Slatter, M.A., Booth, C., Moshous, D., Neven, B., Blanche, S., Cavazzana, M., Laberko, A., Shcherbina, A., Balashov, D., Soncini, E., Porta, F., Al-Mousa, H., Al-Saud, B., Al-Dhekri, H., Arnaout, R., Formankova, R., Bertrand, Y., Lange, A., Smart, J., Wolska-Kusnierz, B., Aquino, V.M., Dvorak, C.C., Fasth, A., Fouyssac, F., Heilmann, C., Hoenig, M., Schuetz, C., Kelecic, J., Bredius, R.G.M., Lankester, A.C., Lindemans, C.A., Suarez, F., Sullivan, K.E., Albert, M.H., Kalwak, K., Barlogis, V., Bhatia, M., Bordon, V., Czogala, W., Alonso, L., Dogu, F., Gozdzik, J., Ikinciogullari, A., Krivan, G., Ljungman, P., Meyts, I., Mustillo, P., Smith, A.R., Speckmann, C., Sundin, M., Keogh, S.J., Shaw, P.J., Boelens, J.J., Schulz, A.S., Sedlacek, P., Veys, P., Mahlaoui, N., Janda, A., Davies, E.G., Fischer, A., Cowan, M.J., Gennery, A.R., SCETIDE, PIDTC, EBMT, ESID IEWP, Ferrua, F, Galimberti, S, Courteille, V, Slatter, M, Booth, C, Moshous, D, Neven, B, Blanche, S, Laberko, A, Shcherbina, A, Balashov, D, Soncini, E, Porta, F, Al-Mousa, H, Al-Saud, B, Al-Dhekri, H, Arnaout, R, Formankova, R, Bertrand, Y, Lange, A, Smart, J, Wolska-Kusnierz, B, Aquino, V, Dvorak, C, Fasth, A, Fouyssac, F, Heilmann, C, Hoenig, M, Schuetz, C, Kelečić, J, Bredius, R, Lankester, A, Lindemans, C, Suarez, F, Sullivan, K, Albert, M, Kałwak, K, Barlogis, V, Bhatia, M, Bordon, V, Czogala, W, Alonso, L, Dogu, F, Gozdzik, J, Ikinciogullari, A, Kriván, G, Ljungman, P, Meyts, I, Mustillo, P, Smith, A, Speckmann, C, Sundin, M, Keogh, S, Shaw, P, Boelens, J, Schulz, A, Sedlacek, P, Veys, P, Mahlaoui, N, Janda, A, Davies, E, Fischer, A, Cowan, M, and Gennery, A

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Immunology, Hematopoietic stem cell transplantation, X-Linked Combined Immunodeficiency Diseases, primary immunodeficiency, Donor lymphocyte infusion, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, X-linked hyper-IgM syndrome, Humans, Medicine, Immunology and Allergy, Risk factor, Child, Prospective cohort study, business.industry, Infant, Newborn, Infant, medicine.disease, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Graft-versus-host disease, surgical procedures, operative, Supportive psychotherapy, Child, Preschool, hematopoietic stem cell transplantation, Primary immunodeficiency, Bone marrow, CD40 ligand, business, 030215 immunology
Abstract

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:143 issue:6 pages:2238-2253 ispartof: location:United States status: published

Published
2019

17. Secondary C1q Deficiency in Activated PI3K delta Syndrome Type 2

Author

Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología, Instituto de Biomedicina de Sevilla (IBIS), Programa Juan Rodes, Instituto de Salud Carlos III, Hong, Y., Nanthapisal, S., Omoyinmi, E., Olbrich, Peter, Neth, O., Speckmann, C., Lucena, J.M., Gilmour, K., Genomics England Res Consortium, Zarowiecki, M., Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología, Instituto de Biomedicina de Sevilla (IBIS), Programa Juan Rodes, Instituto de Salud Carlos III, Hong, Y., Nanthapisal, S., Omoyinmi, E., Olbrich, Peter, Neth, O., Speckmann, C., Lucena, J.M., Gilmour, K., Genomics England Res Consortium, and Zarowiecki, M.

Published
2019

18. Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

Author

Ferrua, F, Galimberti, S, Courteille, V, Slatter, M, Booth, C, Moshous, D, Neven, B, Blanche, S, Laberko, A, Shcherbina, A, Balashov, D, Soncini, E, Porta, F, Al-Mousa, H, Al-Saud, B, Al-Dhekri, H, Arnaout, R, Formankova, R, Bertrand, Y, Lange, A, Smart, J, Wolska-Kusnierz, B, Aquino, V, Dvorak, C, Fasth, A, Fouyssac, F, Heilmann, C, Hoenig, M, Schuetz, C, Kelečić, J, Bredius, R, Lankester, A, Lindemans, C, Suarez, F, Sullivan, K, Albert, M, Kałwak, K, Barlogis, V, Bhatia, M, Bordon, V, Czogala, W, Alonso, L, Dogu, F, Gozdzik, J, Ikinciogullari, A, Kriván, G, Ljungman, P, Meyts, I, Mustillo, P, Smith, A, Speckmann, C, Sundin, M, Keogh, S, Shaw, P, Boelens, J, Schulz, A, Sedlacek, P, Veys, P, Mahlaoui, N, Janda, A, Davies, E, Fischer, A, Cowan, M, Gennery, A, Ferrua, Francesca, Galimberti, Stefania, Courteille, Virginie, Slatter, Mary Anne, Booth, Claire, Moshous, Despina, Neven, Benedicte, Blanche, Stephane, Laberko, Alexandra, Shcherbina, Anna, Balashov, Dmitry, Soncini, Elena, Porta, Fulvio, Al-Mousa, Hamoud, Al-Saud, Bandar, Al-Dhekri, Hasan, Arnaout, Rand, Formankova, Renata, Bertrand, Yves, Lange, Andrzej, Smart, Joanne, Wolska-Kusnierz, Beata, Aquino, Victor M, Dvorak, Christopher C, Fasth, Anders, Fouyssac, Fanny, Heilmann, Carsten, Hoenig, Manfred, Schuetz, Catharina, Kelečić, Jadranka, Bredius, Robbert G M, Lankester, Arjan C, Lindemans, Caroline A, Suarez, Felipe, Sullivan, Kathleen E, Albert, Michael H, Kałwak, Krzysztof, Barlogis, Vincent, Bhatia, Monica, Bordon, Victoria, Czogala, Wojciech, Alonso, Laura, Dogu, Figen, Gozdzik, Jolanta, Ikinciogullari, Aydan, Kriván, Gergely, Ljungman, Per, Meyts, Isabelle, Mustillo, Peter, Smith, Angela R, Speckmann, Carsten, Sundin, Mikael, Keogh, Steven John, Shaw, Peter John, Boelens, Jaap Jan, Schulz, Ansgar S, Sedlacek, Petr, Veys, Paul, Mahlaoui, Nizar, Janda, Ales, Davies, E Graham, Fischer, Alain, Cowan, Morton J, Gennery, Andrew Richard, Ferrua, F, Galimberti, S, Courteille, V, Slatter, M, Booth, C, Moshous, D, Neven, B, Blanche, S, Laberko, A, Shcherbina, A, Balashov, D, Soncini, E, Porta, F, Al-Mousa, H, Al-Saud, B, Al-Dhekri, H, Arnaout, R, Formankova, R, Bertrand, Y, Lange, A, Smart, J, Wolska-Kusnierz, B, Aquino, V, Dvorak, C, Fasth, A, Fouyssac, F, Heilmann, C, Hoenig, M, Schuetz, C, Kelečić, J, Bredius, R, Lankester, A, Lindemans, C, Suarez, F, Sullivan, K, Albert, M, Kałwak, K, Barlogis, V, Bhatia, M, Bordon, V, Czogala, W, Alonso, L, Dogu, F, Gozdzik, J, Ikinciogullari, A, Kriván, G, Ljungman, P, Meyts, I, Mustillo, P, Smith, A, Speckmann, C, Sundin, M, Keogh, S, Shaw, P, Boelens, J, Schulz, A, Sedlacek, P, Veys, P, Mahlaoui, N, Janda, A, Davies, E, Fischer, A, Cowan, M, Gennery, A, Ferrua, Francesca, Galimberti, Stefania, Courteille, Virginie, Slatter, Mary Anne, Booth, Claire, Moshous, Despina, Neven, Benedicte, Blanche, Stephane, Laberko, Alexandra, Shcherbina, Anna, Balashov, Dmitry, Soncini, Elena, Porta, Fulvio, Al-Mousa, Hamoud, Al-Saud, Bandar, Al-Dhekri, Hasan, Arnaout, Rand, Formankova, Renata, Bertrand, Yves, Lange, Andrzej, Smart, Joanne, Wolska-Kusnierz, Beata, Aquino, Victor M, Dvorak, Christopher C, Fasth, Anders, Fouyssac, Fanny, Heilmann, Carsten, Hoenig, Manfred, Schuetz, Catharina, Kelečić, Jadranka, Bredius, Robbert G M, Lankester, Arjan C, Lindemans, Caroline A, Suarez, Felipe, Sullivan, Kathleen E, Albert, Michael H, Kałwak, Krzysztof, Barlogis, Vincent, Bhatia, Monica, Bordon, Victoria, Czogala, Wojciech, Alonso, Laura, Dogu, Figen, Gozdzik, Jolanta, Ikinciogullari, Aydan, Kriván, Gergely, Ljungman, Per, Meyts, Isabelle, Mustillo, Peter, Smith, Angela R, Speckmann, Carsten, Sundin, Mikael, Keogh, Steven John, Shaw, Peter John, Boelens, Jaap Jan, Schulz, Ansgar S, Sedlacek, Petr, Veys, Paul, Mahlaoui, Nizar, Janda, Ales, Davies, E Graham, Fischer, Alain, Cowan, Morton J, and Gennery, Andrew Richard

Abstract

Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow–derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

Published
2019

19. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Author

Lawless, D, Geier, CB, Farmer, JR, Lango Allen, H, Thwaites, D, Atschekzei, F, Brown, M, Buchbinder, D, Burns, SO, Butte, MJ, Csomos, K, Deevi, SVV, Egner, W, Ehl, S, Eibl, MM, Fadugba, O, Foldvari, Z, Green, DM, Henrickson, SE, Holland, SM, John, T, Klemann, C, Kuijpers, TW, Moreira, F, Piller, A, Rayner-Matthews, P, Romberg, ND, Sargur, R, Schmidt, RE, Schröder, C, Schuetz, C, Sharapova, SO, Smith, KGC, Sogkas, G, Speckmann, C, Stirrups, K, Thrasher, AJ, Wolf, HM, Notarangelo, LD, Anwar, R, Boyes, J, Ujhazi, B, NIHR BioResource - Rare Diseases Consortium, Thaventhiran, J, Walter, JE, Savic, S, Lango Allen, Hana [0000-0002-7803-8688], Smith, Kenneth [0000-0003-3829-4326], Johnson, Kathleen [0000-0002-6823-3252], Thaventhiran, James [0000-0001-8616-074X], and Apollo - University of Cambridge Repository

Subjects
Adult, DNA-Binding Proteins, Homeodomain Proteins, Immunologic Deficiency Syndromes, Prevalence, Humans, Nuclear Proteins
Published
2018
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20. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Author

Barzaghi, F., Hernandez, L.C.A., Neven, B., Ricci, S., Kucuk, Z.Y., Bleesing, J.J., Nademi, Z., Slatter, M.A., Ulloa, E.R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J.F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L.D., Gambineri, E., Lionetti, P., Shearer, W.T., Forbes, L.R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F.M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M.H., Kobayashi, I., Alonso, L., Heredia, C.D. de, Kanegane, H., Lawitschka, A., Seo, J.J., Gonzalez-Vicent, M., Diaz, M.A., Goyal, R.K., Sauer, M.G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Padilla, E.J.R., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M.L., Bredius, R.G., Kawak, K., Haddad, E., Seidel, M.G., Duckers, G., Pai, S.Y., Dvorak, C.C., Ehl, S., Locatelli, F., Goldman, F., Gennery, A.R., Cowan, M.J., Roncarolo, M.G., Bacchetta, R., PIDTC, IEWP, European Soc Blood Marrow, Barzaghi, Federica, Hernandez, Laura Cristina Amaya, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J., Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R., Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M., Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frederic, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H., Kobayashi, Ichiro, Alonso, Laura, De Heredia, Cristina Diaz, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G., Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Padilla, Erick J. Richmond, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G., Kalwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C., Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J., Roncarolo, Maria-Grazia, Bacchetta, Rosa, Amaya Hernandez, Laura Cristina, Murguia-Favela, Lui, Shearer, William Thoma, Rieux-Laucat, Frédéric, Diaz De Heredia, Cristina, Richmond Padilla, Erick J., and Kałwak, Krzysztof

Subjects
0301 basic medicine, Male, Allergy, medicine.medical_treatment, Medizin, Disease, Hematopoietic stem cell transplantation, SIROLIMUS, Regenerative Medicine, primary immune deficiency, Medicine and Health Sciences, IPEX, Immunology and Allergy, 2.1 Biological and endogenous factors, Enteropathy, Aetiology, POLYENDOCRINOPATHY, Child, Pediatric, CÉLULAS-TRONCO, immunosuppression, Hematopoietic Stem Cell Transplantation, Genetic Diseases, X-Linked, Immunosuppression, Forkhead Transcription Factors, X-LINKED SYNDROME, Allografts, Survival Rate, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immune System Diseases, Genetic Diseases, Child, Preschool, hematopoietic stem cell transplantation, Female, hematopoietic stem, neonatal diabetes, FOXP3, Primary Immune Deficiency, Treg cells, enteropathy, genetic autoimmunity, rapamycin, Type 1, Diarrhea, Adult, medicine.medical_specialty, Adolescent, Immunology, Neonatal onset, Article, Disease-Free Survival, 03 medical and health sciences, Neonatal diabete, Clinical Research, Internal medicine, IMMUNODYSREGULATION, medicine, Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Diabetes Mellitus, Genetics, Humans, REGULATORY T-CELLS, cell transplantation, Preschool, Retrospective Studies, Immunosuppression Therapy, Transplantation, IMMUNE DYSREGULATION, business.industry, MUTATIONS, Infant, Retrospective cohort study, STEM-CELL TRANSPLANTATION, IPEX syndrome, X-Linked, medicine.disease, Stem Cell Research, BONE-MARROW-TRANSPLANTATION, Treg cell, FOXP3 MUTATIONS, Diabetes Mellitus, Type 1, 030104 developmental biology, ENGRAFTMENT, Mutation, business, Follow-Up Studies
Abstract

Background Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., GRAPHICAL ABSTRACT

Published
2018

21. Infektionsanfälligkeit bei Immundefizienz

Author

Speckmann, C, Ehl, S, Liese, J, Trück, Johannes, University of Zurich, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, Berner, Reinhard, Bialek, Ralf, Forster, Johannes, Härtel, Christoph, Heininger, Ulrich, Huppertz, Hans-Iko, Liese, Johannes G, Nadal, David, and Simon, Arne

Subjects
10036 Medical Clinic, 610 Medicine & health
Published
2018

22. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects

Author

Schwab, C., Gabrysch, A., Olbrich, P., Patino, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J.A., Sansom, D.M., Lucena, J.M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., Bulashevska, A., Salzer, U., Schubert, Desiree, Hayakawa, S., Okada, S., Kanariou, M., Kucuk, Z.Y., Chapdelaine, H., Petruzelkova, L., Sumnik, Z., Sediva, A., Slatter, M., Arkwright, P.D., Cant, A., Lorenz, H.M., Giese, T., Lougaris, V., Plebani, A., Price, C., Sullivan, K.E., Moutschen, M., Litzman, J., Freiberger, T., Veerdonk, F.L. van de, Recher, M., Albert, M.H., Hauck, F., Seneviratne, S., Schmid, J., Kolios, A., Unglik, G., Klemann, C., Speckmann, C., Ehl, S., Leichtner, A., Blumberg, R., Franke, A., Snapper, S., Zeissig, S., Cunningham-Rundles, C., Giulino-Roth, L., Elemento, O., Duckers, G., Niehues, T., Fronkova, E., Kanderova, V., Platt, C.D., Chou, J., Chatila, T.A., Geha, R., McDermott, E., Bunn, S., Kurzai, M., Schulz, A., Alsina, L., Casals, F., Deya-Martinez, A., Hambleton, S., Kanegane, H., Tasken, K., Neth, O., Grimbacher, B., Schwab, C., Gabrysch, A., Olbrich, P., Patino, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J.A., Sansom, D.M., Lucena, J.M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., Bulashevska, A., Salzer, U., Schubert, Desiree, Hayakawa, S., Okada, S., Kanariou, M., Kucuk, Z.Y., Chapdelaine, H., Petruzelkova, L., Sumnik, Z., Sediva, A., Slatter, M., Arkwright, P.D., Cant, A., Lorenz, H.M., Giese, T., Lougaris, V., Plebani, A., Price, C., Sullivan, K.E., Moutschen, M., Litzman, J., Freiberger, T., Veerdonk, F.L. van de, Recher, M., Albert, M.H., Hauck, F., Seneviratne, S., Schmid, J., Kolios, A., Unglik, G., Klemann, C., Speckmann, C., Ehl, S., Leichtner, A., Blumberg, R., Franke, A., Snapper, S., Zeissig, S., Cunningham-Rundles, C., Giulino-Roth, L., Elemento, O., Duckers, G., Niehues, T., Fronkova, E., Kanderova, V., Platt, C.D., Chou, J., Chatila, T.A., Geha, R., McDermott, E., Bunn, S., Kurzai, M., Schulz, A., Alsina, L., Casals, F., Deya-Martinez, A., Hambleton, S., Kanegane, H., Tasken, K., Neth, O., and Grimbacher, B.

Abstract

Item does not contain fulltext, BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

Published
2018

23. Infektionsanfälligkeit bei Immundefizienz

Author

DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, Berner, Reinhard, Bialek, Ralf, Forster, Johannes, Härtel, Christoph, Heininger, Ulrich, Huppertz, Hans-Iko, Liese, Johannes G, Nadal, David, Simon, Arne, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, ( ), Berner, R ( Reinhard ), Bialek, R ( Ralf ), Forster, J ( Johannes ), Härtel, C ( Christoph ), Heininger, U ( Ulrich ), Huppertz, H ( Hans-Iko ), Liese, J G ( Johannes G ), Nadal, D ( David ), Simon, A ( Arne ), Speckmann, C, Ehl, S, Liese, J, Trück, Johannes; https://orcid.org/0000-0002-0418-7381, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, Berner, Reinhard, Bialek, Ralf, Forster, Johannes, Härtel, Christoph, Heininger, Ulrich, Huppertz, Hans-Iko, Liese, Johannes G, Nadal, David, Simon, Arne, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, ( ), Berner, R ( Reinhard ), Bialek, R ( Ralf ), Forster, J ( Johannes ), Härtel, C ( Christoph ), Heininger, U ( Ulrich ), Huppertz, H ( Hans-Iko ), Liese, J G ( Johannes G ), Nadal, D ( David ), Simon, A ( Arne ), Speckmann, C, Ehl, S, Liese, J, and Trück, Johannes; https://orcid.org/0000-0002-0418-7381

Published
2018

25. Neugeborenenscreening 2020

Author

Gramer, G., primary, Hauck, F., additional, Lobitz, S., additional, Sommerburg, O., additional, Speckmann, C., additional, and Hoffmann, G. F., additional

Published
2017
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26. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency

Author

Hassan, A., Booth, C., Brightwell, A., Allwood, Z., Veys, P., Rao, K., Honig, M., Friedrich, W., Gennery, A., Slatter, M., Bredius, R., Finocchi, A., Cancrini, C., Aiuti, A., Porta, F., Lanfranchi, A., Ridella, M., Steward, C., Filipovich, A., Marsh, R., Bordon, V., Al-Muhsen, S., Al-Mousa, H., Alsum, Z., Al-Dhekri, H., Ghonaium, A. al, Speckmann, C., Fischer, A., Mahlaoui, N., Nichols, K.E., Grunebaum, E., Zahrani, D. al, Roifman, C.M., Boelens, J., Davies, E.G., Cavazzana-Calvo, M., Notarangelo, L., Gaspar, H.B., European Grp Blood Marrow Transpla, European Soc Immunodeficiency, Hassan, A, Booth, C, Brightwell, A, Allwood, Z, Veys, P, Rao, K, Hönig, M, Friedrich, W, Gennery, A, Slatter, M, Bredius, R, Finocchi, A, Cancrini, C, Aiuti, Alessandro, Porta, F, Lanfranchi, A, Ridella, M, Steward, C, Filipovich, A, Marsh, R, Bordon, V, AL MUHSEN, S, AL MOUSA, H, Alsum, Z, AL DHEKRI, H, AL GHONAIUM, A, Speckmann, C, Fischer, A, Mahlaoui, N, Nichols, Ke, Grunebaum, E, AL ZAHRANI, D, Roifman, Cm, Boelens, J, Davies, Eg, CAVAZZANA CALVO, M, Notarangelo, L, and Gaspar, Hb

Subjects
Oncology, Male, Transplantation Conditioning, Adenosine Deaminase, Genetic enhancement, medicine.medical_treatment, T-Lymphocytes, Hematopoietic stem cell transplantation, Kaplan-Meier Estimate, Biochemistry, humoral, Adenosine deaminase, newborn, immune system diseases, Agammaglobulinemia, hemic and lymphatic diseases, Child, Immunity, Cellular, Hematology, biology, Histocompatibility Testing, Graft Survival, Hematopoietic Stem Cell Transplantation, surgical procedures, operative, Treatment Outcome, Child, Preschool, Female, Unrelated Donors, medicine.medical_specialty, Immunology, preschool, Internal medicine, medicine, Humans, Lymphocyte Count, Retrospective Studies, Settore MED/38 - Pediatria Generale e Specialistica, Severe combined immunodeficiency, agammaglobulinemia, transplantation conditioning, severe combined immunodeficiency, humans, retrospective studies, infant, newborn, child, child, preschool, kaplan-meier estimate, infant, lymphocyte count, histocompatibility testing, immunity, cellular, unrelated donors, graft survival, treatment outcome, myeloablative agonists, hematopoietic stem cell transplantation, siblings, adenosine deaminase, male, female, t-lymphocytes, immunity, humoral, business.industry, Siblings, Infant, Newborn, Infant, Cell Biology, Myeloablative Agonists, medicine.disease, immunity, Adenosine deaminase deficiency, Immunity, Humoral, Transplantation, biology.protein, Severe Combined Immunodeficiency, business, cellular
Abstract

Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.

Published
2012

27. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency

Author

Gamez-Diaz, L., August, D., Stepensky, P., Revel-Vilk, S., Seidel, M.G., Noriko, M., Morio, T., Worth, A.J., Blessing, J., Veerdonk, F.L. van de, Feuchtinger, T., Kanariou, M., Schmitt-Graeff, A., Jung, S., Seneviratne, S., Burns, S., Belohradsky, B.H., Rezaei, N., Bakhtiar, S., Speckmann, C., Jordan, M., Grimbacher, B., Gamez-Diaz, L., August, D., Stepensky, P., Revel-Vilk, S., Seidel, M.G., Noriko, M., Morio, T., Worth, A.J., Blessing, J., Veerdonk, F.L. van de, Feuchtinger, T., Kanariou, M., Schmitt-Graeff, A., Jung, S., Seneviratne, S., Burns, S., Belohradsky, B.H., Rezaei, N., Bakhtiar, S., Speckmann, C., Jordan, M., and Grimbacher, B.

Abstract

Item does not contain fulltext, BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. OBJECTIVE: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. METHODS: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. RESULTS: Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents. CONCLUSION: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.

Published
2016

28. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Author

Coulter, TI, Chandra, A, Bacon, CM, Babar, J, Curtis, J, Screaton, N, Goodlad, JR, Farmer, G, Steele, CL, Leahy, TR, Doffinger, R, Baxendale, H, Bernatoniene, J, Edgar, JD, Longhurst, HJ, Ehl, S, Speckmann, C, Grimbacher, B, Sediva, A, Milota, T, Faust, SN, Williams, AP, Hayman, G, Kucuk, ZY, Hague, R, French, P, Brooker, R, Forsyth, P, Herriot, R, Cancrini, C, Palma, P, Ariganello, P, Conlon, N, Feighery, C, Gavin, PJ, Jones, A, Imai, K, Ibrahim, MA, Markelj, G, Abinun, M, Rieux-Laucat, F, Latour, S, Pellier, I, Fischer, A, Touzot, F, Casanova, JL, Durandy, A, Burns, SO, Savic, S, Kumararatne, DS, Moshous, D, Kracker, S, Vanhaesebroeck, B, Okkenhaug, K, Picard, C, Nejentsev, S, Condliffe, AM, Cant, AJ, Chandra, Anita [0000-0002-9061-879X], Okkenhaug, Klaus [0000-0002-9432-4051], Nezhentsev, Sergey [0000-0002-7528-4461], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Adolescent, bronchiectasis, Class I Phosphatidylinositol 3-Kinases, International Cooperation, Immunology, PPV, Pneumococcal polysaccharide vaccine, HSCT, Hematopoietic stem cell transplantation, Cohort Studies, Mice, Young Adult, APDS, Activated phosphoinositide-3 kinase δ syndrome, phosphoinositide 3-kinase inhibitor, Immune Deficiencies, Infection, and Systemic Immune Disorders, Recurrence, PI3K, Phosphoinositide 3-kinase, Surveys and Questionnaires, BALF, Bronchoalveolar lavage fluid, Activated phosphoinositide 3-kinase δ syndrome, Animals, Humans, Immunology and Allergy, Enzyme Inhibitors, CMV, Cytomegalovirus, Child, HSV, Herpes simplex virus, Respiratory Tract Infections, CNS, Central nervous system, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes, Immunoglobulins, Intravenous, Infant, GOF, Gain of function, Herpesviridae Infections, Antibiotic Prophylaxis, Middle Aged, PIK3CD gene, Survival Analysis, Lymphoproliferative Disorders, Child, Preschool, Mutation, CT, Computed tomography, p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency, Female, immunodeficiency, phosphoinositide 3-kinase δ, OR, Odds ratio
Abstract

Background: Activated PI3-Kinase Delta Syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).\ud Objective: To review the clinical, immunological, histopathological and radiological features of APDS in a large genetically-defined international cohort.\ud Methods: Clinical questionnaire, and review of medical notes, radiology histopathology and laboratory investigations of 53 APDS patients.\ud Results: Recurrent sino-pulmonary infections (96%) and non-neoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system (CNS); consistent with this PI3Kδ is broadly expressed in the developing murine CNS. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60% in cohort); the incidence of bronchiectasis was greater than in common variable immunodeficiency (CVID). Elevated IgM (78%), IgG deficiency (43%) and CD4 lymphopenia (84%) were significant immunological features. No immunological marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and five patients underwent haematopoietic stem cell transplant (HSCT). Five patients died from complications of APDS.\ud Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of HSCT for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Published
2017
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29. From autoinflammatory disease to primary immunodeficiency

Author

Dückers, G, Ehl, S, Speckmann, C, and Niehues, T

Subjects
XIAP, ddc: 610, Fever, Autoinflammation, 610 Medical sciences, Medicine, SoJIA
Abstract

Case: A 3 year old boy of German non consanguineous family with relapsing episodes of severe autoinflammation (spiking fever, transient exanthema, hepatosplenomegaly, hyperferritinemia > 27.500µg/l, LDH >3.500 U/ml, S100 > 8.700 ng/ml) was initially suspected for systemic[for full text, please go to the a.m. URL], 42. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 28. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 24. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Published
2014
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32. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

Author

Elgizouli, M, primary, Lowe, D M, additional, Speckmann, C, additional, Schubert, D, additional, Hülsdünker, J, additional, Eskandarian, Z, additional, Dudek, A, additional, Schmitt-Graeff, A, additional, Wanders, J, additional, Jørgensen, S F, additional, Fevang, B, additional, Salzer, U, additional, Nieters, A, additional, Burns, S, additional, and Grimbacher, B, additional

Published
2015
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34. Reduced memory B cells in patients with hyper IgE syndrome

Author

Speckmann, C, Enders, A, Woellner, C, Thiel, D, RENSING EHL, A, Schlesier, M, Rohr, J, Jakob, T, Oswald, E, Kopp, M, Sanal, O, Litzman, J, Plebani, Alessandro, Pietrogrande, Mc, Franco, Jl, Espanol, T, Grimbacher, B, and Ehl, S.

Subjects
Hyper IgE syndrome, memory B cells
Published
2008

35. X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis

Author

Speckmann, C., Lehmberg, K., Albert, M. H., Damgaard, R. B., Fritsch, M., Gyrd-Hansen, M., Rensing-Ehl, A., Vraetz, T., Grimbacher, B., Salzer, U., Fuchs, I., Ufheil, H., Belohradsky, B. H., Hassan, A., Cale, C. M., Elawad, M., Strahm, B., Schibli, S., Lauten, M., Kohl, M., Meerpohl, J. J., Rodeck, B., Kolb, R., Eberl, W., Soerensen, J., von Bernuth, H., Lorenz, M., Schwarz, K., zur Stadt, U., Ehl, S., Speckmann, C., Lehmberg, K., Albert, M. H., Damgaard, R. B., Fritsch, M., Gyrd-Hansen, M., Rensing-Ehl, A., Vraetz, T., Grimbacher, B., Salzer, U., Fuchs, I., Ufheil, H., Belohradsky, B. H., Hassan, A., Cale, C. M., Elawad, M., Strahm, B., Schibli, S., Lauten, M., Kohl, M., Meerpohl, J. J., Rodeck, B., Kolb, R., Eberl, W., Soerensen, J., von Bernuth, H., Lorenz, M., Schwarz, K., zur Stadt, U., and Ehl, S.

Abstract

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n = 6), severe infectious mononucleosis (n = 4), isolated splenomegaly (n = 3), uveitis (n = 1), periodic fever (n = 1), fistulating skin abscesses (n = 1) and severe Giardia enteritis (n = 1). Subsequent manifestations included celiac-like disease, antibody deficiency, spienomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations. (C) 2013 Elsevier Inc. All rights reserved.

Published
2013

36. X-linked inhibitor of apoptosis (XIAP) deficiency:The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis

Author

Speckmann, C., Lehmberg, K., Albert, M.H., Damgaard, R.B., Fritsch, M., Gyrd-Hansen, M., Rensing-Ehl, A., Vraetz, T., Grimbacher, B., Salzer, U., Fuchs, I., Ufheil, H., Belohradsky, B.H., Hassan, A., Cale, C.M., Elawad, M., Strahm, B., Schibli, S., Lauten, M., Kohl, M., Meerpohl, J.J., Rodeck, B., Kolb, R., Eberl, W., Soerensen, J., von Bernuth, H., Lorenz, M., Schwarz, Kai-Uwe, zur Stadt, U., Ehl, S., Speckmann, C., Lehmberg, K., Albert, M.H., Damgaard, R.B., Fritsch, M., Gyrd-Hansen, M., Rensing-Ehl, A., Vraetz, T., Grimbacher, B., Salzer, U., Fuchs, I., Ufheil, H., Belohradsky, B.H., Hassan, A., Cale, C.M., Elawad, M., Strahm, B., Schibli, S., Lauten, M., Kohl, M., Meerpohl, J.J., Rodeck, B., Kolb, R., Eberl, W., Soerensen, J., von Bernuth, H., Lorenz, M., Schwarz, Kai-Uwe, zur Stadt, U., and Ehl, S.

Abstract

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n. =. 6), severe infectious mononucleosis (n. =. 4), isolated splenomegaly (n. =. 3), uveitis (n. =. 1), periodic fever (n. =. 1), fistulating skin abscesses (n. =. 1) and severe Giardia enteritis (n. =. 1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

Published
2013

37. X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis

Author

Speckmann, C., primary, Lehmberg, K., additional, Albert, M.H., additional, Damgaard, R.B., additional, Fritsch, M., additional, Gyrd-Hansen, M., additional, Rensing-Ehl, A., additional, Vraetz, T., additional, Grimbacher, B., additional, Salzer, U., additional, Fuchs, I., additional, Ufheil, H., additional, Belohradsky, B.H., additional, Hassan, A., additional, Cale, C.M., additional, Elawad, M., additional, Strahm, B., additional, Schibli, S., additional, Lauten, M., additional, Kohl, M., additional, Meerpohl, J.J., additional, Rodeck, B., additional, Kolb, R., additional, Eberl, W., additional, Soerensen, J., additional, von Bernuth, H., additional, Lorenz, M., additional, Schwarz, K., additional, zur Stadt, U., additional, and Ehl, S., additional

Published
2013
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38. Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia

Author

Rensing-Ehl, A., primary, Janda, A., additional, Lorenz, M. R., additional, Gladstone, B. P., additional, Fuchs, I., additional, Abinun, M., additional, Albert, M., additional, Butler, K., additional, Cant, A., additional, Cseh, A.-M., additional, Ebinger, M., additional, Goldacker, S., additional, Hambleton, S., additional, Hebart, H., additional, Houet, L., additional, Kentouche, K., additional, Kuhnle, I., additional, Lehmberg, K., additional, Mejstrikova, E., additional, Niemeyer, C., additional, Minkov, M., additional, Neth, O., additional, Duckers, G., additional, Owens, S., additional, Rosler, J., additional, Schilling, F. H., additional, Schuster, V., additional, Seidel, M. G., additional, Smisek, P., additional, Sukova, M., additional, Svec, P., additional, Wiesel, T., additional, Gathmann, B., additional, Schwarz, K., additional, Vach, W., additional, Ehl, S., additional, and Speckmann, C., additional

Published
2013
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41. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

Author

Rohr, J., primary, Beutel, K., additional, Maul-Pavicic, A., additional, Vraetz, T., additional, Thiel, J., additional, Warnatz, K., additional, Bondzio, I., additional, Gross-Wieltsch, U., additional, Schundeln, M., additional, Schutz, B., additional, Woessmann, W., additional, Groll, A. H., additional, Strahm, B., additional, Pagel, J., additional, Speckmann, C., additional, Janka, G., additional, Griffiths, G., additional, Schwarz, K., additional, zur Stadt, U., additional, and Ehl, S., additional

Published
2010
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42. Reduced memory B cells in patients with hyper IgE syndrome

Author

Speckmann, C., primary, Enders, A., additional, Woellner, C., additional, Thiel, D., additional, Rensing-Ehl, A., additional, Schlesier, M., additional, Rohr, J., additional, Jakob, T., additional, Oswald, E., additional, Kopp, M.V., additional, Sanal, O., additional, Litzman, J., additional, Plebani, A., additional, Pietrogrande, M.C., additional, Franco, J.L., additional, Espanol, T., additional, Grimbacher, B., additional, and Ehl, S., additional

Published
2008
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46. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Author

Tim Niehues, Catherine Waruiru, Conleth Feighery, Uwe Schauer, Virginie Courteille, Kai Lehmberg, Ingo Müller, I. Esteves, Henner Morbach, Michael Borte, Patrick Hundsdoerfer, Klaus Schwarz, Ewelina Gowin, Alessandro Aiuti, Andreas Holbro, Federica Barzaghi, João Farela Neves, Dagmar Graf, Hannah Tamary, Veneta Milenova, Benedikt Boetticher, Eleonora Gambineri, Vera Goda, Alia Eldash, Jan-Christian Wasmuth, Fabio Candotti, Svetlana O. Sharapova, Markus Metzler, Juergen Brunner, Anna Hilfanova, Brindusa Ruxandra Capilna, Pere Soler-Palacín, Arnau Antolí, Horst von Bernuth, Vassilios Lougaris, Maria Carrabba, Bernd H. Belohradsky, Julian Thalhammer, Nathalie de Vergnes, Peter Olbrich, Peter Kopač, Leif G. Hanitsch, Alexandra Nieters, Filomeen Haerynck, Juliana Gabzdilova, Sezin Aydemir, Rabab El Hawary, Patrick F.K. Yong, Maria Giovanna Danieli, Alberto Tommasini, Sandra Steinmann, Ulrich Baumann, Figen Dogu, Elisabeth Förster-Waldl, Carolina Marasco, Donato Amodio, Lorenzo Lodi, Xavier Solanich, Caterina Cancrini, Brigita Sitkauskiene, Torsten Witte, Clementina Vanessa, Nima Rezaei, Jean-Christophe Goffard, Kirsten Wittke, Emmanouil Liatsis, Helen Baxendale, Susana L. Silva, Bodo Grimbacher, Henrike Ritterbusch, Evangelia Farmaki, Safa Meshaal, Sujal Ghosh, Larysa Kostyuchenko, David Edgar, Simone Cesaro, R Zeuner, Nerea Salmón Rodríguez, Isabella Quinti, Stephan Ehl, Pauline Brosselin, Joerg C. Henes, Pilar Llobet Agulló, Rosa Maria Dellepiane, Andrea Meinhardt, Marina Kojić, Georgios Sogkas, Stephan Borte, Catharina Schuetz, Suheyla Ocak, Karin Marschall, Lukas M. Gasteiger, Stefan Raffac, Sofia Tantou, Sadia Noorani, Matthaios Speletas, Philippe Randrianomenjanahary, Ursula Holzer, Ayca Kiykim, Johannes G. Liese, Angelo Vacca, Gisela Fecker, Ekrem Unal, Koen J. van Aerde, Alba Parra-Martínez, Kaan Boztug, Sophie Stiehler, Sybille Landwehr-Kenzel, Claudio Pignata, Jennifer Neubert, Janine Reichenbach, Shahnaz Parvin, Sarah Goddard, Andrea Schroll, Dirk Holzinger, Asghar Aghamohammadi, Hassan Abolhassani, Johannes Trück, Estela Paz-Artal, Shereen M. Reda, Anna Shcherbina, Maria Raptaki, Jaroslava Orosova, Beata Wolska-Kuśnierz, Tessa Kerre, Gerrit Ahrenstorf, Ben Zion Garty, Dirk Foell, Benjamin Becker, Ulrike F. Demel, Androniki Kapousouzi, Abraham Rutgers, Klaus Warnatz, Gemma Rocamora Blanch, Stephan Rusch, Luis M. Allende, Dalia Abd Elaziz, Safa Baris, Jorisvan Montfrans, Dominik T. Schneider, Raphael Scheible, Juana Gil-Herrera, Gerhard Kindle, Annarosa Soresina, Giovanna Fabio, Uwe Wintergerst, Emilia Faria, Maria Fasshauer, Silvia Ricci, Aisha Elmarsafy, Barbara Pietrucha, Carsten Speckmann, Nizar Mahlaoui, Ulrich Heininger, Isabelle Meyts, Matthew Buckland, Efimia Papadopoulou-Alataki, Robin Kobbe, A Herwadkar, Sebastian F. N. Bode, Ali Sobh, László Maródi, Baldassarre Martire, Chiara Azzari, Maximilian Heeg, Katja Masjosthusmann, Michael H. Albert, Matteo Chinello, Juan Luis Santos-Pérez, Aarnoud Huissoon, Tanya I. Coulter, Hendrik Schulze-Koops, Norbert Graf, Radwa Alkady, Jolanta Bernatoniene, Seraina Prader, Alenka Gagro, Joachim Roesler, Taco W. Kuijpers, Ewa Więsik-Szewczyk, Maria Elena Maccari, Conrad Ferdinand Lippert, Miriam González-Amores, Johannes Dirks, Daniel E Pleguezuelo, Christof M. Kramm, Anders Fasth, Volker Schuster, Olov Ekwall, Nikolaus Rieber, Javier Carbone, Petra Kaiser-Labusch, Diana Ernst, Lucia Augusta Baselli, Luis Ignacio Gonzalez-Granado, Maria Kanariou, Stefanie S. V. Henriet, Sigune Goldacker, Kerstin Felgentreff, Oana Joean, Fine Roosens, Fabian Hauck, Eva C. Schwaneck, Milos Jesenak, Manfred Hoenig, Lenka Kapustova, Christoph Boesecke, Alain Fischer, Sara Pereira da Silva, Julia Körholz, Ansgar Schulz, Carolynne Schwarze-Zander, Mikko Seppänen, Nermeen Galal, Nora Naumann-Bartsch, Tomaz Garcez, Peter Ciznar, Klara M. Posfay-Barbe, Zelimir Pavle Eric, Reinhold E. Schmidt, Hermann J. Girschick, Sabine Heine, Anika-Kerstin Biegner, Annick A. J. M. van de Ven, Stefan Schreiber, J. Merlijn van den Berg, Nurit Assia Batzir, Alexandra Jablonka, Kim Stol, Gregor Dückers, Antonios G.A. Kolios, Ioannis Kakkas, Christian Klemann, Marina N. Guseva, Sofia Grigoriadou, Elif Karakoc-Aydiner, Antonio Marzollo, Peter D. Arkwright, Urs C. Steiner, Sara Sebnem Kilic, Romina Dieli-Crimi, Gergely Kriván, Monika Sparber-Sauer, Marco Cazzaniga, Fulvio Porta, Paraskevi Maggina, Tomas Milota, Robbert G. M. Bredius, Martine Pergent, Klaus Tenbrock, Jana Pachlopnik Schmid, Florentia Dimitriou, Cathal Laurence Steele, Helen Bourne, Anna Bobcakova, Gerd Horneff, Judith Potjewijd, Marc Schmalzing, Tobias Ankermann, Paul Ryan, Oksana Boyarchuk, Necil Kutukculer, Carl Friedrich Classen, Zita Chovancová, Moira Thomas, Cinzia Milito, Michaela Bitzenhofer-Grüber, Faranaz Atschekzei, Eva Hlaváčková, Viviana Moschese, Julie Smet, Hans-Hartmut Peter, Carla Teixeira, Sabine M El-Helou, Suzanne de Kruijf Bazen, Helmut Wittkowski, Donate Jakoby, Marina Garcia-Prat, Esther de Vries, Richard Herriot, Sven Kracker, Alessandro Plebani, Lisa Göschl, Laura Hora Marques, Anna Sediva, Jiri Litzman, Mark M. Gompels, Renate Krüger, Şefika İlknur Kökçü Karadağ, Nadine Binder, Anna Szaflarska, Peter Jandus, Lisa Ibberson, Johann Greil, Ulf Schulze-Sturm, Mehtap Sirin, Aydan Ikinciogullari, Edyta Heropolitańska-Pliszka, Michael E. Weiss, Alla Skapenko, Lukas Wisgrill, Hana Alachkar, Uta Behrends, Silvia Sánchez-Ramón, Maria N. Hatzistilianou, Otilia Petrovicova, Darko Richter, Zoreh Nademi, Jürgen K. Rockstroh, Sohilla Lotfy, Markus G. Seidel, Timothy Ronan Leahy, Audra Blažienė, Translational Immunology Groningen (TRIGR), Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Zurich, Ehl, Stephan, Thalhammer, J., Kindle, G., Nieters, A., Rusch, S., Seppanen, M. R. J., Fischer, A., Grimbacher, B., Edgar, D., Buckland, M., Mahlaoui, N., Ehl, S., Boztug, K., Brunner, J., Demel, U. F., Forster-Waldl, E., Gasteiger, L. M., Goschl, L., Kojic, M., Schroll, A., Seidel, M. G., Wintergerst, U., Wisgrill, L., Sharapova, S. O., Goffard, J. -C., Kerre, T., Meyts, I., Roosens, F., Smet, J., Haerynck, F., Eric, Z. P., Milenova, V., Gagro, A., Richter, D., Chovancova, Z., Hlavackova, E., Litzman, J., Milota, T., Sediva, A., Elaziz, D. A., Alkady, R. S., El Sayed El Hawary, R., Eldash, A. S., Galal, N., Lotfy, S., Meshaal, S. S., Reda, S. M., Sobh, A., Elmarsafy, A., Brosselin, P., Courteille, V., De Vergnes, N., Kracker, S., Pergent, M., Randrianomenjanahary, P., Ahrenstorf, G., Albert, M. H., Ankermann, T., Atschekzei, F., Baumann, U., Becker, B. C., Behrends, U., Belohradsky, B. H., Biegner, A. -K., Binder, N., Bode, S. F. N., Boesecke, C., Boetticher, B., Borte, M., Borte, S., Classen, C. F., Dirks, J., Duckers, G., El-Helou, S., Ernst, D., Fasshauer, M., Fecker, G., Felgentreff, K., Foell, D., Ghosh, S., Girschick, H. J., Goldacker, S., Graf, N., Graf, D., Greil, J., Hanitsch, L. G., Hauck, F., Heeg, M., Heine, S. I., Henes, J. C., Hoenig, M., Holzer, U., Holzinger, D., Horneff, G., Hundsdoerfer, P., Jablonka, A., Jakoby, D., Joean, O., Kaiser-Labusch, P., Klemann, C., Kobbe, R., Korholz, J., Kramm, C. M., Kruger, R., Landwehr-Kenzel, S., Lehmberg, K., Liese, J. G., Lippert, C. F., Maccari, M. E., Masjosthusmann, K., Meinhardt, A., Metzler, M., Morbach, H., Muller, I., Naumann-Bartsch, N., Neubert, J., Niehues, T., Peter, H. -H., Rieber, N., Ritterbusch, H., Rockstroh, J. K., Roesler, J., Schauer, U., Scheible, R., Schmalzing, M., Schmidt, R. E., Schneider, D. T., Schreiber, S., Schuetz, C., Schulz, A., Schulze-Koops, H., Schulze-Sturm, U., Schuster, V., Schwaneck, E. C., Schwarz, K., Schwarze-Zander, C., Sirin, M., Skapenko, A., Sogkas, G., Sparber-Sauer, M., Speckmann, C., Steinmann, S., Stiehler, S., Tenbrock, K., von Bernuth, H., Warnatz, K., Wasmuth, J. -C., Weiss, M., Witte, T., Wittke, K., Wittkowski, H., Zeuner, R. A., Farmaki, E., Hatzistilianou, M. N., Kakkas, I., Kanariou, M. G., Kapousouzi, A., Liatsis, E., Maggina, P., Papadopoulou-Alataki, E., Raptaki, M., Speletas, M., Tantou, S., Goda, V., Krivan, G., Marodi, L., Abolhassani, H., Aghamohammadi, A., Rezaei, N., Feighery, C., Leahy, T. R., Ryan, P., Batzir, N. A., Garty, B. Z., Tamary, H., Aiuti, A., Amodio, D., Azzari, C., Barzaghi, F., Baselli, L. A., Cancrini, C., Carrabba, M., Cazzaniga, M., Cesaro, S., Chinello, M., Danieli, M. G., Dellepiane, R. M., Fabio, G., Gambineri, E., Lodi, L., Lougaris, V., Marasco, C., Martire, B., Marzollo, A., Milito, C., Moschese, V., Pignata, C., Plebani, A., Porta, F., Quinti, I., Ricci, S., Soresina, A., Tommasini, A., Vacca, A., Vanessa, C., Blaziene, A., Sitkauskiene, B., Gowin, E., Heropolitanska-Pliszka, E., Pietrucha, B., Szaflarska, A., Wiesik-Szewczyk, E., Wolska-Kusnierz, B., Esteves, I., Faria, E., Marques, L. H., Neves, J. F., Silva, S. L., Teixeira, C., Pereira da Silva, S., Capilna, B. R., Guseva, M. N., Shcherbina, A., Bobcakova, A., Ciznar, P., Gabzdilova, J., Jesenak, M., Kapustova, L., Orosova, J., Petrovicova, O., Raffac, S., Kopac, P., Allende, L. M., Antoli, A., Blanch, G. R., Carbone, J., Dieli-Crimi, R., Garcia-Prat, M., Gil-Herrera, J., Gonzalez-Granado, L. I., Agullo, P. L., Olbrich, P., Parra-Martinez, A., Paz-Artal, E., Pleguezuelo, D. E., Rodriguez, N. S., Sanchez-Ramon, S., Santos-Perez, J. L., Solanich, X., Soler-Palacin, P., Gonzalez-Amores, M., Ekwall, O., Fasth, A., Bitzenhofer-Gruber, M., Candotti, F., Dimitriou, F., Heininger, U., Holbro, A., Jandus, P., Kolios, A. G. A., Marschall, K., Schmid, J. P., Posfay-Barbe, K. M., Prader, S., Reichenbach, J., Steiner, U. C., Truck, J., Bredius, R. G., de Kruijf- Bazen, S., de Vries, E., Henriet, S. S. V., Kuijpers, T. W., Potjewijd, J., Rutgers, A., Stol, K., van Aerde, K. J., Van den Berg, J. M., van de Ven, A. A. J. M., Montfrans, J., Aydemir, S., Baris, S., Dogu, F., Ikinciogullari, A., Karakoc-Aydiner, E., Kilic, S. S., Kiykim, A., Kokcu Karadag, S. I., Kutukculer, N., Ocak, S., Unal, E., Boyarchuk, O., Hilfanova, A., Kostyuchenko, L. V., Alachkar, H., Arkwright, P. D., Baxendale, H. E., Bernatoniene, J., Coulter, T. I., Garcez, T., Goddard, S., Gompels, M. M., Grigoriadou, S., Herriot, R., Herwadkar, A., Huissoon, A., Ibberson, L., Nademi, Z., Noorani, S., Parvin, S., Steele, C. L., Thomas, M., Waruiru, C., Yong, P. F. K., and Bourne, H.

Subjects
0301 basic medicine, Male, Pediatrics, syndromic, Sex Factor, Disease, registry, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Primary Immunodeficiency Disease, inborn error of immunity, Immunology and Allergy, warning signs, Age Factor, Registries, Family history, presenting symptom, Child, Primary immunodeficiency, Granuloma, autoimmune, immune dysregulation, inflammatory, Adult, Autoimmune Diseases, Female, Humans, Infections, Lymphoproliferative Disorders, Middle Aged, Primary Immunodeficiency Diseases, Sex Factors, Age Factors, 10177 Dermatology Clinic, Infections/epidemiology, 3. Good health, Settore MED/02, Warning signs, Lymphoproliferative Disorder, 2723 Immunology and Allergy, Infection, Human, medicine.medical_specialty, Immunology, 610 Medicine & health, Malignancy, primary immunodeficiency, Autoimmune Disease, 03 medical and health sciences, Immunity, Autoimmune Diseases/epidemiology, medicine, 2403 Immunology, business.industry, warning sign, Common variable immunodeficiency, Granuloma/epidemiology, Immune dysregulation, medicine.disease, Primary Immunodeficiency Diseases/epidemiology, 030104 developmental biology, Lymphoproliferative Disorders/epidemiology, Cohort Studie, business, 030215 immunology
Abstract

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Published
2021

47. Newborn screening for SCID and severe T lymphocytopenia in Europe.

Author

Blom M, Soomann M, Soler-Palacín P, Šedivá A, Stray-Pedersen A, Zetterström R, Speckmann C, Gennery AR, and van der Burg M

Abstract

Initiation of newborn screening (NBS) programs in Europe dates back to the 1960s. One of the most recent expansions of NBS programs was the addition of severe combined immunodeficiency (SCID) based on detection of T-cell receptor excision circles (TRECs). In this review, we present an overview of the current situation in Europe. To avoid a biased overview based on only published results, a 37-item survey on TREC-based NBS was sent to representatives of 46 European countries. With a response rate of 83%, we collected data of 38 countries. Seventeen of the 38 European countries that have completed the survey have nationally or regionally implemented TREC-based NBS. The survey results emphasize similarities and differences as well as common practices and challenges in TREC-based NBS. Because TRECs are a general surrogate marker for severe T lymphocytopenia, conditions other than SCID are also identified. Therefore, the initial definition of the target disease as "SCID" might need to be reconsidered and extended to "SCID and severe T lymphocytopenia." Even though complete harmonization of TREC-based NBS programs across Europe will remain challenging, collaboration and close partnerships will help in the move toward universal TREC-based screening for all newborns, resulting in more infants with SCID and severe T lymphocytopenia being detected each year., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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49. Hematopoietic stem cell transplantation for CTLA-4 insufficiency across Europe: A European Society for Blood and Marrow Transplantation Inborn Errors Working Party study.

Author

Tsilifis C, Speckmann C, Lum SH, Fox TA, Soler AM, Mozo Y, Corral D, Ewins AM, Hague R, Oikonomopoulou C, Kałwak K, Drabko K, Wynn R, Morris EC, Elcombe S, Bigley V, Lougaris V, Malagola M, Hauck F, Sedlacek P, Laberko A, Tjon JML, Buddingh EP, Wehr C, Grimbacher B, Gennery AR, Lankester AC, Albert MH, Neven B, and Slatter MA

Abstract

Background: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterized by lymphoproliferation, dysgammaglobulinemia, and multiorgan autoimmunity including cytopenias and colitis., Objective: We examined the outcome of hematopoietic stem cell transplantation (HSCT) for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4 fusion protein (CTLA-4-Ig) therapy and pre-HSCT immune dysregulation on survival and immunologic outcome., Methods: This was a retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Primary end points were overall survival (OS) and disease- and chronic graft-versus-host disease-free survival (DFS). Secondary end point was immunologic outcome assessed by immune dysregulation disease activity (IDDA) score., Results: Forty patients were included over a 25-year period. Before HSCT, 60% received CTLA-4-Ig, and median (range) IDDA score was 23.3 (3.9-84.0). Median (range) age at HSCT was 14.2 (1.3-56.0) years. Patients received peripheral blood stem cell (58%) or marrow (43%) from a matched unrelated donor (75%), mismatched unrelated donor (12.5%), or matched family donor (12.5%). Median (range) follow-up was 3 (0.6-15) years, and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, disease of 28 of 30 surviving patients was in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity before HSCT (IDDA < 23, P = .002 and P = .006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant related in 7 of 8 patients., Conclusion: HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity., Competing Interests: Disclosure statement Supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre (to E.C.M.). Data used in this study are not publicly available, but deidentified data may be available from the authors on reasonable request. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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50. The different faces of GATA2 deficiency: implications for therapy and surveillance.

Author

Vinci L, Strahm B, Speckmann C, and Erlacher M

Abstract

GATA2 deficiency is one of the most common genetic predispositions to pediatric myelodysplastic syndrome (MDS) in children and adolescents. The wide spectrum of disease comprises, among others, hematological, immunological and pulmonary manifestations, as well as occasionally distinct organ anomalies. Due to the elevated risk of progression, nearly all individuals with GATA2-related MDS eventually undergo a hematopoietic stem cell transplantation (HSCT) at some point in their lives. Nevertheless, the optimal timing, method, and even the indication for HSCT in certain cases are still matter of debate and warrant further research. In this article, we report five patients with different hematological and immunological manifestations of GATA2 deficiency ranging from immunodeficiency and refractory cytopenia of childhood without chromosomal aberrations to relapsed MDS-related acute myeloid leukemia. We discuss the adopted strategies, including intensity of surveillance, indication and timing of HSCT, based on morphological, clinical and molecular markers, as well as individual patient needs. We conclude that a better characterization of the natural disease course, a better understanding of the prognostic significance of somatic aberrations and a thorough evaluation of patients´ perspectives and preferences are required to achieve a personalized approach aimed at improving the care of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vinci, Strahm, Speckmann and Erlacher.)

Published
2024
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