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5. 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

11. Identification of epilepsy concomitant candidate genes recognized in Saudi epileptic patients.

Author

YOUNIS, N. S., MOHAMED, M. E., ALOLAYAN, A. A., ALHUSSAIN, G. Y., AL-MOUSA, H. A., ALSHAMRANI, J. A., ALMUTAYIB, M. M., ALQAHTANI, M. M., ALHADDAD, Z. A., ALFARHAN, Z. S., ALOMRAN, Z. A., and ALMOSTAFA, M. M.

Abstract

Saudi Genome program is a revolutionary nationwide transformation initiative of Saudi Vision 2030. The program goals are to recognize and reduce the incidence of genetic diseases in the Kingdom of Saudi Arabia (KSA). Accordingly, the program will establish the foundation for personalized and genomic medicine in the KSA. Epilepsy has a high prevalence in KSA reaching around 6.54 of 1000 individuals with a subsequent massive financial burden. One of the main risk factors for this high prevalence and associated with increased risk of epilepsy development is consanguinity marriage, which is traditional in KSA. In this review, we executed a comprehensive state-of-art literature review regarding epilepsy genetics to offer a perception into the genes associated with epilepsy recognized in Saudi epileptic patients. Several genes’ mutations were incorporated in this review including AFG3L2, ASPM, ATN1, ATP1A2, BMP5, CCDC88A, C12orf57, DNAJA1, EML1, ERLIN2, FRRS1L, GABRG3, NRXN3, MDH1, KCNJ10, KCNMA1, KCNT1, KIAA0226, OPHN1, PCCA, PCCB, PEX, PGAP2, PI4K2A, PODXL, PRICKLE1, PNKP, RELN, SCN2A, SCN1B, SLC2A1, SLC19A3, SLC25, SIAH1, SYNJ1, SZT2, TBCK, TMX2, TSC1, TSC2, TSEN, WDR45B, WWOX, UBR, UGDH, and YIF1B. For each of these genes, we tried to explain a little about the gene associated proteins and their roles in epilepsy development. [ABSTRACT FROM AUTHOR]

Published
2022

13. The worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children

Author

Versporten A1, Bielicki J2, Drapier N1, Sharland M2, Goossens H3, ARPEC project group. Calle GM, Garrahan JP, Clark J, Cooper C, Blyth CC, Francis JR, Alsalman J, Jansens H, Mahieu L, Van Rossom P, Vandewal W, Lepage P, Blumental S, Briquet C, Robbrecht D, Maton P, Gabriels P, Rubic Z, Kovacevic T, Nielsen JP, Petersen JR, Poorisrisak P, Jensen LH, Laan M, Tamm E, Matsinen M, Rummukainen ML, Gajdos V, Olivier R, Le Maréchal F, Martinot A, Dubos F, Lagrée M, Prot-Labarthe S, Lorrot M, Orbach D, Pagava K, Hufnagel M, Knuf M, Schlag SA, Liese J, Renner L, Enimil A, Awunyo M, Syridou G, Spyridis N, Critselis E, Kouni S, Mougkou K, Ladomenou F, Gkentzi D, Iosifidis E, Roilides E, Sahu S, Murki S, Malviya M, Kalavalapalli DB, Singh S, Singhal T, Garg G, Garg P, Kler N, Soltani J, Jafarpour Z, Pouladfar G, Nicolini G, Montagnani C, Galli L, Esposito S, Tenconi R, Lo Vecchio A, Dona' D, Giaquinto C, Borgia E, D'Argenio P, De Luca M, Centenari C, Raka L, Raka D, Omar A, Al-Mousa H, Mozgis D, Sviestina I, Burokiene S, Usonis V, Tavchioska G, Hargadon-Lowe A, Zarb P, Borg MA, González Lozano CA, Zárate Castañon P, Cancino ME, McCullagh B, McCorry A, Gormley C, Al Maskari Z, Al-Jardani A, Pluta M, Rodrigues F, Brett A, Esteves I, Marques L, Ali AlAjmi J, Claudia Cambrea S, Rashed AN, Mubarak Al Azmi AA, Chan SM, Isa MS, Najdenov P, Čižman M, Unuk S, Finlayson H, Dramowski A, Maté-Cano I, Soto B, Calvo C, Santiago B, Saavedra-Lozano J, Bustinza A, Escosa-García L, Ureta N, Lopez-Varela E, Rojo P, Tagarro A, Barrero PT, Rincon-Lopez EM, Abubakar I, Aston J, Heginbothom M, Satodia P, Garbash M, Johnson A, Sharpe D, Barton C, Menson E, Arenas-Lopez S, Luck S, Doerholt K, McMaster P, Caldwell NA, Lunn A, Drysdale SB, Howe R, Scorrer T, Gahleitner F, Gupta R, Nash C, Alexander J, Raman M, Bell E, Rajagopal V, Kohlhoff S, Cox E, Zaoutis T., Mahieu, Ludo, ARPEC Project Grp, ARPEC project group, Versporten, A1, Bielicki, J2, Drapier, N1, Sharland, M2, Goossens, H3, ARPEC project group., Calle GM, Garrahan, Jp, Clark, J, Cooper, C, Blyth, Cc, Francis, Jr, Alsalman, J, Jansens, H, Mahieu, L, Van Rossom, P, Vandewal, W, Lepage, P, Blumental, S, Briquet, C, Robbrecht, D, Maton, P, Gabriels, P, Rubic, Z, Kovacevic, T, Nielsen, Jp, Petersen, Jr, Poorisrisak, P, Jensen, Lh, Laan, M, Tamm, E, Matsinen, M, Rummukainen, Ml, Gajdos, V, Olivier, R, Le Maréchal, F, Martinot, A, Dubos, F, Lagrée, M, Prot-Labarthe, S, Lorrot, M, Orbach, D, Pagava, K, Hufnagel, M, Knuf, M, Schlag, Sa, Liese, J, Renner, L, Enimil, A, Awunyo, M, Syridou, G, Spyridis, N, Critselis, E, Kouni, S, Mougkou, K, Ladomenou, F, Gkentzi, D, Iosifidis, E, Roilides, E, Sahu, S, Murki, S, Malviya, M, Kalavalapalli, Db, Singh, S, Singhal, T, Garg, G, Garg, P, Kler, N, Soltani, J, Jafarpour, Z, Pouladfar, G, Nicolini, G, Montagnani, C, Galli, L, Esposito, S, Tenconi, R, Lo Vecchio, A, Dona', D, Giaquinto, C, Borgia, E, D'Argenio, P, De Luca, M, Centenari, C, Raka, L, Raka, D, Omar, A, Al-Mousa, H, Mozgis, D, Sviestina, I, Burokiene, S, Usonis, V, Tavchioska, G, Hargadon-Lowe, A, Zarb, P, Borg, Ma, González Lozano, Ca, Zárate Castañon, P, Cancino, Me, Mccullagh, B, Mccorry, A, Gormley, C, Al Maskari, Z, Al-Jardani, A, Pluta, M, Rodrigues, F, Brett, A, Esteves, I, Marques, L, Ali AlAjmi, J, Claudia Cambrea, S, Rashed, An, Mubarak Al Azmi, Aa, Chan, Sm, Isa, M, Najdenov, P, Čižman, M, Unuk, S, Finlayson, H, Dramowski, A, Maté-Cano, I, Soto, B, Calvo, C, Santiago, B, Saavedra-Lozano, J, Bustinza, A, Escosa-García, L, Ureta, N, Lopez-Varela, E, Rojo, P, Tagarro, A, Barrero, Pt, Rincon-Lopez, Em, Abubakar, I, Aston, J, Heginbothom, M, Satodia, P, Garbash, M, Johnson, A, Sharpe, D, Barton, C, Menson, E, Arenas-Lopez, S, Luck, S, Doerholt, K, Mcmaster, P, Caldwell, Na, Lunn, A, Drysdale, Sb, Howe, R, Scorrer, T, Gahleitner, F, Gupta, R, Nash, C, Alexander, J, Raman, M, Bell, E, Rajagopal, V, Kohlhoff, S, Cox, E, and Zaoutis, T.

Subjects
0301 basic medicine, Male, Pediatrics, Latin Americans, Cross-sectional study, Prevalence, Psychological intervention, Drug resistance, Global Health, infectious diseases, 0302 clinical medicine, Global health, Medicine, 030212 general & internal medicine, Child, antibiotics, children, Drugs -- Prescribing, Pharmacology. Therapy, Hospitals -- Europe, Drug Resistance, Microbial, Hospitals, Anti-Bacterial Agents, Europe, Child, Preschool, Anti-infective agents, Female, medicine.drug, Microbiology (medical), medicine.medical_specialty, Cefepime, 030106 microbiology, Drug Prescriptions, 03 medical and health sciences, Surgical prophylaxis, pharmacology, pharmacology (medical), Environmental health, Humans, Biology, Quality Indicators, Health Care, business.industry, Health status indicators -- Europe, Infant, Drug Utilization, Cross-Sectional Studies, Health Care Surveys, Human medicine, business
Abstract

Objectives: Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. Methods: A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). Results: Of 17693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). Conclusions: Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to monitor future interventions in hospitalized neonates and children. To our knowledge, this study has derived the first global quality indicators for antibiotic use in hospitalized neonates and children., peer-reviewed

Published
2018

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, 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

16. World alliance against antibiotic resistance: The WAAAR declaration against antibiotic resistance

Author

Carlet, J, Aaron, L, Abassi, M, Abbo, L, Aboderin, O, Abraham, E, Abroug, F, Acar, J, Achour, W, Adachi, J, Al-Abri, S, Al-Mousa, H, Albaya-Moreno, A, Alberti, C, Alfandari, S, Alnimr, A, Aranda, C, de Lerma, F, Amer, F, Andremont, A, Angoulvant, F, Anguill, M, Antonelli, M, Antoniadou, E, Arlet, G, Armaganidis, A, Arnera, A, Artigas, A, Attali, C, Auber, F, Aubert, J, Augereau, B, Aupee, M, Bahri, O, Ballereau, F, Bapt, G, Baquero, F, Barkhan, T, Barouti, O, Barthelemy, M, Barton, G, Bastoni, D, Baussier, M, Bavestrello, L, Beger, B, Benenson, S, Bensalem, F, Beraud, G, Bergheau, F, Bernard, G, Berthelot, P, Bertrand, X, Beuhorry-Sassus, F, Beuret, P, Billington, J, Birge, J, Biscardi, S, Blanch, L, Blanchard, H, Bleck, T, Blondeau, J, Blot, F, Borgey, F, Bousquet-Melou, A, Brami, J, Brard, C, Bretagne, S, Bretonniere, C, Brink, A, Brown, S, Bruant-Rodier, C, Brun-Buisson, C, Bruneel, F, de Carvalho, F, Buhot, C, Bukharie, H, Cabie, A, Calandra, T, Caniaux, I, Canica, M, Canton, R, Carenco, P, Carlet, C, Carlet, F, Carlet, R, Cars, O, Cassiano-Neves, M, Castan, B, Castellan, V, Cazenave-Roblot, F, Ceretti, A, Chakarian, J, Chalumeau-Lemoine, L, Chandy, J, Chanfreau, B, Chastre, J, Chausset, R, Chavanet, P, Cheadle, W, Chiche, J, Chidiac, C, Chosidow, O, Chueca, N, Cohen, J, Cohen, R, Collignon, P, Collot, F, Coloby, P, Conly, J, Cordero, C, Cordonnier, C, Corso, A, Cosgrove, S, Courcol, R, Crane, S, Craven, D, Crespin, A, Cyrillo, M, Danin, P, Waele, J, Dellamonica, P, Patchen Dellinger, E, Dellinger, P, Delmont, J, Denes, E, Dimopoulos, G, Drekonja, D, Mansilla, A, Druais, P, Dufour-Pierrat, S, Dumartin, C, Dunser, M, Dupont, M, Durlach, R, Dyar, O, Echaniz, G, Edelstein, P, Eggimann, P, Elghonemi, M, Elmdaghri, N, Elsaid, R, Elsokari, R, Engelhard, D, Fabry, J, Farmer, C, Fernandez, J, Finfer, S, Finn, P, Fjeldsted, K, Floret, D, Flozaro, F, Foegle, J, Forceville, X, Fournier, S, Frachon, I, Friedrich, A, Funuel, P, Gaillard, D, Gaillat, J, Galperine, T, Gambarotto, K, Garo, B, Garrouste-Orgeas, M, Gastemeier, P, Gauchot, J, Gauzit, R, Gavazzi, G, Gazagne, L, Gerberding, J, Ghafur, A, Giamarellos-Bourboulis, E, Giamarellou, E, Giard, M, Gilchrist, M, Gilquin, J, Gilsanz, F, Gniadkowski, M, Gogos, C, Goldman, D, Gordon, F, Gottlieb, T, Gould, I, Gouveia, J, Grant, J, Grason, L, Greder, A, Grundman, H, Guaguere, E, Gueroult-Locher, G, Guery, B, Guidet, B, Guignabert, C, Gupta, P, Gupta, S, Gurjar, M, Guzman, M, Hajjar, J, Hammad, N, Hammerum, A, Hanberger, H, Hanke, R, Harbarth, S, Harel, A, Heisbourg, E, Hermes, I, Hermet, J, Hirschel, B, Hoen, B, Hollis, A, Honghong, X, Hooper, D, Horcajada, J, Housset, B, Hryniewicz, W, Hsu, L, Huang, S, Hughes, J, Hunault, J, Jakobsen, L, Jalil, N, Jansens, H, Jarlier, V, Jarvis, W, Jean, D, Jereb, M, Johnson, J, Joly-Guillou, M, Jonquet, O, Kac, G, Kaddu-Mulindwa, D, Kaku, M, Kilani, B, Kim, E, Gazard, D, Klugman, K, Klutts, S, Kluytmans, J, Kollef, M, Koulenti, D, Kresken, M, Lacoin, F, Lajonchere, J, Landgraf, N, Larroussinie, G, Laterre, P, Lavenaire, A, Lavigne, T, Laxminarayan, R, Le, T, Leblanc-Jouffre, F, Lee, N, Lehiani, O, Lelouet, H, Lemanach-Kergueris, F, Lepape, A, Leroy, J, Lescure, X, Levy, M, Levy-Hara, G, Lin, L, Lipman, J, Livartowski, J, Looke, D, Cardozo, F, Medrano, F, Lotthe, A, Lucet, J, Lupande, D, Madec, J, Mainardi, J, Maiylagan, S, Mancebo, J, Mansour-Adeoti, F, Maravi, E, Marchou, B, Marciniuk, D, Marshall, J, Martin, C, Martin, D, Martinez-Martinez, L, Martinot, A, Maseda, E, Matamis, D, Matheron, S, Matos, R, Matthews, M, May, T, Mayet, T, Mcgowan, J, Mehtar, S, Teles, J, Mendelson, M, Michelet, C, Mifsud, A, Mikaszewska-Sokolewicz, M, Minion, J, Miquel, C, Mira, J, Miro, J, Misset, B, Monot, J, Montravers, P, Mootien, J, Moreno, R, Morris, A, Moulin, G, Mourlan, C, Mouthon, G, Mowafy, W, Muhl, E, Muruganathan, A, Mushira, E, N'Doye, B, Nana, A, Niederman, M, Nitenberg, G, Nordman, P, Novira, A, Nowak, C, Okeke, I, Olaechea, P, Omar, A, Opal, S, Leyba, C, Oudega, B, Oziol, E, Page, B, Paiva, J, Palmer, L, Palomar-Martinez, M, Parneix, P, de la Garanderie, D, Perencevich, E, Perl, T, Perronne, C, Peters, G, Peters, M, Peyramond, D, Philippart, F, Pittet, D, Pittet, J, Plesiat, P, Pletz, M, Ploy, M, Pospisil, F, Pouedras, P, Poulakou, G, Poursinoff, A, Pronovost, P, Pulcini, C, Puoti, M, Puvanendiram, S, Quintel, M, Rabaud, C, Rambaud, C, Ramos, H, Rassla, O, Raymond, J, Regnier, B, Reinhart, K, Condomines, J, Revil, J, Riche, A, Richman, P, Richmann, R, Rodriguez, V, Rodriguez-Bano, J, Romain, O, Romand, K, Rossines, E, Rothan-Tondeur, M, Rousselot, J, Rubinstein, E, Rudnov, V, Saini, N, Salmon, D, Salomao, R, Garcia, M, Santos-Bouza, A, Saux, M, Savey, A, Saxinger, L, Schlemmer, B, Schmit, J, Schneider, D, Schoemaker, J, Singh, S, Sole-Violan, J, Soto, S, Stahl, J, Stoclin, A, Tabah, A, Tabut, J, Tambyah, P, Tamion, F, Tarr, P, Tattevin, P, Tenover, F, Terzi, N, Lecompte, M, Theodore, J, Thevenin, D, Thevenot, P, Thiriet, L, Thompson, C, Thurn, J, Tillotson, G, Tiouiri, H, Torres, A, Tremolieres, F, Troadec, M, Umar, R, Upham, G, Urban, C, Vaarten, J, Valla, D, Van Der Mee-Marquet, N, Van der Meer, J, Van Der Poll, T, Vancel, J, Vanhems, P, Varin, R, Varon, E, Vaughan, D, Veilly, M, Vijayakumar, K, Villanueva, A, Vincent, J, Vitrat, V, Voss, A, Wachter, R, Walsh, T, Wark, P, Waterer, G, Wegener, H, Weinbreck, P, Weinstein, R, Weissman, S, Wiener-Kronish, J, Wilmer, A, Wyplosz, B, Yacoub-Agha, I, Young, M, Yusuf, I, Zein, E, Zhanel, G, Zinner, S, Zoungrana, J, Zubareva, N, Carlet J., Aaron L., Abassi M. S., Abbo L., Aboderin O., Abraham E., Abroug F., Acar J., Achour W., Adachi J., Al-Abri S., Al-Mousa H., Albaya-Moreno A., Alberti C., Alfandari S., Alnimr A., Aranda C. A., de Lerma F. A., Amer F., Andremont A., Angoulvant F., Anguill M., Antonelli M., Antoniadou E., Arlet G., Armaganidis A., Arnera A., Artigas A., Attali C., Auber F., Aubert J. -P., Augereau B., Aupee M., Bahri O., Ballereau F., Bapt G., Baquero F., Barkhan T., Barouti O., Barthelemy M. -A., Barton G., Bastoni D., Baussier M., Bavestrello L., Beger B., Benenson S., Bensalem F., Beraud G., Bergheau F., Bernard G., Berthelot P., Bertrand X., Beuhorry-Sassus F., Beuret P., Billington J., Birge J., Biscardi S., Blanch L., Blanchard H., Bleck T., Blondeau J., Blot F., Borgey F., Bousquet-Melou A., Brami J., Brard C., Bretagne S., Bretonniere C., Brink A., Brown S., Bruant-Rodier C., Brun-Buisson C., Bruneel F., de Carvalho F. B., Buhot C., Bukharie H., Cabie A., Calandra T., Caniaux I., Canica M., Canton R., Carenco P., Carlet C., Carlet F., Carlet R., Cars O., Cassiano-Neves M., Castan B., Castellan V., Cazenave-Roblot F., Ceretti A. -M., Chakarian J. -C., Chalumeau-Lemoine L., Chandy J., Chanfreau B., Chastre J., Chausset R., Chavanet P., Cheadle W., Chiche J. -D., Chidiac C., Chosidow O., Chueca N., Cohen J., Cohen R., Collignon P., Collot F., Coloby P., Conly J., Cordero C., Cordonnier C., Corso A., Cosgrove S., Courcol R., Crane S., Craven D., Crespin A., Cyrillo M., Danin P. -E., Waele J. D., Dellamonica P., Patchen Dellinger E., Dellinger P., Delmont J., Denes E., Dimopoulos G., Drekonja D., Mansilla A. D., Druais P. -L., Dufour-Pierrat S., Dumartin C., Dunser M., Dupont M., Durlach R., Dyar O., Echaniz G., Edelstein P., Eggimann P., Elghonemi M., Elmdaghri N., Elsaid R., Elsokari R., Engelhard D., Fabry J., Farmer C., Fernandez J., Finfer S., Finn P., Fjeldsted K., Floret D., Flozaro F., Foegle J., Forceville X., Fournier S., Frachon I., Friedrich A., Funuel P., Gaillard D., Gaillat J., Galperine T., Gambarotto K., Garo B., Garrouste-Orgeas M., Gastemeier P., Gauchot J. -Y., Gauzit R., Gavazzi G., Gazagne L., Gerberding J., Ghafur A., Giamarellos-Bourboulis E., Giamarellou E., Giard M., Gilchrist M., Gilquin J., Gilsanz F., Gniadkowski M., Gogos C., Goldman D., Gordon F., Gottlieb T., Gould I., Gouveia J., Grant J., Grason L., Greder A., Grundman H., Guaguere E., Gueroult-Locher G., Guery B., Guidet B., Guignabert C., Gupta P., Gupta S., Gurjar M., Guzman M., Hajjar J., Hammad N., Hammerum A., Hanberger H., Hanke R., Harbarth S., Harel A., Heisbourg E., Hermes I., Hermet J. -P., Hirschel B., Hoen B., Hollis A., Honghong X., Hooper D., Horcajada J. P., Housset B., Hryniewicz W., Hsu L. Y., Huang S., Hughes J., Hunault J. -L., Jakobsen L., Jalil N., Jansens H., Jarlier V., Jarvis W., Jean D., Jereb M., Johnson J., Joly-Guillou M. -L., Jonquet O., Kac G., Kaddu-Mulindwa D., Kaku M., Kilani B., Kim E. -C., Gazard D. K., Klugman K., Klutts S., Kluytmans J., Kollef M., Koulenti D., Kresken M., Lacoin F., Lajonchere J. -P., Landgraf N., Larroussinie G., Laterre P. -F., Lavenaire A. -M., Lavigne T., Laxminarayan R., Le T. A. T., Leblanc-Jouffre F., Lee N. Y., Lehiani O., Lelouet H., Lemanach-Kergueris F., Lepape A., Leroy J., Lescure X., Levy M., Levy-Hara G., Lin L. M., Lipman J., Livartowski J., Looke D., Cardozo F. L. L., Medrano F. L., Lotthe A., Lucet J. C., Lupande D., Madec J. -Y., Mainardi J. -L., Maiylagan S., Mancebo J., Mansour-Adeoti F., Maravi E., Marchou B., Marciniuk D., Marshall J., Martin C., Martin D., Martinez-Martinez L., Martinot A., Maseda E., Matamis D., Matheron S., Matos R., Matthews M., May T., Mayet T., McGowan J., Mehtar S., Teles J. M. M., Mendelson M., Michelet C., Mifsud A., Mikaszewska-Sokolewicz M., Minion J., Miquel C., Mira J. -P., Miro J., Misset B., Monot J. -J., Montravers P., Mootien J., Moreno R., Morris A., Moulin G., Mourlan C., Mouthon G., Mowafy W., Muhl E., Muruganathan A., Mushira E., N'Doye B., Nana A., Niederman M., Nitenberg G., Nordman P., Novira A., Nowak C., Okeke I., Olaechea P. M., Omar A., Opal S., Leyba C. O., Oudega B., Oziol E., Page B., Paiva J. A., Palmer L., Palomar-Martinez M., Parneix P., de la Garanderie D. P., Perencevich E., Perl T., Perronne C., Peters G., Peters M., Peyramond D., Philippart F., Pittet D., Pittet J. -F., Plesiat P., Pletz M., Ploy M. -C., Pospisil F., Pouedras P., Poulakou G., Poursinoff A., Pronovost P., Pulcini C., Puoti M., Puvanendiram S., Quintel M., Rabaud C., Rambaud C., Ramos H., Rassla O., Raymond J., Regnier B., Reinhart K., Condomines J. R., Revil J. -C., Riche A., Richman P., Richmann R., Rodriguez V., Rodriguez-Bano J., Romain O., Romand K., Rossines E., Rothan-Tondeur M. I., Rousselot J. -F., Rubinstein E., Rudnov V., Saini N., Salmon D., Salomao R., Garcia M. S., Santos-Bouza A., Saux M. -C., Savey A., Saxinger L., Schlemmer B., Schmit J. -L., Schneider D., Schoemaker J., Singh S., Sole-Violan J., Soto S., Stahl J. -P., Stoclin A., Tabah A., Tabut J. -P., Tambyah P. A., Tamion F., Tarr P., Tattevin P., Tenover F., Terzi N., Lecompte M. T., Theodore J., Thevenin D., Thevenot P., Thiriet L., Thompson C., Thurn J., Tillotson G., Tiouiri H., Torres A., Tremolieres F., Troadec M., Umar R., Upham G., Urban C., Vaarten J., Valla D., Van Der Mee-Marquet N., Van der Meer J., Van Der Poll T., Vancel J., Vanhems P., Varin R., Varon E., Vaughan D., Veilly M., Vijayakumar K., Villanueva A., Vincent J. -L., Vitrat V., Voss A., Wachter R., Walsh T., Wark P., Waterer G., Wegener H. C., Weinbreck P., Weinstein R., Weissman S., Wiener-Kronish J., Wilmer A., Wyplosz B., Yacoub-Agha I., Young M., Yusuf I., Zein E., Zhanel G., Zinner S., Zoungrana J., Zubareva N., Carlet, J, Aaron, L, Abassi, M, Abbo, L, Aboderin, O, Abraham, E, Abroug, F, Acar, J, Achour, W, Adachi, J, Al-Abri, S, Al-Mousa, H, Albaya-Moreno, A, Alberti, C, Alfandari, S, Alnimr, A, Aranda, C, de Lerma, F, Amer, F, Andremont, A, Angoulvant, F, Anguill, M, Antonelli, M, Antoniadou, E, Arlet, G, Armaganidis, A, Arnera, A, Artigas, A, Attali, C, Auber, F, Aubert, J, Augereau, B, Aupee, M, Bahri, O, Ballereau, F, Bapt, G, Baquero, F, Barkhan, T, Barouti, O, Barthelemy, M, Barton, G, Bastoni, D, Baussier, M, Bavestrello, L, Beger, B, Benenson, S, Bensalem, F, Beraud, G, Bergheau, F, Bernard, G, Berthelot, P, Bertrand, X, Beuhorry-Sassus, F, Beuret, P, Billington, J, Birge, J, Biscardi, S, Blanch, L, Blanchard, H, Bleck, T, Blondeau, J, Blot, F, Borgey, F, Bousquet-Melou, A, Brami, J, Brard, C, Bretagne, S, Bretonniere, C, Brink, A, Brown, S, Bruant-Rodier, C, Brun-Buisson, C, Bruneel, F, de Carvalho, F, Buhot, C, Bukharie, H, Cabie, A, Calandra, T, Caniaux, I, Canica, M, Canton, R, Carenco, P, Carlet, C, Carlet, F, Carlet, R, Cars, O, Cassiano-Neves, M, Castan, B, Castellan, V, Cazenave-Roblot, F, Ceretti, A, Chakarian, J, Chalumeau-Lemoine, L, Chandy, J, Chanfreau, B, Chastre, J, Chausset, R, Chavanet, P, Cheadle, W, Chiche, J, Chidiac, C, Chosidow, O, Chueca, N, Cohen, J, Cohen, R, Collignon, P, Collot, F, Coloby, P, Conly, J, Cordero, C, Cordonnier, C, Corso, A, Cosgrove, S, Courcol, R, Crane, S, Craven, D, Crespin, A, Cyrillo, M, Danin, P, Waele, J, Dellamonica, P, Patchen Dellinger, E, Dellinger, P, Delmont, J, Denes, E, Dimopoulos, G, Drekonja, D, Mansilla, A, Druais, P, Dufour-Pierrat, S, Dumartin, C, Dunser, M, Dupont, M, Durlach, R, Dyar, O, Echaniz, G, Edelstein, P, Eggimann, P, Elghonemi, M, Elmdaghri, N, Elsaid, R, Elsokari, R, Engelhard, D, Fabry, J, Farmer, C, Fernandez, J, Finfer, S, Finn, P, Fjeldsted, K, Floret, D, Flozaro, F, Foegle, J, Forceville, X, Fournier, S, Frachon, I, Friedrich, A, Funuel, P, Gaillard, D, Gaillat, J, Galperine, T, Gambarotto, K, Garo, B, Garrouste-Orgeas, M, Gastemeier, P, Gauchot, J, Gauzit, R, Gavazzi, G, Gazagne, L, Gerberding, J, Ghafur, A, Giamarellos-Bourboulis, E, Giamarellou, E, Giard, M, Gilchrist, M, Gilquin, J, Gilsanz, F, Gniadkowski, M, Gogos, C, Goldman, D, Gordon, F, Gottlieb, T, Gould, I, Gouveia, J, Grant, J, Grason, L, Greder, A, Grundman, H, Guaguere, E, Gueroult-Locher, G, Guery, B, Guidet, B, Guignabert, C, Gupta, P, Gupta, S, Gurjar, M, Guzman, M, Hajjar, J, Hammad, N, Hammerum, A, Hanberger, H, Hanke, R, Harbarth, S, Harel, A, Heisbourg, E, Hermes, I, Hermet, J, Hirschel, B, Hoen, B, Hollis, A, Honghong, X, Hooper, D, Horcajada, J, Housset, B, Hryniewicz, W, Hsu, L, Huang, S, Hughes, J, Hunault, J, Jakobsen, L, Jalil, N, Jansens, H, Jarlier, V, Jarvis, W, Jean, D, Jereb, M, Johnson, J, Joly-Guillou, M, Jonquet, O, Kac, G, Kaddu-Mulindwa, D, Kaku, M, Kilani, B, Kim, E, Gazard, D, Klugman, K, Klutts, S, Kluytmans, J, Kollef, M, Koulenti, D, Kresken, M, Lacoin, F, Lajonchere, J, Landgraf, N, Larroussinie, G, Laterre, P, Lavenaire, A, Lavigne, T, Laxminarayan, R, Le, T, Leblanc-Jouffre, F, Lee, N, Lehiani, O, Lelouet, H, Lemanach-Kergueris, F, Lepape, A, Leroy, J, Lescure, X, Levy, M, Levy-Hara, G, Lin, L, Lipman, J, Livartowski, J, Looke, D, Cardozo, F, Medrano, F, Lotthe, A, Lucet, J, Lupande, D, Madec, J, Mainardi, J, Maiylagan, S, Mancebo, J, Mansour-Adeoti, F, Maravi, E, Marchou, B, Marciniuk, D, Marshall, J, Martin, C, Martin, D, Martinez-Martinez, L, Martinot, A, Maseda, E, Matamis, D, Matheron, S, Matos, R, Matthews, M, May, T, Mayet, T, Mcgowan, J, Mehtar, S, Teles, J, Mendelson, M, Michelet, C, Mifsud, A, Mikaszewska-Sokolewicz, M, Minion, J, Miquel, C, Mira, J, Miro, J, Misset, B, Monot, J, Montravers, P, Mootien, J, Moreno, R, Morris, A, Moulin, G, Mourlan, C, Mouthon, G, Mowafy, W, Muhl, E, Muruganathan, A, Mushira, E, N'Doye, B, Nana, A, Niederman, M, Nitenberg, G, Nordman, P, Novira, A, Nowak, C, Okeke, I, Olaechea, P, Omar, A, Opal, S, Leyba, C, Oudega, B, Oziol, E, Page, B, Paiva, J, Palmer, L, Palomar-Martinez, M, Parneix, P, de la Garanderie, D, Perencevich, E, Perl, T, Perronne, C, Peters, G, Peters, M, Peyramond, D, Philippart, F, Pittet, D, Pittet, J, Plesiat, P, Pletz, M, Ploy, M, Pospisil, F, Pouedras, P, Poulakou, G, Poursinoff, A, Pronovost, P, Pulcini, C, Puoti, M, Puvanendiram, S, Quintel, M, Rabaud, C, Rambaud, C, Ramos, H, Rassla, O, Raymond, J, Regnier, B, Reinhart, K, Condomines, J, Revil, J, Riche, A, Richman, P, Richmann, R, Rodriguez, V, Rodriguez-Bano, J, Romain, O, Romand, K, Rossines, E, Rothan-Tondeur, M, Rousselot, J, Rubinstein, E, Rudnov, V, Saini, N, Salmon, D, Salomao, R, Garcia, M, Santos-Bouza, A, Saux, M, Savey, A, Saxinger, L, Schlemmer, B, Schmit, J, Schneider, D, Schoemaker, J, Singh, S, Sole-Violan, J, Soto, S, Stahl, J, Stoclin, A, Tabah, A, Tabut, J, Tambyah, P, Tamion, F, Tarr, P, Tattevin, P, Tenover, F, Terzi, N, Lecompte, M, Theodore, J, Thevenin, D, Thevenot, P, Thiriet, L, Thompson, C, Thurn, J, Tillotson, G, Tiouiri, H, Torres, A, Tremolieres, F, Troadec, M, Umar, R, Upham, G, Urban, C, Vaarten, J, Valla, D, Van Der Mee-Marquet, N, Van der Meer, J, Van Der Poll, T, Vancel, J, Vanhems, P, Varin, R, Varon, E, Vaughan, D, Veilly, M, Vijayakumar, K, Villanueva, A, Vincent, J, Vitrat, V, Voss, A, Wachter, R, Walsh, T, Wark, P, Waterer, G, Wegener, H, Weinbreck, P, Weinstein, R, Weissman, S, Wiener-Kronish, J, Wilmer, A, Wyplosz, B, Yacoub-Agha, I, Young, M, Yusuf, I, Zein, E, Zhanel, G, Zinner, S, Zoungrana, J, Zubareva, N, Carlet J., Aaron L., Abassi M. S., Abbo L., Aboderin O., Abraham E., Abroug F., Acar J., Achour W., Adachi J., Al-Abri S., Al-Mousa H., Albaya-Moreno A., Alberti C., Alfandari S., Alnimr A., Aranda C. A., de Lerma F. A., Amer F., Andremont A., Angoulvant F., Anguill M., Antonelli M., Antoniadou E., Arlet G., Armaganidis A., Arnera A., Artigas A., Attali C., Auber F., Aubert J. -P., Augereau B., Aupee M., Bahri O., Ballereau F., Bapt G., Baquero F., Barkhan T., Barouti O., Barthelemy M. -A., Barton G., Bastoni D., Baussier M., Bavestrello L., Beger B., Benenson S., Bensalem F., Beraud G., Bergheau F., Bernard G., Berthelot P., Bertrand X., Beuhorry-Sassus F., Beuret P., Billington J., Birge J., Biscardi S., Blanch L., Blanchard H., Bleck T., Blondeau J., Blot F., Borgey F., Bousquet-Melou A., Brami J., Brard C., Bretagne S., Bretonniere C., Brink A., Brown S., Bruant-Rodier C., Brun-Buisson C., Bruneel F., de Carvalho F. B., Buhot C., Bukharie H., Cabie A., Calandra T., Caniaux I., Canica M., Canton R., Carenco P., Carlet C., Carlet F., Carlet R., Cars O., Cassiano-Neves M., Castan B., Castellan V., Cazenave-Roblot F., Ceretti A. -M., Chakarian J. -C., Chalumeau-Lemoine L., Chandy J., Chanfreau B., Chastre J., Chausset R., Chavanet P., Cheadle W., Chiche J. -D., Chidiac C., Chosidow O., Chueca N., Cohen J., Cohen R., Collignon P., Collot F., Coloby P., Conly J., Cordero C., Cordonnier C., Corso A., Cosgrove S., Courcol R., Crane S., Craven D., Crespin A., Cyrillo M., Danin P. -E., Waele J. D., Dellamonica P., Patchen Dellinger E., Dellinger P., Delmont J., Denes E., Dimopoulos G., Drekonja D., Mansilla A. D., Druais P. -L., Dufour-Pierrat S., Dumartin C., Dunser M., Dupont M., Durlach R., Dyar O., Echaniz G., Edelstein P., Eggimann P., Elghonemi M., Elmdaghri N., Elsaid R., Elsokari R., Engelhard D., Fabry J., Farmer C., Fernandez J., Finfer S., Finn P., Fjeldsted K., Floret D., Flozaro F., Foegle J., Forceville X., Fournier S., Frachon I., Friedrich A., Funuel P., Gaillard D., Gaillat J., Galperine T., Gambarotto K., Garo B., Garrouste-Orgeas M., Gastemeier P., Gauchot J. -Y., Gauzit R., Gavazzi G., Gazagne L., Gerberding J., Ghafur A., Giamarellos-Bourboulis E., Giamarellou E., Giard M., Gilchrist M., Gilquin J., Gilsanz F., Gniadkowski M., Gogos C., Goldman D., Gordon F., Gottlieb T., Gould I., Gouveia J., Grant J., Grason L., Greder A., Grundman H., Guaguere E., Gueroult-Locher G., Guery B., Guidet B., Guignabert C., Gupta P., Gupta S., Gurjar M., Guzman M., Hajjar J., Hammad N., Hammerum A., Hanberger H., Hanke R., Harbarth S., Harel A., Heisbourg E., Hermes I., Hermet J. -P., Hirschel B., Hoen B., Hollis A., Honghong X., Hooper D., Horcajada J. P., Housset B., Hryniewicz W., Hsu L. Y., Huang S., Hughes J., Hunault J. -L., Jakobsen L., Jalil N., Jansens H., Jarlier V., Jarvis W., Jean D., Jereb M., Johnson J., Joly-Guillou M. -L., Jonquet O., Kac G., Kaddu-Mulindwa D., Kaku M., Kilani B., Kim E. -C., Gazard D. K., Klugman K., Klutts S., Kluytmans J., Kollef M., Koulenti D., Kresken M., Lacoin F., Lajonchere J. -P., Landgraf N., Larroussinie G., Laterre P. -F., Lavenaire A. -M., Lavigne T., Laxminarayan R., Le T. A. T., Leblanc-Jouffre F., Lee N. Y., Lehiani O., Lelouet H., Lemanach-Kergueris F., Lepape A., Leroy J., Lescure X., Levy M., Levy-Hara G., Lin L. M., Lipman J., Livartowski J., Looke D., Cardozo F. L. L., Medrano F. L., Lotthe A., Lucet J. C., Lupande D., Madec J. -Y., Mainardi J. -L., Maiylagan S., Mancebo J., Mansour-Adeoti F., Maravi E., Marchou B., Marciniuk D., Marshall J., Martin C., Martin D., Martinez-Martinez L., Martinot A., Maseda E., Matamis D., Matheron S., Matos R., Matthews M., May T., Mayet T., McGowan J., Mehtar S., Teles J. M. M., Mendelson M., Michelet C., Mifsud A., Mikaszewska-Sokolewicz M., Minion J., Miquel C., Mira J. -P., Miro J., Misset B., Monot J. -J., Montravers P., Mootien J., Moreno R., Morris A., Moulin G., Mourlan C., Mouthon G., Mowafy W., Muhl E., Muruganathan A., Mushira E., N'Doye B., Nana A., Niederman M., Nitenberg G., Nordman P., Novira A., Nowak C., Okeke I., Olaechea P. M., Omar A., Opal S., Leyba C. O., Oudega B., Oziol E., Page B., Paiva J. A., Palmer L., Palomar-Martinez M., Parneix P., de la Garanderie D. P., Perencevich E., Perl T., Perronne C., Peters G., Peters M., Peyramond D., Philippart F., Pittet D., Pittet J. -F., Plesiat P., Pletz M., Ploy M. -C., Pospisil F., Pouedras P., Poulakou G., Poursinoff A., Pronovost P., Pulcini C., Puoti M., Puvanendiram S., Quintel M., Rabaud C., Rambaud C., Ramos H., Rassla O., Raymond J., Regnier B., Reinhart K., Condomines J. R., Revil J. -C., Riche A., Richman P., Richmann R., Rodriguez V., Rodriguez-Bano J., Romain O., Romand K., Rossines E., Rothan-Tondeur M. I., Rousselot J. -F., Rubinstein E., Rudnov V., Saini N., Salmon D., Salomao R., Garcia M. S., Santos-Bouza A., Saux M. -C., Savey A., Saxinger L., Schlemmer B., Schmit J. -L., Schneider D., Schoemaker J., Singh S., Sole-Violan J., Soto S., Stahl J. -P., Stoclin A., Tabah A., Tabut J. -P., Tambyah P. A., Tamion F., Tarr P., Tattevin P., Tenover F., Terzi N., Lecompte M. T., Theodore J., Thevenin D., Thevenot P., Thiriet L., Thompson C., Thurn J., Tillotson G., Tiouiri H., Torres A., Tremolieres F., Troadec M., Umar R., Upham G., Urban C., Vaarten J., Valla D., Van Der Mee-Marquet N., Van der Meer J., Van Der Poll T., Vancel J., Vanhems P., Varin R., Varon E., Vaughan D., Veilly M., Vijayakumar K., Villanueva A., Vincent J. -L., Vitrat V., Voss A., Wachter R., Walsh T., Wark P., Waterer G., Wegener H. C., Weinbreck P., Weinstein R., Weissman S., Wiener-Kronish J., Wilmer A., Wyplosz B., Yacoub-Agha I., Young M., Yusuf I., Zein E., Zhanel G., Zinner S., Zoungrana J., and Zubareva N.

Abstract

We must change how antibiotics are used and adopt proactive strategies, similar to those used to save endangered species. Preservation of the efficacy of antibiotics and to stabilization of antibiotic-susceptible bacterial ecosystems should be global goals. (C) 2014 Elsevier Espana, S.L.U. and SEMICYUC. All rights reserved.

Published
2015

17. The worldwide antibiotic resistance and prescribing in european children (ARPEC) point prevalence survey: Developing hospital-quality indicators of antibiotic prescribing for children

Author

Versporten, A. Bielicki, J. Drapier, N. Sharland, M. Goossens, H. Calle, G.M. Clark, J. Cooper, C. Blyth, C.C. Francis, J.R. Alsalman, J. Jansens, H. Mahieu, L. Van Rossom, P. Vandewal, W. Lepage, P. Blumental, S. Briquet, C. Robbrecht, D. Maton, P. Gabriels, P. Rubic, Z. Kovacevic, T. Nielsen, J.P. Petersen, J.R. Poorisrisak, P. Jensen, L.H. Laan, M. Tamm, E. Matsinen, M. Rummukainen, M.-L. Gajdos, V. Olivier, R. Le Maréchal, F. Martinot, A. Prot-Labarthe, S. Lorrot, M. Orbach, D. Pagava, K. Hufnagel, M. Knuf, M. Schlag, S.A.A. Liese, J. Renner, L. Enimil, A. Awunyo, M. Syridou, G. Spyridis, N. Critselis, E. Kouni, S. Mougkou, K. Ladomenou, F. Gkentzi, D. Iosifidis, E. Roilides, E. Sahu, S. Murki, S. Malviya, M. Kalavalapalli, D.B. Singh, S. Singhal, T. Garg, G. Garg, P. Kler, N. Soltani, J. Jafarpour, Z. Pouladfar, G. Nicolini, G. Montagnani, C. Galli, L. Esposito, S. Vecchio, A.L. Dona', D. Giaquinto, C. Borgia, E. D'Argenio, P. De Luca, M. Centenari, C. Raka, L. Omar, A. Al-Mousa, H. Mozgis, D. Sviestina, I. Burokiene, S. Usonis, V. Tavchioska, G. Hargadon-Lowe, A. Zarb, P. Borg, M.A. González Lozano, C.A. Castañon, P.Z. Cancino, M.E. McCullagh, B. McCorry, A. Gormley, C. Al Maskari, Z. Al-Jardani, A. Pluta, M. Rodrigues, F. Brett, A. Esteves, I. Marques, L. AlAjmi, J.A. Cambrea, S.C. Rashed, A.N. Al Azmi, A.A.M. Chan, S.M. Isa, M.S. Najdenov, P. Čižman, M. Unuk, S. Finlayson, H. Dramowski, A. Maté-Cano, I. Soto, B. Calvo, C. Santiago, B. Saavedra-Lozano, J. Bustinza, A. Escosa-García, L. Ureta, N. Tagarro, A. Barrero, P.T. Rincon-Lopez, E.M. Abubakar, I. Aston, J. Heginbothom, M. Satodia, P. Garbash, M. Johnson, A. Sharpe, D. Barton, C. Menson, E. Arenas-Lopez, S. Luck, S. Doerholt, K. McMaster, P. Caldwell, N.A. Lunn, A. Drysdale, S.B. Howe, R. Scorrer, T. Gahleitner, F. Gupta, R. Nash, C. Alexander, J. Raman, M. Bell, E. Rajagopal, V. Kohlhoff, S. Cox, E. Zaoutis, T. ARPEC project group

Abstract

Objectives: Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. Methods: A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). Results: Of 17 693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). Conclusions: Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to monitor future interventions in hospitalized neonates and children. To our knowledge, this study has derived the first global quality indicators for antibiotic use in hospitalized neonates and children. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Published
2016

18. Haematopoietic stem cell transplantation for CD40 ligand deficiency: results from an EBMT Inborn Errors Working Party (IEWP) study

Author

Ferrua, F., Courteille, V., Janda, A., Slatter, M., Albert, M.H., Al-Mousa, H., Al-Saud, B., Balashov, D., Bertrand, Y., Booth, C., Bordon, V., Czogala, W., Dogu, F., Fasth, A., Formankova, R., Gozdzik, J., Heilmann, C., Honig, M., Ikinciogullari, A., Kalwak, K., Keogh, S.J., Krivan, G., Lange, A., Lankester, A.C., Ljungman, P., Meyts, I., Neven, B., Soncini, E., Suarez, F., Mahlaoui, N., Fischer, A., Davies, E.G., Gennery, A.R., and EBMT IEWP

Published
2015

19. 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

20. The worldwide antibiotic resistance and prescribing in european children (ARPEC) point prevalence survey: Developing hospital-quality indicators of antibiotic prescribing for children.

Author

Soltani J., Kovacevic T., Nielsen J.P., Petersen J.R., Poorisrisak P., Jensen L.H., Laan M., Tamm E., Matsinen M., Rummukainen M.-L., Gajdos V., Olivier R., Le Marechal F., Martinot A., Prot-Labarthe S., Lorrot M., Orbach D., Pagava K., Hufnagel M., Knuf M., Schlag S.A.A., Liese J., Renner L., Enimil A., Awunyo M., Syridou G., Spyridis N., Critselis E., Kouni S., Mougkou K., Ladomenou F., Gkentzi D., Iosifidis E., Roilides E., Sahu S., Murki S., Malviya M., Kalavalapalli D.B., Singh S., Singhal T., Garg G., Garg P., Kler N., Jafarpour Z., Pouladfar G., Nicolini G., Montagnani C., Galli L., Esposito S., Vecchio A.L., Dona' D., Giaquinto C., Borgia E., D'Argenio P., De Luca M., Centenari C., Raka L., Omar A., Al-Mousa H., Mozgis D., Sviestina I., Burokiene S., Usonis V., Tavchioska G., Hargadon-Lowe A., Zarb P., Borg M.A., Gonzalez Lozano C.A., Castanon P.Z., Cancino M.E., McCullagh B., McCorry A., Gormley C., Al Maskari Z., Al-Jardani A., Pluta M., Rodrigues F., Brett A., Esteves I., Marques L., AlAjmi J.A., Cambrea S.C., Rashed A.N., Al Azmi A.A.M., Chan S.M., Isa M.S., Najdenov P., Cizman M., Unuk S., Finlayson H., Dramowski A., Mate-Cano I., Soto B., Calvo C., Santiago B., Saavedra-Lozano J., Bustinza A., Escosa-Garcia L., Ureta N., Tagarro A., Barrero P.T., Rincon-Lopez E.M., Abubakar I., Aston J., Heginbothom M., Satodia P., Garbash M., Johnson A., Sharpe D., Barton C., Menson E., Arenas-Lopez S., Luck S., Doerholt K., McMaster P., Caldwell N.A., Lunn A., Drysdale S.B., Howe R., Scorrer T., Gahleitner F., Gupta R., Nash C., Alexander J., Raman M., Bell E., Rajagopal V., Kohlhoff S., Cox E., Zaoutis T., Versporten A., Bielicki J., Drapier N., Sharland M., Goossens H., Calle G.M., Clark J., Cooper C., Blyth C.C., Francis J.R., Alsalman J., Jansens H., Mahieu L., Van Rossom P., Vandewal W., Lepage P., Blumental S., Briquet C., Robbrecht D., Maton P., Gabriels P., Rubic Z., Soltani J., Kovacevic T., Nielsen J.P., Petersen J.R., Poorisrisak P., Jensen L.H., Laan M., Tamm E., Matsinen M., Rummukainen M.-L., Gajdos V., Olivier R., Le Marechal F., Martinot A., Prot-Labarthe S., Lorrot M., Orbach D., Pagava K., Hufnagel M., Knuf M., Schlag S.A.A., Liese J., Renner L., Enimil A., Awunyo M., Syridou G., Spyridis N., Critselis E., Kouni S., Mougkou K., Ladomenou F., Gkentzi D., Iosifidis E., Roilides E., Sahu S., Murki S., Malviya M., Kalavalapalli D.B., Singh S., Singhal T., Garg G., Garg P., Kler N., Jafarpour Z., Pouladfar G., Nicolini G., Montagnani C., Galli L., Esposito S., Vecchio A.L., Dona' D., Giaquinto C., Borgia E., D'Argenio P., De Luca M., Centenari C., Raka L., Omar A., Al-Mousa H., Mozgis D., Sviestina I., Burokiene S., Usonis V., Tavchioska G., Hargadon-Lowe A., Zarb P., Borg M.A., Gonzalez Lozano C.A., Castanon P.Z., Cancino M.E., McCullagh B., McCorry A., Gormley C., Al Maskari Z., Al-Jardani A., Pluta M., Rodrigues F., Brett A., Esteves I., Marques L., AlAjmi J.A., Cambrea S.C., Rashed A.N., Al Azmi A.A.M., Chan S.M., Isa M.S., Najdenov P., Cizman M., Unuk S., Finlayson H., Dramowski A., Mate-Cano I., Soto B., Calvo C., Santiago B., Saavedra-Lozano J., Bustinza A., Escosa-Garcia L., Ureta N., Tagarro A., Barrero P.T., Rincon-Lopez E.M., Abubakar I., Aston J., Heginbothom M., Satodia P., Garbash M., Johnson A., Sharpe D., Barton C., Menson E., Arenas-Lopez S., Luck S., Doerholt K., McMaster P., Caldwell N.A., Lunn A., Drysdale S.B., Howe R., Scorrer T., Gahleitner F., Gupta R., Nash C., Alexander J., Raman M., Bell E., Rajagopal V., Kohlhoff S., Cox E., Zaoutis T., Versporten A., Bielicki J., Drapier N., Sharland M., Goossens H., Calle G.M., Clark J., Cooper C., Blyth C.C., Francis J.R., Alsalman J., Jansens H., Mahieu L., Van Rossom P., Vandewal W., Lepage P., Blumental S., Briquet C., Robbrecht D., Maton P., Gabriels P., and Rubic Z.

Abstract

Objectives: Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. Method(s): A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). Result(s): Of 17 693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). Conclusion(s): Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to

Published
2016

21. Inherited IL-12p40 Deficiency Genetic, Immunologic, and Clinical Features of 49 Patients From 30 Kindreds

Author

Prando, C, Samarina, A, Bustamante, J, Boisson-Dupuis, S, Cobat, A, Picard, C, AlSum, Z, Al-Jumaah, S, Al-Hajjar, S, Frayha, H, Alangari, A, Al-Mousa, H, Mobaireek, KF, Ben-Mustapha, I, Adimi, P, Feinberg, J, de Suremain, M, Jannière, L, Filipe-Santos, O, Mansouri, N, Stephan, JL, Nallusamy, R, Kumararatne, DS, Bloorsaz, MR, Ben-Ali, M, Elloumi-Zghal, H, Chemli, J, Bouguila, J, Bejaoui, M, Alaki, E, AlFawaz, TS, Al Idrissi, E, ElGhazali, G, Pollard, AJ, Murugasu, B, Wah Lee, B, Halwani, R, Al-Zahrani, M, Al Shehri, MA, Bin-Hussain, I, Mahdaviani, SA, Parvaneh, N, Abel, L, Mansouri, D, Barbouche, R, Al-Muhsen, S, Casanova, JL, Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], King Saud University [Riyadh] (KSU), King Faisal Specialist Hospital and Research Center, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pediatrie, Université de St Etienne, Department of Pediatrics, Penang Medical College, Addenbrookes Hospital, Sahloul Hospital, Farhat Hached Hospital, Bone Marrow Transplantation Center, King Fahad Med City, Dept Pediat, Univ Oxford, NIHR Oxford Biomed Res Ctr, Childrens Hosp, Dept Paediat, Natl Univ Singapore, Dept Pediat, Secur Forces Hosp, Dept Pediat, King Fahad Medical City, Univ Tehran Med Sci, Pediat Infect Dis Res Ctr, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), The Laboratory of Human Genetics of Infectious Diseases is supported by institutional grants to INSERM and The Rockefeller University, and grants from the Agence Nationale de la Recherche (ANR), the European Union HOMITB (E08153KK) and NEOTIM (018736), the St. Giles Foundation, the Thrasher Research Fund, the Jeffrey Modell Foundation, Talecris Biotherapeutics, National Institutes of Health (1R01AI089970-01), European Project: 200732,EC:FP7:HEALTH,FP7-HEALTH-2007-A,HOMITB(2008), European Project: 33419,NEOTIM, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Shahid Beheshti University of Medical Sciences, King Saud Univ, Coll Med, Dept Pediat, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet - Saint-Étienne (UJM), and National University of Singapore (NUS)

Subjects
MESH: Asia, Western, MESH: Age of Onset, [SDV]Life Sciences [q-bio], MESH: Founder Effect, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Genetic etiology, MESH: Penetrance, MESH: Child, Medicine, MESH: DNA Mutational Analysis, MESH: Cohort Studies, Survival analysis, 030304 developmental biology, Genetics, MESH: Adolescent, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Salmonella Infections, MESH: Humans, business.industry, Il 12p40, MESH: Child, Preschool, MESH: Genetic Predisposition to Disease, Interleukin, MESH: Adult, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Mycobacterium Infections, Nontuberculous, Penetrance, MESH: Infant, MESH: Male, 3. Good health, MESH: Young Adult, MESH: Interleukin-12 Subunit p40, MESH: Survival Analysis, Immunology, Mendelian inheritance, symbols, Age of onset, business, MESH: Tunisia, MESH: Female, 030215 immunology, Founder effect
Abstract

International audience; Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-gamma). The clinical features are characterized by childhood onset of bacille Calmette-Guerin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor beta 1 (IL-12R beta 1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular. (Medicine 2013; 92: 109-122)

Published
2013
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22. MANAGEMENT OF DOCK8 DEFICIENCY BY HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)

Author

Aydin, S., Freeman, A. F., Sanal, O., Al-Mousa, H., Matthes-Martin, S., Cuellar-Rodriguez, J., Hickstein, D. D., Tavil, B., Azik, F. M., Bittner, T. C., Bredius, R. G., Ayvaz, D., Kuskonmaz, B., Hoenig, M., Schulz, A., Picard, C., Barlogis, V., Gennery, A., Ifversen, M., Montfrans, J. M., Kuijpers, T. W., Dueckers, G., Al-Herz, W., Pai, S. Y., Geha, R. S., Notheis, G., Schwarze, C. P., Schuster, F., Gathmann, B., Grimbacher, B., Gaspar, B., Belohradsky, B. H., Ochs, H., Ellen Renner, Chatila, T., Engelhardt, K. R., and Albert, M. H.

Published
2012

23. Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?

Author

Fernandes, Jf, Rocha, V, Labopin, M, Neven, B, Moshous, D, Gennery, Ar, Friedrich, W, Porta, F, Diaz de Heredia, C, Wall, D, Bertrand, Y, Veys, P, Slatter, M, Schulz, A, Chan, Kw, Grimley, M, Ayas, M, Gungor, T, Ebell, W, Bonfim, C, Kalwak, K, Taupin, P, Blanche, S, Gaspar, Hb, Landais, P, Fischer, A, Gluckman, E, Cavazzana Calvo, M, Eurocord, Inborn Errors Working Party of European Group for Blood, Marrow Transplantation: Ahmed, A, Auiti, A, Biffi, A, Cant, A, Fasth, A, Gennery, A, Hassan, A, Lankester, A, O'Mera, A, Plabani, A, Rovelli, A, Salmon, A, Scarselli, A, Thrasher, A, Van Royen, A, Villa, A, Wawer, A, Wahadneh, A, Worth, A, Belohradsky, B, Wolska, B, Gaspar, B, Bonfirm, C, Booth, C, Klein, C, Messina, C, Peters, C, Steward, C, Lindemans, C, Schuetz, C, de Heredia Rubio CD, Bensoussan, D, Gleadow, D, Lilic, D, Gambineri, Eleonora, Smith, E, Aerts, F, Caracseghi, F, Roberts, G, Davies, G, Al Mousa, H, Jossanc, H, Ozsahim, H, Hirsch, I, Meyts, I, Tezcan, I, Mueller, I, Andresc, I, Boelens, J, Fernandes, J, Folloni, J, Keuhl, J, Reichenbach, J, Stary, J, Wachowiak, J, Xu Bayford, J, Cunha, Jm, Ehlert, J, Rao, K, Sykora, K, Andais, L, Brown, L, Dal Cortivo, L, Griffith, L, Notarangelo, L, Abinun, M, Albert, M, Bierings, M, Bouchet, M, Cavazzana, M, Hirschfield, M, Cowan, M, Hoenig, M, Loubser, M, Roncarolo, M, Sauer, M, Schneider, M, Verstegen, M, Schroeder, M, Essink, M, Yesilipek, M, Entz Werle, N, Mahlaoui, N, Schlautmann, N, Taylor, N, Vanroyen, N, Walffraat, N, Sanal, O, Amrolia, P, Bordigoni, P, De Coppi, P, Frange, P, Orchard, P, Sedlacek, P, Shaw, P, Stephensky, P, Bacchetta, R, Bredius, R, Formankova, R, Gale, R, Seger, R, Wynn, R, Corbacioglu, S, Ehl, S, Hacein Bey, S, Hambleton, S, Mohsen, S, Mueller, S, Pai, Sy, Espanol, T, Flood, T, Guengoer, T, Bordon, V, Ormoor, V, Pashano, V, Courteille, V, Czogala, W, Qasim, W, Camci, Y, and Nademi, Z.

Subjects
Male, medicine.medical_specialty, Transplantation Conditioning, medicine.medical_treatment, Immunology, Graft vs Host Disease, Kaplan-Meier Estimate, Cord Blood Stem Cell Transplantation, Hematopoietic stem cell transplantation, Biochemistry, Gastroenterology, SCID HSCT, Internal medicine, medicine, Humans, Proportional Hazards Models, Retrospective Studies, Preparative Regimen, Severe combined immunodeficiency, business.industry, Umbilical Cord Blood Transplantation, Incidence, Hematopoietic Stem Cell Transplantation, Infant, Newborn, Infant, Cell Biology, Hematology, medicine.disease, Surgery, Transplantation, Treatment Outcome, Child, Preschool, Histocompatibility, Cord blood, Female, Severe Combined Immunodeficiency, business
Abstract

Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4+ and CD3+ cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.

Published
2012

24. Long-Term Safety and Efficacy of Gene Therapyfor Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency

Author

Aiuti, A, Cattaneo, F, Galimberti, S, Benninghoff, U, Cassani, B, Callegaro, L, Scaramuzza, S, Andolfi, G, Mirolo, M, Brigida, I, Tabucchi, A, Carlucci, F, Eibl, M, Aker, M, Slavin, S, Al Mousa, H, Ghonaium, A, Ferster, A, A, Duppenthaler, A, Luigi, N, Wintergerst, U, H. Buckley, R, Bregni, M, Marktel, S, Valsecchi, M, Rossi, P, Ciceri, F, Miniero, R, Bordignon, C, and Roncarolo, M

Subjects
Settore MED/38 - Pediatria Generale e Specialistica
Published
2009

25. المواصفات الجينية و السريرية لأول عائلة تعاني من ضعف المناعة الأولي بسبب خلل وراثي في الجين المتفاعل مع بروتين مرض وسكوت - الدريتش WIP = Clinical and Molecular Features of the First Family with Primary Immune Deficiency Due to Human WASP Interacting Protein ( WIP ) Mutation

Author

Arnaout, R., primary, Al Bahkali, Mohammed, additional, and Al-Mousa, H., additional

Published
2015
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27. Gene therapy for immunodeficiency due to adenosine deaminase deficiency

Author

Aiuti, A, Cattaneo, F, Galimberti, S, Benninghoff, U, Cassani, B, Callegaro, L, Scaramuzza, S, Andolfi, G, Mirolo, M, Brigida, I, Tabucchi, A, Carlucci, F, Eibl, M, Aker, M, Slavin, S, Al Mousa, H, Al Ghonaium, A, Ferster, A, Duppenthaler, A, Notarangelo, L, Wintergerst, U, Buckley, R, Bregni, M, Marktel, S, Valsecchi, M, Rossi, P, Ciceri, F, Miniero, R, Bordignon, C, Roncarolo, M, Buckley, RH, Roncarolo, MG, GALIMBERTI, STEFANIA, VALSECCHI, MARIA GRAZIA, Aiuti, A, Cattaneo, F, Galimberti, S, Benninghoff, U, Cassani, B, Callegaro, L, Scaramuzza, S, Andolfi, G, Mirolo, M, Brigida, I, Tabucchi, A, Carlucci, F, Eibl, M, Aker, M, Slavin, S, Al Mousa, H, Al Ghonaium, A, Ferster, A, Duppenthaler, A, Notarangelo, L, Wintergerst, U, Buckley, R, Bregni, M, Marktel, S, Valsecchi, M, Rossi, P, Ciceri, F, Miniero, R, Bordignon, C, Roncarolo, M, Buckley, RH, Roncarolo, MG, GALIMBERTI, STEFANIA, and VALSECCHI, MARIA GRAZIA

Abstract

BACKGROUND: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. METHODS: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. RESULTS: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). CONCLUSIONS: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.) 2009 Massachusetts Medical Society

Published
2009

32. Unrelated cord blood transplantation in pediatric patients: a report from Saudi Arabia

Author

Ayas, M, primary, Al-Seraihi, A, additional, Al-Jefri, A, additional, Al-Ahmari, A, additional, Al-Mahr, M, additional, Al-Ghonaium, A, additional, Al-Muhsen, S, additional, Al-Mousa, H, additional, Al-Dhekri, H, additional, Alsaud, B, additional, Eldali, A, additional, Mohamad, A, additional, Al-Humaidan, H, additional, Chadrawi, A, additional, Al-Kaff, M, additional, Al-Hassnan, Z, additional, and El-Solh, H, additional

Published
2009
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36. Gene therapy for immunodeficiency due to adenosine deaminase deficiency

Author

Uwe Wintergerst, Pier Luca Rossi, Alina Ferster, Roberto Miniero, Maria Grazia Roncarolo, Filippo Carlucci, Massimiliano Mirolo, Grazia Andolfi, Andrea Duppenthaler, Federica Cattaneo, Sarah Marktel, Rebecca H. Buckley, Fabio Ciceri, Hamoud Al-Mousa, Claudio Bordignon, Luigi D. Notarangelo, Abdulaziz Al Ghonaium, Alessandro Aiuti, Ulrike Benninghoff, Antonella Tabucchi, Stefania Galimberti, Marco Bregni, Memet Aker, Martha M. Eibl, Luciano Callegaro, Samantha Scaramuzza, Maria Grazia Valsecchi, Barbara Cassani, Immacolata Brigida, Shimon Slavin, Aiuti, A, Cattaneo, F, Galimberti, S, Benninghoff, U, Cassani, B, Callegaro, L, Scaramuzza, S, Andolfi, G, Mirolo, M, Brigida, I, Tabucchi, A, Carlucci, F, Eibl, M, Aker, M, Slavin, S, Al Mousa, H, Al Ghonaium, A, Ferster, A, Duppenthaler, A, Notarangelo, L, Wintergerst, U, Buckley, R, Bregni, M, Marktel, S, Valsecchi, M, Rossi, P, Ciceri, F, Miniero, R, Bordignon, C, Roncarolo, M, Aiuti, Alessandro, AL MOUSA, H, AL GHONAIUM, A, BUCKLEY R., H, Valsecchi, M. G., Ciceri, Fabio, Bordignon, Claudio, and Roncarolo, MARIA GRAZIA

Subjects
Transplantation Conditioning, medicine.medical_treatment, central venous catheter, thrombocytopenia, Antigens, CD34, Hematopoietic stem cell transplantation, newborn, genetic transduction, diphtheria toxin, T lymphocyte, genetics, CD34 antigen, busulfan, Child, Immunodeficiency, catheter infection, clinical article, Retrovirus, pegademase, Hematopoietic Stem Cell Transplantation, adenosine deaminase deficiency, Epstein Barr virus, clinical trial, immunosuppressive treatment, General Medicine, Gene Therapy, virus antigen, priority journal, Child, Preschool, HLA system, hypertension, Transduction, Genetic, neutropenia, Humans, human, Lymphocyte Count, protein expression, Settore MED/38 - Pediatria Generale e Specialistica, pertussis toxin, autoimmune hepatitis, infection prevention, Infant, antibody response, medicine.disease, Adenosine deaminase deficiency, drug efficacy, nonmyeloablative conditioning, phase 2 clinical trial, multicenter study, Retroviridae, Immunology, hematopoietic stem cell, Severe Combined Immunodeficiency, CD34, tetanus toxoid, immunoglobulin, drug safety, Adenosine Deaminase, phase 1 clinical trial, Genetic enhancement, preschool child, immunology, Adenosine deaminase, Transduction, Genetic, Haemophilus influenzae type b vaccine, sibling, viral gene therapy, multimodality cancer therapy, donor, biology, article, Combined Modality Therapy, autoimmune thrombocytopenia, Haematopoiesis, female, medicine.anatomical_structure, lymphoid cell, adenosine deaminase, retrovirus vector, antigen specificity, area under the curve, bone marrow cell, cell function, child, controlled clinical trial, controlled study, enzyme replacement, follow up, immune reconstitution inflammatory syndrome, infant, lymphocyte count, male, outcome assessment, physical development, severe combined immunodeficiency, virus reactivation, gene therapy, gene vector, hematopoietic stem cell transplantation, Bone Marrow Cells, Follow-Up Studies, Genetic Vectors, medicine, Antigens, Preschool, Severe combined immunodeficiency, business.industry, Genetic Therapy, biology.protein, Bone marrow, business
Abstract

Background: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07 x 10(sup 9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). Conclusions: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.) N Engl J Med 2009;360:447-58. RI rossi, paolo/D-6504-2012; galimberti, stefania/H-2594-2012 BACKGROUND:We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.METHODS:We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.RESULTS:All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one).CONCLUSIONS:Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.) BackgroundWe investigated the long-term outcome of gene therapy for severe combined immunodeficiency(SCID) due to the lack of adenosine deaminase (ADA), a fatal disorderof purine metabolism and immunodeficiency.MethodsWe infused autologous CD34+ bone marrow cells transduced with a retroviral vectorcontaining the ADA gene into 10 children with SCID due to ADA deficiency wholacked an HLA-identical sibling donor, after nonmyeloablative conditioning withbusulfan. Enzyme-replacement therapy was not given after infusion of the cells.ResultsAll patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transducedhematopoietic stem cells have stably engrafted and differentiated into myeloidcells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%)and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patientsdo not require enzyme-replacement therapy, their blood cells continue to expressADA, and they have no signs of defective detoxification of purine metabolites. Ninepatients had immune reconstitution with increases in T-cell counts (median countat 3 years, 1.07×109 per liter) and normalization of T-cell function. In the five patientsin whom intravenous immune globulin replacement was discontinued, antigenspecificantibody responses were elicited after exposure to vaccines or viral antigens.Effective protection against infections and improvement in physical development madea normal lifestyle possible. Serious adverse events included prolonged neutropenia(in two patients), hypertension (in one), central-venous-catheter–related infections (intwo), Epstein–Barr virus reactivation (in one), and autoimmune hepatitis (in one).ConclusionsGene therapy, combined with reduced-intensity conditioning, is a safe and effectivetreatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers,NCT00598481 and NCT00599781.)

Published
2009

37. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells

Author

Biasco, Luca, Scala, Serena, Basso Ricci, Luca, Dionisio, Francesca, Baricordi, Cristina, Calabria, Andrea, Giannelli, Stefania, Cieri, Nicoletta, Barzaghi, Federica, Pajno, Roberta, Al-Mousa, Hamoud, Scarselli, Alessia, Cancrini, Caterina, Bordignon, Claudio, Roncarolo, Maria Grazia, Montini, Eugenio, BONINI, CHIARA, Aiuti, Alessandro, Biasco, Luca, Scala, Serena, Basso Ricci, Luca, Dionisio, Francesca, Baricordi, Cristina, Calabria, Andrea, Giannelli, Stefania, Cieri, Nicoletta, Barzaghi, Federica, Pajno, Roberta, Al-Mousa, Hamoud, Scarselli, Alessia, Cancrini, Caterina, Bordignon, Claudio, Roncarolo, Maria Grazia, Montini, Eugenio, Bonini, Chiara, Aiuti, Alessandro, Biasco, L, Scala, S, Basso, Ricci L, Dionisio, F, Baricordi, C, Calabria, A, Giannelli, S, Cieri, N, Barzaghi, F, Pajno, R, Al-Mousa, H, Scarselli, A, Cancrini, C, Bordignon, C, Roncarolo, M G, Montini, E, Bonini, C, and Aiuti, A

Subjects
Time Factors, T-Lymphocytes, Genetic enhancement, Cell, Longitudinal Studie, Biochemistry, Longitudinal Studies, Child, Medicine (all), Hematology, General Medicine, Phenotype, Tissue Donors, Haematopoiesis, Settore MED/02, medicine.anatomical_structure, Cell Tracking, Tetradecanoylphorbol Acetate, Stem cell, Genetic Engineering, Human, Adult, Time Factor, Cell Survival, T cell, Immunology, Tissue Donor, Biology, Viral vector, Clone Cell, In vivo, medicine, Humans, Severe combined immunodeficiency, Hematopoietic Stem Cell, Cell Biology, Genetic Therapy, Hematopoietic Stem Cells, medicine.disease, Lymphocyte Subsets, In vitro, Clone Cells, T-Lymphocyte, Lymphocyte Subset, Cancer research, Interleukin-2, T memory stem cells, Bone marrow, Immunologic Memory, Ex vivo
Abstract

A deeper understanding of T lymphocytes survival and differentiation potential in humans is paramount for the development of effective gene/cell therapies based on T-cell engineering. We here performed a comprehensive study of T-cells dynamics and plasticity in humans by a unique combination of phenotypic/functional studies and high-throughput integration sites (IS) analyses. We analyzed samples from hematopoietic stem cells (HSC) (n=10) or mature lymphocytes (PBL) gene therapy (GT) (n=4) treated ADA (adenosine deaminase) deficient-SCID patients. For comparative analyses, we also collected data from pediatric (n=19) and adult (n=52) healthy donors (HD), and from bone marrow transplanted patients (BMT) with primary immunodeficiencies (n=10, 4 with ADA-SCID). We observed that vector-positive CD62L+/CD45RA+ putative T naïve cells were detectable 12 years after last infusion of gene-corrected lymphocytes in peripheral blood of PBL-GT patients that lack the support of transduced lymphocytes precursors. We then unveiled that the vast majority of these CD62L+/CD45RA+ cells (80.3%) in PBL-GT patients could be actually classified phenotypically (CD95, IL2Rβ and IL7Rα surface expression) and functionally (IFNγ production and aCD3/aCD28 in vitro differentiation) as active long-lasting T memory stem cells (Tscm). The peculiar Tscm frequency found in PBL-GT patients was most likely due to a combinatorial in vitro and in vivo effect. Indeed, by a series of in vitro assays, we showed that Tscm relative enrichment in CD45RA+CD62L+ compartment have occurred during the in vitro manipulation of T cells before infusion. Additionally, we found higher-then-normal Tscm contribution among CD45RA+/CD62L+ cells even in ADA-SCID patients receiving HSC-GT and BMT, suggesting a role of disease background on in vivo Tscm persistence. Analyzing our cohorts of healthy donors and treated individuals we were able to further correlate Tscm contribution in vivo with age, conditioning regimen, disease background, cell source, and long-term T-cell reconstitution. One unique aspect of our study consisted in the opportunity to track Tscm clonal dynamics in vivo in humans since each gene-corrected cell infused in our GT patients is univocally and permanently tagged by a retroviral integration site.To perform in vivo molecular tracing of individual T-cell clones we sorted T naïve, Tscm, central memory and effector memory subtypes. We then collected from these subpopulations, by LAM-PCR+Illumina-Miseq sequencing, 2.584.137 integration sites (IS) sequences mapped to 1.746 unique chromosomal positions, corresponding to 910 integrations from 5 HSC-GT patients in vivo, 79 integrations from 2 PBL-GT samples of transduced cell products prior to infusion and 754 integrations from 4 PBL-GT patients in vivo. Firstly, to establish a relationship between precursors and terminally differentiated T cells we searched for the presence of identical insertion sites detected in multiple T-cell subtypes, applying stringent analytical filters for cross-contaminations. Strikingly, the level of shared integrations in each subtype was directly correlated to its stage of differentiation with Tscm, isolated from PBL-GT patients, showing the highest proportion of integration sites shared with the other T-cell subsets. Importantly, the results of the same analysis performed on HSC-GT patients were outstandingly coherent with the progressive developmental model of memory T-cell differentiation. We then assessed the survival of individual Tscm clones by performing a longitudinal IS analysis of different T-cell subtypes isolated from 3 PBL-GT patients over a 2 to 5 years timeframe up to 12 years after last infusion. We were able to formally prove the persistence of individual Tscm by re-capturing identical IS tagging specific Tscm clones in two independent timepoints in a 5- years window. Importantly, the same IS were also detected in multiple T-cell subtypes, representing the best indirect evidence that these clones were endowed with long-term precursor activity. We also documented, by IS sequencing reads, the long-term polyclonal composition of each subtype and we did not observe enrichment for IS flanking proto-oncogenes. Overall, this study validates, for the first time in humans, the safe and functional decade-long survival of engineered Tscm, paving the way for their future application in clinical settings. Disclosures No relevant conflicts of interest to declare.

Published
2015

38. Outcomes of Hematopoietic Stem Cell Transplantation in 5 Patients with Autosomal Recessive RIPK1-Deficiency.

Author

Walsh RB, McNaughton P, Nademi Z, Laberko A, Balashov D, Al-Mousa H, Arkwright PD, Wynn RF, Flood T, Williams E, Cant A, Abinun M, Hambleton S, Slatter M, Gennery AR, Lum SH, and Owens S

Subjects
Child, Preschool, Female, Humans, Infant, Male, Genes, Recessive, Inflammatory Bowel Diseases therapy, Inflammatory Bowel Diseases genetics, Mutation, Transplantation Conditioning methods, Treatment Outcome, Hematopoietic Stem Cell Transplantation methods, Receptor-Interacting Protein Serine-Threonine Kinases genetics
Abstract

Receptor Interacting Serine/Threonine Kinase 1 (RIPK1) is widely expressed and integral to inflammatory and cell death responses. Autosomal recessive RIPK1-deficiency, due to biallelic loss of function mutations in RIPK1, is a rare inborn error of immunity (IEI) resulting in uncontrolled necroptosis, apoptosis and inflammation. Although hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy, the extent to which disease may be driven by extra-hematopoietic effects of RIPK1-deficiency, which are non-amenable to HSCT, is not clear. We present a multi-centre, international review of an additional 5 RIPK1-deficient children who underwent HSCT. All patients presented with very early onset inflammatory bowel disease, 2 also suffered from inflammatory arthritis. Median age at transplant was 3 years (range 1-5 years); 1 received matched sibling marrow, 1 matched unrelated peripheral blood stem cells (PBSC), 2 TCRαβ/CD19-depleted PBSC from maternal-haploidentical donors, and 1 had TCRαβ/CD19-depleted PBSC from a mismatched unrelated donor. All received reduced-toxicity conditioning, based on treosulfan (n = 4) or busulfan (n = 1); 1 patient underwent a successful second transplant following autologous reconstitution. Four of five patients (80%) survived; 1 child died due to multi-drug resistant pseudomonas infection and multi-organ failure. With a median duration of 14 months follow-up, 2 survivors were disease-free, and 2 had substantially improving enteropathy. These findings demonstrated that HSCT is a potential curative therapy for RIPK1-deficiency., Competing Interests: Declarations. Ethical Approval: No formal ethical approval was obtained for this retrospective case study. Consent to Participate: Freely given written informed consent was obtained from participants/parents or legal guardians for data collection and participation as per institutional practice. Consent for Publication: Informed consent was obtained from all individual participants included in the study for publication as per institutional practice. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s).)

Published
2025
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39. Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity.

Author

Alajlan H, Raducanu VS, Lopez de Los Santos Y, Tehseen M, Alruwaili H, Al-Mazrou A, Mohammad R, Al-Alwan M, De Biasio A, Merzaban JS, Al-Mousa H, Hamdan SM, and Alazami AM

Subjects
Female, Humans, Male, Fibroblasts, Molecular Dynamics Simulation, Infant, DNA Ligase ATP genetics, DNA Ligase ATP metabolism, Homozygote, Mutation genetics, Severe Combined Immunodeficiency genetics
Abstract

A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease., (© 2024. The Author(s).)

Published
2024
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40. Quality of Life Evaluation in Saudi Arabian Pediatric Patients with Primary Immunodeficiency Diseases Receiving 20% Subcutaneous IgG Infusions at Home.

Author

Al-Saud B, AlRumayyan N, Alfattani A, Awwad SA, Al Saud D, Mohammed R, Albuhairi S, Elshorbagi S, Balhareth SS, Al-Dhekri H, Arnaout R, De Vol EB, and Al-Mousa H

Subjects
Male, Female, Humans, Child, Infant, Newborn, Infant, Child, Preschool, Adolescent, Immunoglobulins, Intravenous therapeutic use, Immunoglobulin G therapeutic use, Quality of Life, Saudi Arabia, Prospective Studies, Infusions, Subcutaneous, Immunologic Deficiency Syndromes therapy, Immunologic Deficiency Syndromes drug therapy, Primary Immunodeficiency Diseases drug therapy
Abstract

Background and Aims: Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG., Methods: In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG., Results: Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0-14 years). The patients' diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5-125 months). The QoL score showed a significant improvement in the patients' global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients' general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively)., Conclusions: This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20% SCIG., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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41. Outcome of BCG Vaccination in ADA-SCID Patients: A 12-Patient Series.

Author

Canarutto D, Oltolini C, Barzaghi F, Calbi V, Migliavacca M, Tucci F, Gallo V, Consiglieri G, Ferrua F, Recupero S, Cervi MC, Al-Mousa H, Pituch-Noworolska A, Tassan Din C, Scarpellini P, Silvani P, Fossati C, Casiraghi M, Cirillo DM, Castagna A, Bernardo ME, Aiuti A, and Cicalese MP

Abstract

Vaccination with Bacillus Calmette-Guérin (BCG) can be harmful to patients with combined primary immunodeficiencies. We report the outcome of BCG vaccination in a series of twelve patients affected by adenosine deaminase deficiency (ADA-SCID). BCG vaccination resulted in a very high incidence of complications due to uncontrolled replication of the mycobacterium. All patients who developed BCG-related disease were treated successfully and remained free from recurrence of disease. We recommend the prompt initiation of enzyme replacement therapy and secondary prophylaxis to reduce the risk of BCG-related complications in ADA-SCID patients.

Published
2023
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42. Genetics of Inborn Errors of Immunity in highly consanguineous Middle Eastern and North African populations.

Author

Al-Mousa H and Barbouche MR

Subjects
Humans, Africa, Northern epidemiology, Consanguinity, North African People genetics, Middle Eastern People genetics, Immune System Diseases genetics
Abstract

Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics., Competing Interests: Competing interests The authors declared that they have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Published
2023
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43. Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Author

Lévy R, Gothe F, Momenilandi M, Magg T, Materna M, Peters P, Raedler J, Philippot Q, Rack-Hoch AL, Langlais D, Bourgey M, Lanz AL, Ogishi M, Rosain J, Martin E, Latour S, Vladikine N, Distefano M, Khan T, Rapaport F, Schulz MS, Holzer U, Fasth A, Sogkas G, Speckmann C, Troilo A, Bigley V, Roppelt A, Dinur-Schejter Y, Toker O, Bronken Martinsen KH, Sherkat R, Somekh I, Somech R, Shouval DS, Kühl JS, Ip W, McDermott EM, Cliffe L, Ozen A, Baris S, Rangarajan HG, Jouanguy E, Puel A, Bustamante J, Alyanakian MA, Fusaro M, Wang Y, Kong XF, Cobat A, Boutboul D, Castelle M, Aguilar C, Hermine O, Cheminant M, Suarez F, Yildiran A, Bousfiha A, Al-Mousa H, Alsohime F, Cagdas D, Abraham RS, Knutsen AP, Fevang B, Bhattad S, Kiykim A, Erman B, Arikoglu T, Unal E, Kumar A, Geier CB, Baumann U, Neven B, Rohlfs M, Walz C, Abel L, Malissen B, Marr N, Klein C, Casanova JL, Hauck F, and Béziat V

Subjects
Humans, Mutation genetics, Phenotype, CD4-Positive T-Lymphocytes, CD28 Antigens metabolism, Microfilament Proteins genetics
Abstract

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28., (© 2022 Lévy et al.)

Published
2023
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44. A homozygous truncating mutation of FGL2 is associated with immune dysregulation.

Author

Janssen E, Alosaimi MF, Alazami AM, Alsuliman A, Alaiya A, Al-Saud B, Al-Mousa H, Al-Zaid TJ, Smith E, Platt CD, Alruwaili H, Albanyan S, Al-Mayouf SM, and Geha RS

Subjects
Mice, Humans, Animals, HEK293 Cells, Lymphocyte Activation, Mutation, Fibrinogen genetics, Fibrinogen metabolism, T-Lymphocytes, Regulatory, Autoantibodies
Abstract

Background: The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2 -/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function., Objective: Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies., Methods: Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro., Results: The patient had a homozygous mutation in FGL2 (c.614&#95;617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2 V205fs mutant failed to suppress T-cell proliferation., Conclusions: We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2023
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45. Phenotypic and Genotypic Characterization of Hereditary Angioedema in Saudi Arabia.

Author

Sheikh F, Alajlan H, Albanyan M, Alruwaili H, Alawami F, Sumayli S, Al Gazlan S, Abu Awwad S, Al-Dhekri H, Al-Saud B, Arnaout R, Alrayes H, Sayes N, Al-Hamed MH, Al-Mousa H, AlShareef S, and Alazami AM

Subjects
Humans, Saudi Arabia epidemiology, Complement C1 Inhibitor Protein genetics, Mutation genetics, Sequence Deletion, Genotype, Angioedemas, Hereditary diagnosis, Angioedemas, Hereditary epidemiology, Angioedemas, Hereditary genetics
Abstract

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disorder affecting roughly 1:50,000 individuals. It is commonly characterized by swelling of the larynx, gastrointestinal tract, extremities, and skin. There is growing genetic heterogeneity associated with this disease but more than 95% of mutations are found in SERPING1, the gene which encodes complement 1 inhibitor (C1-INH). HAE cohorts from several populations have been published but no large scale study has been reported from the Arab world to date. Here we document the clinical and genetic findings of HAE patients from a single Saudi institution, which is a major referral center at the national level. A total of 51 patients across 17 unrelated families were recruited including two large multi-generational families, of which one contained an in-frame exonic deletion that was resolved through MLPA. Two cases were negative for all the genes we tested (including F12, PLG, ANGPT1, MYOF, KNG1, and HS3ST6). The predominant HAE subtype in our cohort was type I, at 76%. We were able to uncover a mutation in 49 patients (96%). No type III (normal C1-INH) patients were encountered in the clinic, suggesting that this subtype does not play a major role in HAE pathogenesis in Saudi Arabia. Additionally, the existence of four patients with consistently normal complement 4 (C4) levels alongside abnormal C1-INH profiles highlights the utility of dual screening for both proteins in suspected patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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46. The Middle East and North Africa Diagnosis and Management Guidelines for Inborn Errors of Immunity.

Author

Baris S, Abolhassani H, Massaad MJ, Al-Nesf M, Chavoshzadeh Z, Keles S, Reisli I, Tahiat A, Shendi HM, Elaziz DA, Belaid B, Al Dhaheri F, Haskologlu S, Dogu F, Ben-Mustapha I, Sobh A, Galal N, Meshaal S, Elhawary R, El-Marsafy A, Alroqi FJ, Al-Saud B, Al-Ahmad M, Al Farsi T, Al Sukaiti N, Al-Tamemi S, Mehawej C, Dbaibo G, ElGhazali G, Kilic SS, Genel F, Kiykim A, Musabak U, Artac H, Guner SN, Boukari R, Djidjik R, Kechout N, Cagdas D, El-Sayed ZA, Karakoc-Aydiner E, Alzyoud R, Barbouche MR, Adeli M, Wakim RH, Reda SM, Ikinciogullari A, Ozen A, Bousfiha A, Al-Mousa H, Rezaei N, Al-Herz W, and Geha RS

Subjects
Adult, Child, Humans, Africa, Northern epidemiology, Middle East epidemiology, Phenotype, Registries, Consanguinity
Abstract

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient populations., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Published
2023
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47. Proteomics Profiling to Distinguish DOCK8 Deficiency From Atopic Dermatitis.

Author

Jacob M, Masood A, Shinwari Z, Abdel Jabbar M, Al-Mousa H, Arnaout R, AlSaud B, Dasouki M, Alaiya AA, and Abdel Rahman AM

Abstract

Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 ( n = 10), AD ( n = 9) patients and healthy control (Ctrl) groups ( n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering ( R 2 = 0.957, Q 2 = 0.732). Significantly differentially abundant proteins ( p < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl ( n = 105, and n = 109) and between DOCK8-deficient and AD groups ( n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications., 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 © 2021 Jacob, Masood, Shinwari, Abdel Jabbar, Al-Mousa, Arnaout, AlSaud, Dasouki, Alaiya and Abdel Rahman.)

Published
2021
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48. Lupus manifestations in children with primary immunodeficiency diseases: Comprehensive phenotypic and genetic features and outcome.

Author

Al-Mayouf SM, Alreefi HA, Alsinan TA, AlSalmi G, AlRowais A, Al-Herz W, Alazami AM, Alsonbul A, and Al-Mousa H

Subjects
Child, Female, Humans, Mutation, Purine-Nucleoside Phosphorylase, Retrospective Studies, Lupus Erythematosus, Systemic complications, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic genetics, Primary Immunodeficiency Diseases, Purine-Pyrimidine Metabolism, Inborn Errors
Abstract

Objectives: To report the phenotypic, genetic findings and outcome of children with lupus manifestations associated with primary immunodeficiency diseases (PIDs)., Methods: Data are retrospectively collected on patients with lupus manifestations and PIDs seen between 1998 and 2019. Data comprised the clinical findings and genetic testing, the response to treatment and the accrual damage related to SLE., Results: A total of 39 patients (22 female) were reviewed. Thirty-four patients had lupus manifestations and six patients with SLE-like manifestations. Genetic analysis was performed in 25 patients. Complement deficiency was the most frequent PIDs; 26 patients were C1q deficient, three patients had C3 deficiency, two patients had C4 deficiency and one patient with heterozygous C8b variant. The other seven patients had different PIDs genetic defects that include SCID caused by PNP deficiency, CGD, CVID ( PIK3CD) , IL-2RB mutation, DNase II deficiency, STAT1 mutation, ISG15 mutation and Griscelli syndrome type 3. Mucocutaneous lesions, arthritis and lung involvement were the main clinical features. 84.1% experienced recurrent infections. The mean accrual damage was 2.7 ± 2.2. There were five deaths because of infection., Conclusion: This study suggests that patients with lupus manifestations and early onset disease, family history of SLE or recurrent infections should undergo immunological work-up and genetic testing to rule out PIDs.

Published
2021
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49. Autosomal Recessive ISG15 Deficiency Underlies Type I Interferonopathy with Systemic Lupus Erythematosus and Inflammatory Myositis.

Author

Al-Mayouf SM, Akbar L, AlEnazi A, and Al-Mousa H

Subjects
Adolescent, Female, Genetic Predisposition to Disease genetics, Humans, Cytokines deficiency, Cytokines genetics, Inflammation genetics, Interferon Type I genetics, Lupus Erythematosus, Systemic genetics, Myositis genetics, Ubiquitins deficiency, Ubiquitins genetics
Published
2021
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50. Genetic, Immunological, and Clinical Features of 32 Patients with Autosomal Recessive STAT1 Deficiency.

Author

Le Voyer T, Sakata S, Tsumura M, Khan T, Esteve-Sole A, Al-Saud BK, Gungor HE, Taur P, Jeanne-Julien V, Christiansen M, Köhler LM, ElGhazali GE, Rosain J, Nishimura S, Sakura F, Bouaziz M, Oleaga-Quintas C, Nieto-Patlán A, Deyà-Martinez À, Altuner Torun Y, Neehus AL, Roynard M, Bozdemir SE, Al Kaabi N, Al Hassani M, Mersiyanova I, Rozenberg F, Speckmann C, Hainmann I, Hauck F, Alzahrani MH, Alhajjar SH, Al-Muhsen S, Cole T, Fuleihan R, Arkwright PD, Badolato R, Alsina L, Abel L, Desai M, Al-Mousa H, Shcherbina A, Marr N, Boisson-Dupuis S, Casanova JL, Okada S, and Bustamante J

Subjects
Humans, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, Hematopoietic Stem Cell Transplantation, Lymphohistiocytosis, Hemophagocytic, Mycobacterium Infections, Mycobacterium bovis
Abstract

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Published
2021
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