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1. Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency

Author

Smits, BM, Kleine Budde, I, de Vries, E, Berge, IJ, Bredius, RG, van Deuren, M, van Dissel, JTJ, Ellerbroek, PM, Flier, Michiel, van Hagen, P.M., Nieuwhof, C, Rutgers, B, Sanders, LEAM, Simon, A, Kuijpers, TWJ, van Montfrans, JM, Smits, BM, Kleine Budde, I, de Vries, E, Berge, IJ, Bredius, RG, van Deuren, M, van Dissel, JTJ, Ellerbroek, PM, Flier, Michiel, van Hagen, P.M., Nieuwhof, C, Rutgers, B, Sanders, LEAM, Simon, A, Kuijpers, TWJ, and van Montfrans, JM

Abstract

Background: Patients with an IgG subclass deficiency (IgSD) ± specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study. Objective: To compare the efficacy of PA and IRT in a randomized crossover trial. Methods: A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared. Results: The overall efficacy of the two regimens did not differ (p = 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%, p < 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64, p < 0.01). Conclusion: We found comparable efficacy of IRT and PA in patients with IgSD ± SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT. Clinical Implication: Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA.

Published
2021

2. Parents’ Perspectives and Societal Acceptance of Implementation of Newborn Screening for SCID in the Netherlands

Author

Blom, M, Bredius, RG, Jansen, M, Weijman, G, Kemper, EA, Vermont, Clementien, Hollink, Iris, Dik, Wim, van Montfrans, JM, van Gijn, ME, Henriet, SS, van Aerde, KJ, Koole, W, Lankester, AC, Dekkers, EHBM, Schielen, PC, de Vries, MC, Henneman, L, Burg, M, Blom, M, Bredius, RG, Jansen, M, Weijman, G, Kemper, EA, Vermont, Clementien, Hollink, Iris, Dik, Wim, van Montfrans, JM, van Gijn, ME, Henriet, SS, van Aerde, KJ, Koole, W, Lankester, AC, Dekkers, EHBM, Schielen, PC, de Vries, MC, Henneman, L, and Burg, M

Abstract

Purpose: While neonatal bloodspot screening (NBS) for severe combined immunodeficiency (SCID) has been introduced more than a decade ago, implementation in NBS programs remains challenging in many countries. Even if high-quality test methods and follow-up care are available, public uptake and parental acceptance are not guaranteed. The aim of this study was to describe the parental perspective on NBS for SCID in the context of an implementation pilot. Psychosocial aspects have never been studied before for NBS for SCID and are important for societal acceptance, a major criterion when introducing new disorders in NBS programs. Methods: To evaluate the perspective of parents, interviews were conducted with parents of newborns with abnormal SCID screening results (N = 17). In addition, questionnaires about NBS for SCID were sent to 2000 parents of healthy newborns who either participated or declined participation in the SONNET-study that screened 140,593 newborns for SCID. Results: Support for NBS for SCID was expressed by the majority of parents in questionnaires from both a public health perspective and a personal perspective. Parents emphasized the emotional impact of an abnormal screening result in interviews. (Long-term) stress and anxiety can be experienced during and after referral indicating the importance of uniform follow-up protocols and adequate information provision. Conclusion: The perspective of parents has led to several recommendations for NBS programs that are considering screening for SCID or other disorders. A close partnership of NBS programs’ stakeholders, immunologists, geneticists, and pediatricians-immunologists in different countries is required for moving towards universal SCID screening for all infants.

Published
2021

3. Targeted Proteomics Reveals Inflammatory Pathways that Classify Immune Dysregulation in Common Variable Immunodeficiency

Author

Berbers, RM, Drylewicz, J, Ellerbroek, PM, van Montfrans, JM, Dalm, V.A.S.H., van Hagen, P.M., Keller, B, Warnatz, K, van de Ven, A, van Laar, JM, Nierkens, S, Leavis, HL, Berbers, RM, Drylewicz, J, Ellerbroek, PM, van Montfrans, JM, Dalm, V.A.S.H., van Hagen, P.M., Keller, B, Warnatz, K, van de Ven, A, van Laar, JM, Nierkens, S, and Leavis, HL

Abstract

Patients with common variable immunodeficiency (CVID) can develop immune dysregulation complications such as autoimmunity, lymphoproliferation, enteritis, and malignancy, which cause significant morbidity and mortality. We aimed to (i) assess the potential of serum proteomics in stratifying patients with immune dysregulation using two independent cohorts and (ii) identify cytokine and chemokine signaling pathways that underlie immune dysregulation in CVID. A panel of 180 markers was measured in two multicenter CVID cohorts using Olink Protein Extension Assay technology. A classification algorithm was trained to distinguish CVID with immune dysregulation (CVIDid, n = 14) from CVID with infections only (CVIDio, n = 16) in the training cohort, and validated on a second testing cohort (CVIDid n = 23, CVIDio n = 24). Differential expression in both cohorts was used to determine relevant signaling pathways. An elastic net classifier using MILR1, LILRB4, IL10, IL12RB1, and CD83 could discriminate between CVIDid and CVIDio patients with a sensitivity of 0.83, specificity of 0.75, and area under the curve of 0.73 in an independent testing cohort. Activated pathways (fold change > 1.5, FDR-adjusted p < 0.05) in CVIDid included Th1 and Th17-associated signaling, as well as IL10 and other immune regulatory markers (LAG3, TNFRSF9, CD83). Targeted serum proteomics provided an accurate and reproducible tool to discriminate between patients with CVIDid and CVIDio. Cytokine profiles provided insight into activation of Th1 and Th17 pathways and indicate a possible role for chronic inflammation and exhaustion in immune dysregulation. These findings serve as a first step towards the development of biomarkers for immune dysregulation in CVID.

Published
2021

4. National external quality assessment for next-generation sequencing-based diagnostics of primary immunodeficiencies

Author

Elsink, K, Huibers, MMH, Hollink, Iris, van der Veken, LT, Ernst, RF, Simons, A, Zonneveld-Huijssoon, E, van der Hout, AH, Abbott, KM, Hoischen, A, Pieterse, M, Kuijpers, TWJ, van Montfrans, JM, van Gijn, ME, Elsink, K, Huibers, MMH, Hollink, Iris, van der Veken, LT, Ernst, RF, Simons, A, Zonneveld-Huijssoon, E, van der Hout, AH, Abbott, KM, Hoischen, A, Pieterse, M, Kuijpers, TWJ, van Montfrans, JM, and van Gijn, ME

Abstract

Dutch genome diagnostic centers (GDC) use next-generation sequencing (NGS)-based diagnostic applications for the diagnosis of primary immunodeficiencies (PIDs). The interpretation of genetic variants in many PIDs is complicated because of the phenotypic and genetic heterogeneity. To analyze uniformity of variant filtering, interpretation, and reporting in NGS-based diagnostics for PID, an external quality assessment was performed. Four main Dutch GDCs participated in the quality assessment. Unannotated variant call format (VCF) files of two PID patient analyses per laboratory were distributed among the four GDCs, analyzed, and interpreted (eight analyses in total). Variants that would be reported to the clinician and/or advised for further investigation were compared between the centers. A survey measuring the experiences of clinical laboratory geneticists was part of the study. Analysis of samples with confirmed diagnoses showed that all centers reported at least the variants classified as likely pathogenic (LP) or pathogenic (P) variants in all samples, except for variants in two genes (PSTPIP1 and BTK). The absence of clinical information complicated correct classification of variants. In this external quality assessment, the final interpretation and conclusions of the genetic analyses were uniform among the four participating genetic centers. Clinical and immunological data provided by a medical specialist are required to be able to draw proper conclusions from genetic data.

Published
2021

5. A novel method to standardise serum IgA measurements shows an increased prevalence of IgA deficiency in young children with recurrent respiratory tract infections

Author

CTI Boes, Immuno/reuma onderzoek 2 (Boes), Onderzoek, Child Health, Infection & Immunity, IMI, Cluster B, Infectieziekten patientenzorg, Immuno/reuma patientenzorg, Koenen, Mischa, Bosma, Marleen, Roorda, Udo, Wopereis, Fabienne, Roos, Anja, van der Vries, Erhard, Bogaert, D, Sanders, Elisabeth, Boes, Marianne, Heidema, Jojanneke, van Montfrans, JM, Balemans, Walter A F, van Holten, Thijs C, Verhagen, Lilly, CTI Boes, Immuno/reuma onderzoek 2 (Boes), Onderzoek, Child Health, Infection & Immunity, IMI, Cluster B, Infectieziekten patientenzorg, Immuno/reuma patientenzorg, Koenen, Mischa, Bosma, Marleen, Roorda, Udo, Wopereis, Fabienne, Roos, Anja, van der Vries, Erhard, Bogaert, D, Sanders, Elisabeth, Boes, Marianne, Heidema, Jojanneke, van Montfrans, JM, Balemans, Walter A F, van Holten, Thijs C, and Verhagen, Lilly

Published
2021

6. Phenotypic variability including Behçet's disease-like manifestations in DADA2 patients due to a homozygous c.973-2A>G splice site mutation

Author

van Well, G.T.J., Kant, Benjamin, Nisterlrooij, A, Ekmekci, S, Henriet, Stefanie, Hoppenreijs, E.P.A.H., van Deuren, M., van Montfrans, JM, Nierkens, Stefan, Gul, A, van Gijn, Marielle, Kindergeneeskunde, MUMC+: MA Kindergeneeskunde (3), MUMC+: MA Medische Staf Kindergeneeskunde (9), MUMC+: MA Arts Assistenten Kindergeneeskunde (9), and RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health

Subjects
systemic inflammation, Intercellular Signaling Peptides and Proteins/deficiency, Mutation/genetics, phenotype, DADA2, genotype, Homozygote, POLYARTERITIS-NODOSA, CECR1, Behcet's disease-like manifestations, ADA2, Behcet Syndrome/genetics, vasculitis, Adenosine Deaminase/deficiency, DEFICIENCY, polyarteritis nodosa, ADENOSINE-DEAMINASE 2, Biological Variation, Population, Journal Article, Humans, splice site mutation, early-onset stroke, Genetic Association Studies
Abstract

Objective. To describe phenotypic and functional characteristics of patients with the homozygous c.973-2A>G splice site mutation in the adenosine deaminase 2 (ADA2) gene (rs139750129), resulting in deficiency of ADA2 (DADA2). Methods. We present case synopses of six patients from three unrelated families. Clinical data were analysed and next-generation sequencing (NGS) was performed. We also tested for aberrant RNA splicing and measured ADA2 enzyme activity. Results. One family had common DADA2 symptoms, whereas Behcet's disease-like manifestations were observed in the other two families. We detected the homozygous c.973-2A>G splice site mutation in ADA2 in all patients tested. ADA2 enzyme activity was significantly lower in patients than in healthy controls, but no correlation between ADA2 activity levels and disease severity was observed. Aberrant splicing was detected in a minority of mRNA transcripts, but the formation of other, undetected, aberrant splicing products could not be excluded. Patients were treated with TNF-alpha inhibitors to prevent recurrence of inflammatory findings including cerebral vasculitis-associated stroke. Conclusion. We describe three families with the same homozygous splice site mutation in ADA2 and observed a novel combination of manifestations resembling Behcet's disease. This further expands the range of phenotypes caused by ADA2 mutations, although no complete genotype-phenotype association could be determined. Even without active disease, the risk of stroke should be addressed in making decisions regarding treatment of DADA2 patients.

Published
2019

7. In beeld - paraplu juli 2020

Author

Immuno/reuma patientenzorg, Child Health, Infection & Immunity, van Montfrans, JM, Immuno/reuma patientenzorg, Child Health, Infection & Immunity, and van Montfrans, JM

Published
2020

13. Als je afweer tekort schiet: afweerstoornissen

Author

Immuno/reuma patientenzorg, Child Health, Infection & Immunity, van Montfrans, JM, Kuijpers, Taco W., Immuno/reuma patientenzorg, Child Health, Infection & Immunity, van Montfrans, JM, and Kuijpers, Taco W.

Published
2018

18. Neonatal erythroderma and collodion baby

Author

Cuperus, Edwin, van Montfrans, JM, van Hasselt, PM, van der Smagt, JJ, Sigurdsson, V, Dijk, Matthijs, van Gijn, ME, Pasmans, Suzanne, Dermatology, and Medical Oncology

Published
2015

19. Embracing Complexity beyond Systems Medicine: A New Approach to Chronic Immune Disorders

Author

te Velde, AA, Bezema, T, van Kampen, AHC, Kraneveld, AD, Hart, Boris, van Middendorp, H, Hack, E C, van Montfrans, JM, Belzer, C, Jans-Beken, L, Pieters, R H, Knipping, K, Huber, M, Boots, AMH, Garssen, J, Radstake, T R, Evers, AWM, Prakken, BJ, Joosten, I, te Velde, AA, Bezema, T, van Kampen, AHC, Kraneveld, AD, Hart, Boris, van Middendorp, H, Hack, E C, van Montfrans, JM, Belzer, C, Jans-Beken, L, Pieters, R H, Knipping, K, Huber, M, Boots, AMH, Garssen, J, Radstake, T R, Evers, AWM, Prakken, BJ, and Joosten, I

Published
2016

20. Novel mutations in TNFRSF7/CD27 : Clinical, immunologic, and genetic characterization of human CD27 deficiency

Author

Alkhairy, Omar K., Perez-Becker, Ruy, Driessen, Gertjan J., Abolhassani, Hassan, van Montfrans, JM, Borte, Stephan, Choo, Sharon, Wang, Ning, Tesselaar, Kiki, Fang, Mingyan, Bienemann, Kirsten, Boztug, Kaan, Daneva, Ana, Mechinaud, Francoise, Wiesel, Thomas, Becker, Christian, Duckers, Gregor, Siepermann, Kathrin, van Zelm, Menno C., Rezaei, Nima, van der Burg, Mirjam, Aghamohammadi, Asghar, Seidel, Markus G., Niehues, Tim, Hammarstrom, Lennart, Alkhairy, Omar K., Perez-Becker, Ruy, Driessen, Gertjan J., Abolhassani, Hassan, van Montfrans, JM, Borte, Stephan, Choo, Sharon, Wang, Ning, Tesselaar, Kiki, Fang, Mingyan, Bienemann, Kirsten, Boztug, Kaan, Daneva, Ana, Mechinaud, Francoise, Wiesel, Thomas, Becker, Christian, Duckers, Gregor, Siepermann, Kathrin, van Zelm, Menno C., Rezaei, Nima, van der Burg, Mirjam, Aghamohammadi, Asghar, Seidel, Markus G., Niehues, Tim, and Hammarstrom, Lennart

Published
2015

21. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency

Author

Wehr, Claudia, Gennery, Andrew R., Lindemans, Caroline, Schulz, Ansgar, Hoenig, Manfred, Marks, Reinhard, Recher, Mike, Gruhn, Bernd, Holbro, Andreas, Heijnen, Ingmar, Meyer, Deborah, Grigoleit, Goetz, Einsele, Hermann, Baumann, Ulrich, Witte, Thorsten, Sykora, Karl-Walter, Goldacker, Sigune, Regairaz, Lorena, Aksoylar, Serap, Ardeniz, Omur, Zecca, Marco, Zdziarski, Przemyslaw, Meyts, Isabelle, Matthes-Martin, Susanne, Imai, Kohsuke, Kamae, Chikako, Fielding, Adele, Seneviratne, Suranjith, Mahlaoui, Nizar, Slatter, Mary A., Gungor, Tayfun, Arkwright, Peter D., van Montfrans, JM, Sullivan, Kathleen E., Grimbacher, Bodo, Cant, Andrew, Peter, Hans-Hartmut, Finke, Juergen, Gaspar, H. Bobby, Warnatz, Klaus, Rizzi, Marta, European Soc Blood Marrow, European Soc Immunodeficiency, Wehr, Claudia, Gennery, Andrew R., Lindemans, Caroline, Schulz, Ansgar, Hoenig, Manfred, Marks, Reinhard, Recher, Mike, Gruhn, Bernd, Holbro, Andreas, Heijnen, Ingmar, Meyer, Deborah, Grigoleit, Goetz, Einsele, Hermann, Baumann, Ulrich, Witte, Thorsten, Sykora, Karl-Walter, Goldacker, Sigune, Regairaz, Lorena, Aksoylar, Serap, Ardeniz, Omur, Zecca, Marco, Zdziarski, Przemyslaw, Meyts, Isabelle, Matthes-Martin, Susanne, Imai, Kohsuke, Kamae, Chikako, Fielding, Adele, Seneviratne, Suranjith, Mahlaoui, Nizar, Slatter, Mary A., Gungor, Tayfun, Arkwright, Peter D., van Montfrans, JM, Sullivan, Kathleen E., Grimbacher, Bodo, Cant, Andrew, Peter, Hans-Hartmut, Finke, Juergen, Gaspar, H. Bobby, Warnatz, Klaus, Rizzi, Marta, European Soc Blood Marrow, and European Soc Immunodeficiency

Published
2015

22. DOCK8 Deficiency : Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

Author

Aydin, Susanne E., Kilic, Sara Sebnem, Aytekin, Caner, Kumar, Ashish, Porras, Oscar, Kainulainen, Leena, Kostyuchenko, Larysa, Genel, Ferah, Kutukculer, Necil, Karaca, Neslihan, Gonzalez-Granado, Luis, Abbott, Jordan, Al-Zahrani, Daifulah, Rezaei, Nima, Baz, Zeina, Thiel, Jens, Ehl, Stephan, Marodi, Laszlo, Orange, Jordan S., Sawalle-Belohradsky, Julie, Keles, Sevgi, Holland, Steven M., Sanal, Ozden, Ayvaz, Deniz C., Tezcan, Ilhan, Al-Mousa, Hamoud, Alsum, Zobaida, Hawwari, Abbas, Metin, Ayse, Matthes-Martin, Susanne, Hoenig, Manfred, Schulz, Ansgar, Picard, Capucine, Barlogis, Vincent, Gennery, Andrew, Ifversen, Marianne, van Montfrans, JM, Kuijpers, Taco, Bredius, Robbert, Duckers, Gregor, Al-Herz, Waleed, Pai, Sung-Yun, Geha, Raif, Notheis, Gundula, Schwarze, Carl-Philipp, Tavil, Betul, Azik, Fatih, Bienemann, Kirsten, Grimbacher, Bodo, Heinz, Valerie, Gaspar, H. Bobby, Aydin, Roland, Hagl, Beate, Gathmann, Benjamin, Belohradsky, Bernd H., Ochs, Hans D., Chatila, Talal, Renner, Ellen D., Su, Helen, Freeman, Alexandra F., Engelhardt, Karin, Albert, Michael H., Aydin, Susanne E., Kilic, Sara Sebnem, Aytekin, Caner, Kumar, Ashish, Porras, Oscar, Kainulainen, Leena, Kostyuchenko, Larysa, Genel, Ferah, Kutukculer, Necil, Karaca, Neslihan, Gonzalez-Granado, Luis, Abbott, Jordan, Al-Zahrani, Daifulah, Rezaei, Nima, Baz, Zeina, Thiel, Jens, Ehl, Stephan, Marodi, Laszlo, Orange, Jordan S., Sawalle-Belohradsky, Julie, Keles, Sevgi, Holland, Steven M., Sanal, Ozden, Ayvaz, Deniz C., Tezcan, Ilhan, Al-Mousa, Hamoud, Alsum, Zobaida, Hawwari, Abbas, Metin, Ayse, Matthes-Martin, Susanne, Hoenig, Manfred, Schulz, Ansgar, Picard, Capucine, Barlogis, Vincent, Gennery, Andrew, Ifversen, Marianne, van Montfrans, JM, Kuijpers, Taco, Bredius, Robbert, Duckers, Gregor, Al-Herz, Waleed, Pai, Sung-Yun, Geha, Raif, Notheis, Gundula, Schwarze, Carl-Philipp, Tavil, Betul, Azik, Fatih, Bienemann, Kirsten, Grimbacher, Bodo, Heinz, Valerie, Gaspar, H. Bobby, Aydin, Roland, Hagl, Beate, Gathmann, Benjamin, Belohradsky, Bernd H., Ochs, Hans D., Chatila, Talal, Renner, Ellen D., Su, Helen, Freeman, Alexandra F., Engelhardt, Karin, and Albert, Michael H.

Published
2015

25. Overview of 15-year severe combined immunodeficiency in the Netherlands : towards newborn blood spot screening

Author

de Pagter, Anne P. J., Bredius, Robbert G. M., Kuijpers, Taco W., Tramper, Jelco, van der Burg, Mirjam, van Montfrans, JM, Driessen, Gertjan J., Dutch Working Party Immunodeficien, de Pagter, Anne P. J., Bredius, Robbert G. M., Kuijpers, Taco W., Tramper, Jelco, van der Burg, Mirjam, van Montfrans, JM, Driessen, Gertjan J., and Dutch Working Party Immunodeficien

Published
2015

26. Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency

Author

Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Alkhairy, Omar K., Perez-Becker, Ruy, Driessen, Gertjan J., Abolhassani, Hassan, van Montfrans, JM, Borte, Stephan, Choo, Sharon, Wang, Ning, Tesselaar, Kiki, Fang, Mingyan, Bienemann, Kirsten, Boztug, Kaan, Daneva, Ana, Mechinaud, Francoise, Wiesel, Thomas, Becker, Christian, Duckers, Gregor, Siepermann, Kathrin, van Zelm, Menno C., Rezaei, Nima, van der Burg, Mirjam, Aghamohammadi, Asghar, Seidel, Markus G., Niehues, Tim, Hammarstrom, Lennart, Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Alkhairy, Omar K., Perez-Becker, Ruy, Driessen, Gertjan J., Abolhassani, Hassan, van Montfrans, JM, Borte, Stephan, Choo, Sharon, Wang, Ning, Tesselaar, Kiki, Fang, Mingyan, Bienemann, Kirsten, Boztug, Kaan, Daneva, Ana, Mechinaud, Francoise, Wiesel, Thomas, Becker, Christian, Duckers, Gregor, Siepermann, Kathrin, van Zelm, Menno C., Rezaei, Nima, van der Burg, Mirjam, Aghamohammadi, Asghar, Seidel, Markus G., Niehues, Tim, and Hammarstrom, Lennart

Published
2015

27. Overview of 15-year severe combined immunodeficiency in the Netherlands: towards newborn blood spot screening

Author

Immuno/reuma patientenzorg, Infection & Immunity, Child Health, de Pagter, Anne P. J., Bredius, Robbert G. M., Kuijpers, Taco W., Tramper, Jelco, van der Burg, Mirjam, van Montfrans, JM, Driessen, Gertjan J., Dutch Working Party Immunodeficien, Immuno/reuma patientenzorg, Infection & Immunity, Child Health, de Pagter, Anne P. J., Bredius, Robbert G. M., Kuijpers, Taco W., Tramper, Jelco, van der Burg, Mirjam, van Montfrans, JM, Driessen, Gertjan J., and Dutch Working Party Immunodeficien

Published
2015

28. DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

Author

Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Aydin, Susanne E., Kilic, Sara Sebnem, Aytekin, Caner, Kumar, Ashish, Porras, Oscar, Kainulainen, Leena, Kostyuchenko, Larysa, Genel, Ferah, Kutukculer, Necil, Karaca, Neslihan, Gonzalez-Granado, Luis, Abbott, Jordan, Al-Zahrani, Daifulah, Rezaei, Nima, Baz, Zeina, Thiel, Jens, Ehl, Stephan, Marodi, Laszlo, Orange, Jordan S., Sawalle-Belohradsky, Julie, Keles, Sevgi, Holland, Steven M., Sanal, Ozden, Ayvaz, Deniz C., Tezcan, Ilhan, Al-Mousa, Hamoud, Alsum, Zobaida, Hawwari, Abbas, Metin, Ayse, Matthes-Martin, Susanne, Hoenig, Manfred, Schulz, Ansgar, Picard, Capucine, Barlogis, Vincent, Gennery, Andrew, Ifversen, Marianne, van Montfrans, JM, Kuijpers, Taco, Bredius, Robbert, Duckers, Gregor, Al-Herz, Waleed, Pai, Sung-Yun, Geha, Raif, Notheis, Gundula, Schwarze, Carl-Philipp, Tavil, Betul, Azik, Fatih, Bienemann, Kirsten, Grimbacher, Bodo, Heinz, Valerie, Gaspar, H. Bobby, Aydin, Roland, Hagl, Beate, Gathmann, Benjamin, Belohradsky, Bernd H., Ochs, Hans D., Chatila, Talal, Renner, Ellen D., Su, Helen, Freeman, Alexandra F., Engelhardt, Karin, Albert, Michael H., Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Aydin, Susanne E., Kilic, Sara Sebnem, Aytekin, Caner, Kumar, Ashish, Porras, Oscar, Kainulainen, Leena, Kostyuchenko, Larysa, Genel, Ferah, Kutukculer, Necil, Karaca, Neslihan, Gonzalez-Granado, Luis, Abbott, Jordan, Al-Zahrani, Daifulah, Rezaei, Nima, Baz, Zeina, Thiel, Jens, Ehl, Stephan, Marodi, Laszlo, Orange, Jordan S., Sawalle-Belohradsky, Julie, Keles, Sevgi, Holland, Steven M., Sanal, Ozden, Ayvaz, Deniz C., Tezcan, Ilhan, Al-Mousa, Hamoud, Alsum, Zobaida, Hawwari, Abbas, Metin, Ayse, Matthes-Martin, Susanne, Hoenig, Manfred, Schulz, Ansgar, Picard, Capucine, Barlogis, Vincent, Gennery, Andrew, Ifversen, Marianne, van Montfrans, JM, Kuijpers, Taco, Bredius, Robbert, Duckers, Gregor, Al-Herz, Waleed, Pai, Sung-Yun, Geha, Raif, Notheis, Gundula, Schwarze, Carl-Philipp, Tavil, Betul, Azik, Fatih, Bienemann, Kirsten, Grimbacher, Bodo, Heinz, Valerie, Gaspar, H. Bobby, Aydin, Roland, Hagl, Beate, Gathmann, Benjamin, Belohradsky, Bernd H., Ochs, Hans D., Chatila, Talal, Renner, Ellen D., Su, Helen, Freeman, Alexandra F., Engelhardt, Karin, and Albert, Michael H.

Published
2015

29. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency

Author

SCT patientenzorg, Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Wehr, Claudia, Gennery, Andrew R., Lindemans, Caroline, Schulz, Ansgar, Hoenig, Manfred, Marks, Reinhard, Recher, Mike, Gruhn, Bernd, Holbro, Andreas, Heijnen, Ingmar, Meyer, Deborah, Grigoleit, Goetz, Einsele, Hermann, Baumann, Ulrich, Witte, Thorsten, Sykora, Karl-Walter, Goldacker, Sigune, Regairaz, Lorena, Aksoylar, Serap, Ardeniz, Omur, Zecca, Marco, Zdziarski, Przemyslaw, Meyts, Isabelle, Matthes-Martin, Susanne, Imai, Kohsuke, Kamae, Chikako, Fielding, Adele, Seneviratne, Suranjith, Mahlaoui, Nizar, Slatter, Mary A., Gungor, Tayfun, Arkwright, Peter D., van Montfrans, JM, Sullivan, Kathleen E., Grimbacher, Bodo, Cant, Andrew, Peter, Hans-Hartmut, Finke, Juergen, Gaspar, H. Bobby, Warnatz, Klaus, Rizzi, Marta, European Soc Blood Marrow, European Soc Immunodeficiency, SCT patientenzorg, Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Wehr, Claudia, Gennery, Andrew R., Lindemans, Caroline, Schulz, Ansgar, Hoenig, Manfred, Marks, Reinhard, Recher, Mike, Gruhn, Bernd, Holbro, Andreas, Heijnen, Ingmar, Meyer, Deborah, Grigoleit, Goetz, Einsele, Hermann, Baumann, Ulrich, Witte, Thorsten, Sykora, Karl-Walter, Goldacker, Sigune, Regairaz, Lorena, Aksoylar, Serap, Ardeniz, Omur, Zecca, Marco, Zdziarski, Przemyslaw, Meyts, Isabelle, Matthes-Martin, Susanne, Imai, Kohsuke, Kamae, Chikako, Fielding, Adele, Seneviratne, Suranjith, Mahlaoui, Nizar, Slatter, Mary A., Gungor, Tayfun, Arkwright, Peter D., van Montfrans, JM, Sullivan, Kathleen E., Grimbacher, Bodo, Cant, Andrew, Peter, Hans-Hartmut, Finke, Juergen, Gaspar, H. Bobby, Warnatz, Klaus, Rizzi, Marta, European Soc Blood Marrow, and European Soc Immunodeficiency

Published
2015

30. TREC Based Newborn Screening for Severe Combined Immunodeficiency Disease: A Systematic Review

Author

Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Epi Methoden Team 2, Circulatory Health, van der Spek, Jet, Groenwold, Rolf H. H., van der Burg, Mirjam, van Montfrans, JM, Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Epi Methoden Team 2, Circulatory Health, van der Spek, Jet, Groenwold, Rolf H. H., van der Burg, Mirjam, and van Montfrans, JM

Published
2015

31. Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help

Author

Immunologie/Reumatologie, CTI Boes, Infection & Immunity, Reumatologie, Child Health, Genetica Sectie Genoomdiagnostiek, Immuno/reuma patientenzorg, Compeer, E.B., Janssen, Willemijn, van Royen-Kerkhof, A, van Gijn, Marielle, van Montfrans, JM, Boes, Marianne, Immunologie/Reumatologie, CTI Boes, Infection & Immunity, Reumatologie, Child Health, Genetica Sectie Genoomdiagnostiek, Immuno/reuma patientenzorg, Compeer, E.B., Janssen, Willemijn, van Royen-Kerkhof, A, van Gijn, Marielle, van Montfrans, JM, and Boes, Marianne

Published
2015

32. TREC Based Newborn Screening for Severe Combined Immunodeficiency Disease: A Systematic Review

Author

van der Spek, J, Groenwold, RHH, van der Burg, Mirjam, van Montfrans, JM, van der Spek, J, Groenwold, RHH, van der Burg, Mirjam, and van Montfrans, JM

Abstract

Background Newborn screening (NBS) by quantifying T cell receptor excision circles (TRECs) in neonatal dried blood spots (DBS) enables early diagnosis of severe combined immunodeficiency disease (SCID). In recent years, different screening algorithms for TREC based SCID screening were reported. Purpose To systematically review the diagnostic performance of published algorithms for TREC based NBS for SCID. Methods PubMed, EMBASE and the Cochrane Library were systematically searched for case series and prospective cohort studies describing TREC based NBS for SCID. We extracted TREC content and cut-off values, number of retests, repeat DBS and referrals, and type and number of typical SCID and other T cell lymphopenia (TCL) cases. We calculated positive predictive value (PPV), test sensitivity and SCID incidence. Results Thirteen studies were included, re-confirming 89 known SCID cases in case series and reporting 53 new SCID cases in 3.15 million newborns. In case series, the sensitivity for typical SCID was 100 %. In the prospective cohort studies, SCID incidence was similar to 1.7:100,000, re-test rate was 0.20-3.26 %, repeat DBS rate 0.0-0.41 % and referral rate 0.01-1.35 %. PPV within the five largest cohorts was 0.8-11.2 % for SCID and 18.3-81.0 % for TCL. Individual TREC contents in all SCID patients was < 25 TRECs/mu l (except in those evaluated with the New York State assay). Conclusions The sensitivity of TREC based NBS for typical SCID was 100 %. The TREC cut-off score determines the percentage of non-SCID TCL cases detected in newborn screening for TCL. Adapting the screening algorithm for pre-term/ill infants reduces the amount of false positive test results.

Published
2015

33. Paediatric - An HIV-infected infant with Bacille Calmette-Guerin disease, recurrent and multidrug-resistant tuberculosis complicated by acute cor pulmonale and hepatitis while on antiretroviral therapy

Author

van Montfrans, JM, Rabie, H, Schaaf, HS, Hesseling, AC, Cotton, MF, Shipton, SE, and Victor, T

Abstract

We describe the management of an HIV-infected infant with multisystem disease. The infant presented with severe disease at 3 months of age. Initiation of antiretroviral therapy (ART) was delayed through initial lack of access, after which she developed immune reconstitution inflammatory syndrome to BCG. At this time she was also infected with Mycobacterium tuberculosis, with a later recurrence due to multidrug-resistant (MDR) tuberculosis (TB). During this episode she presented with acute cor pulmonale, possibly due to a pulmonary embolus and also transaminitis. Although such infants are seen frequently in sub-Saharan Africa, there are few guidelines or case descriptions to assist clinicians. Southern African Journal of HIV Medicine Vol. 8 (1) 2007: pp. 49-51

Published
2009

34. The PedPAD study: boys predominate in the hypogammaglobulinaemia registry of the ESID online database

Author

Schatorjé, E J H, primary, Gathmann, B, additional, van Hout, R W N M, additional, de Vries, E, additional, Alsina, L, additional, Baumann, U, additional, Belohradsky, BH, additional, Bienemann, K, additional, Boardman, B, additional, Borte, M, additional, Bredius, RG, additional, Brodszki, N, additional, Caracseghi, F, additional, Ciznar, P, additional, Driessen, GJ, additional, Dückers, G, additional, Duppenthaler, A, additional, Farmaki, E, additional, Galal, N, additional, Gennery, A, additional, Gonzalez-Granado, LI, additional, Hlavackova, E, additional, Hoernes, M, additional, Kilic, SS, additional, Krüger, R, additional, Kuijpers, TW, additional, Kütükcüler, N, additional, Llobet, P, additional, Marques, L, additional, van Montfrans, JM, additional, Papadopoulou-Alataki, E, additional, Paschenko, O, additional, Pasic, S, additional, Pietrogrande, MC, additional, Pignata, C, additional, Reda, SM, additional, Reisli, I, additional, Roesler, J, additional, Santos, JL, additional, Schölvinck, EH, additional, Schulze, Ilka, additional, Seidel, MG, additional, Shcherbina, A, additional, Sundin, M, additional, Szaflarska, A, additional, Velbri, S, additional, Warnatz, K, additional, and Warris, A, additional

Published
2014
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40. Connecting clinical and molecular disease features in Common Variable Immunodeficiency Disorder

Author

Janssen, W.J.M., Sanders, Elisabeth, van Montfrans, JM, Boes, Marianne, and University Utrecht

Subjects
T-cell, CVID, pneumococcal polysaccharide, gastrointestinal viruses, immunoglobulin, pulmonary disease
Abstract

Common Variable Immunodeficiency (CVID) disorder is the most prevalent symptomatic primary immunodeficiency in children and adults. Typically, a patient presents with recurrent pulmonary and/or gastrointestinal infections (with or without infection related complications), due to diminished immunoglobulin levels and insufficient specific antibody responses to encapsulated bacteria. Some patients present with autoimmune manifestations related to immune dysregulation. In order to reach the diagnosis of CVID patients must meet certain diagnostic criteria as formulated by the American and European Society for Immunodeficiencies (ESID): A patient should have a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and all of the following criteria: 1) Onset of immunodeficiency at > 2 years of age 2) Absent isohemagglutinins and/or poor response to vaccines and 3) Defined causes of hypogammaglobulinemia have been excluded. Treatment of CVID patients consists of Ig replacement therapy, with the purpose to prevent recurrent infections and subsequent complications. Other treatment options to prevent recurrent pulmonary bacterial infections include antibiotic prophylaxis, while for treatment of autoimmune manifestations immunosuppressive therapy (e.g. systemic corticosteroids) may be considered. The first part of this thesis focuses on possible new gene mutations and molecular mechanisms contributing to the B- and T-cell defects in CVID patients. To this end, we screened 30 primary immunodeficiency patients with a next gen sequencing technique for 170 known PID genes and 300 candidate genes. We found three potentially pathogenic new gene mutations of BLK, PSTPIP1 and STAT3 and performed functional experiments in an attempt to prove disease association. The second part of this thesis looks further into the local pulmonary and gastrointestinal homeostasis of CVID patients and evaluates the use of pneumococcal polysaccharide vaccination responses as a diagnostic criterium for CVID. We found that anti-pneumococcal polysaccharide IgA responses may be of use to differentiate transient antibody deficiency disease from persistent CVID. Secondly, for the assessment of anti-pneumococcal polysaccharide IgG responses, we believe individual measurement of serotypes is superior to combined serotype measurement. Thirdly, we found that CVID patients are more often carrying gastrointestinal viruses than healthy controls. Furthermore, viral presence correlated to signs of inflammation and low secretory IgA levels in feces in CVID patients and not in healthy controls. Finally, this thesis ends with a prospective study on the progression of pulmonary disease on CT scans op CVID patients. Silent progression of pulmonary disease occurred in almost all patients and higher IgG trough levels seemed to correlate to less progression of pulmonary disease. A randomized controlled study should be performed to confirm these findings.

Published
2017

41. B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients

Author

Miriam Casiraghi, Mirjam van der Burg, Maria Grazia Roncarolo, Aisha V. Sauer, Maria Pia Cicalese, Alessandro Aiuti, Stefania Giannelli, Davide Montin, Klaus Müller, Maria Carmina Castiello, Lucia Dora Notarangelo, Joris M. van Montfrans, Samantha Scaramuzza, Barbara H. Barendregt, Immacolata Brigida, Jennifer M. Puck, Jacques J.M. van Dongen, Elisabetta Traggiai, Chiara Brombin, Valentina Pistoia, Francesca Ferrua, Brigida, I, Sauer, Av, Ferrua, F, Giannelli, S, Scaramuzza, S, Pistoia, V, Castiello, Mc, Barendregt, Bh, Cicalese, Mp, Casiraghi, M, Brombin, Chiara, Puck, J, Müller, K, Notarangelo, Ld, Montin, D, van Montfrans, Jm, Roncarolo, Mg, Traggiai, E, van Dongen, Jj, van der Burg, M, Aiuti, Alessandro, Pediatrics, and Immunology

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Allergy, Adenosine Deaminase, adenosine deaminase–deficient severe combined immunodeficiency, Genetic enhancement, B-cell receptor, Immunology, Biology, Regenerative Medicine, Article, Adenosine deaminase, Gene therapy, B-Cell Activating Factor, medicine, Genetics, Immunology and Allergy, 2.1 Biological and endogenous factors, Humans, antibodies, Enzyme Replacement Therapy, Aetiology, Child, Preschool, B cell, Pediatric, Severe combined immunodeficiency, Transplantation, B-Lymphocytes, CD40, 5.2 Cellular and gene therapies, B-cell development, Inflammatory and immune system, Hematopoietic Stem Cell Transplantation, Hematopoietic stem cell, nutritional and metabolic diseases, Infant, Genetic Therapy, medicine.disease, Stem Cell Research, 3. Good health, adenosine deaminase-deficient severe combined immunodeficiency, medicine.anatomical_structure, Child, Preschool, biology.protein, Stem Cell Research - Nonembryonic - Non-Human, Bone marrow, Development of treatments and therapeutic interventions
Abstract

BACKGROUND:Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. OBJECTIVE: We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. METHODS:Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. RESULTS:Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. CONCLUSIONS:ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.

Published
2014
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42. Common variable immunodeficiency to solve the variable of the equation

Author

van de Ven, A.A.J.M., Sanders, Elisabeth, van Montfrans, JM, Boes, Marianne, and University Utrecht

Abstract

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency requiring treatment. Despite significant progress in fundamental research and treatment strategies, many issues in the origins of CVID still need to be addressed. Some disease-causing monogenetic defects in e.g. B cell co-receptors were found, but a molecular diagnosis remains limited to a neglible fraction of patients. Despite improvements in therapy, morbidity remains high. This thesis provides various insights on the pathogenesis and complications of CVID, which were obtained by studies in children with CVID and related antibody deficiencies. As current literature is mainly based on research in adult CVID patients, it had thus far been uncertain whether pediatric CVID is the same disease displayed a younger population, or a dissimilar disease entity. We show that pediatric CVID disorders are analogous to adult CVID regarding lymphocyte characteristics, with increased numbers of transitional B cells accompanied by low memory populations, in comparison to age-related reference values. As a result, CVID classifications show a different patient distribution when applied to children and are thus inapt for this population. The etiology of CVID remains to be elucidated. We have investigated early B cell activation upon triggering of the B cell receptor (BCR). and demonstrate that BCR-mediated calcium signaling is disturbed in a significant proportion of pediatric CVID patients. The defect correlates with disturbed plasmablast differentiation in vitro. These data suggest that defective plasma membrane lateral interaction of the BCR with its co-molecules is a pivotal pathogenetic mechanism in CVID, and is supported by our finding of defective B cell surface dissociation of CD20 and the BCR. Pulmonary abnormalities are the most frequent complications in CVID. We describe for the first time in pediatric CVID patients comparative data on interstitial or parenchymal lung disease. While pulmonary abnormalities in pediatric CVID are common but generally mild as rated by HRCT, they may occur despite what we consider optimal treatment regimens and despite the lack of pulmonary symptoms. We additionally report the first HRCT scoring method and its validation that is specifically designed for CVID. CVID-related lung abnormalities develop via different pathogenetic mechanisms. Accordingly, the separation of complications into two categories revealed that the patients concerned display dissimilar clinical and immunological characteristics. Enteropathy is the most lethal non-malignant intrinsic complication in CVID. We illustrate that human parechovirus is nearly impossible to eradicate in the agammaglobulinemic patients, and may persist in the gastrointestinal tract for many years. Whether there is a relation between persistent enteric virus infections and enteropathy in immunodeficiency remains to be elucidated. To this end, a longitudinal study has been initiated and promising preliminary data are described in this thesis. Children with CVID suffered more often from gastrointestinal discomfort than healthy children. These symptoms were associated with intestinal inflammation. In addition, common enteric infections were numerous and associated with intestinal inflammation in pediatric CVID. This thesis involved the phenotypic and mechanistic clarification of CVID disease and its complications, which should eventually facilitate molecular diagnoses, prevention of complications and optimalization of therapeutic options.

Published
2011

43. Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.

Author

Vallée TC, Glasmacher JS, Buchner H, Arkwright PD, Behrends U, Bondarenko A, Browning MJ, Buchbinder D, Cattoni A, Chernyshova L, Ciznar P, Cole T, Czogała W, Dueckers G, Edgar JDM, Erbey F, Fasth A, Ferrua F, Formankova R, Gambineri E, Gennery AR, Goldman FD, Gonzalez-Granado LI, Heilmann C, Heiskanen-Kosma T, Juntti H, Kainulainen L, Kanegane H, Karaca NE, Kilic SS, Klein C, Kołtan S, Kondratenko I, Meyts I, Nasrullayeva GM, Notarangelo LD, Pasic S, Pellier I, Pignata C, Misbah S, Schulz A, Segundo GR, Shcherbina A, Slatter M, Sokolic R, Soler-Palacin P, Stepensky P, van Montfrans JM, Ryhänen S, Wolska-Kuśnierz B, Ziegler JB, Zhao X, Aiuti A, Ochs HD, and Albert MH

Subjects
Humans, Adolescent, Child, Male, Female, Child, Preschool, Adult, Retrospective Studies, Infant, Young Adult, Biomarkers, Hematopoietic Stem Cell Transplantation, Severity of Illness Index, Wiskott-Aldrich Syndrome Protein genetics, Follow-Up Studies, Middle Aged, Prognosis, Survival Rate, Wiskott-Aldrich Syndrome genetics, Wiskott-Aldrich Syndrome diagnosis, Wiskott-Aldrich Syndrome therapy, Genotype
Abstract

Abstract: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Published
2024
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44. Pulmonary Computed Tomography Screening Frequency in Primary Antibody Deficiency.

Author

Smits BM, Boland SL, Hol ME, Dandis R, Leavis HL, de Jong PA, Prevaes SMPJ, Mohamed Hoesein FAA, van Montfrans JM, and Ellerbroek PM

Subjects
Humans, Retrospective Studies, Longitudinal Studies, Tomography, X-Ray Computed methods, Lung Diseases, Interstitial diagnosis, Lung Diseases, Interstitial epidemiology, Primary Immunodeficiency Diseases, Agammaglobulinemia, Genetic Diseases, X-Linked
Abstract

Background: Patients with primary antibody deficiency (PAD) frequently suffer from pulmonary complications, associated with severe morbidity and mortality. Hence, regular pulmonary screening by computed tomography (CT) scanning is advised. However, predictive risk factors for pulmonary morbidity are lacking., Objective: To identify patients with PAD at risk for pulmonary complications necessitating regular CT screening., Methods: A retrospective, longitudinal cohort study of patients with PAD (median follow-up 7.4 [2.3-14.8] years) was performed. CTs were scored using the modified Brody-II scoring system. Clinical and laboratory parameters were retrospectively collected. Potential risk factors were identified by univariate analysis when P < .2 and confirmed by multivariable logistic regression when P < .05., Results: The following independent risk factors for progression of airway disease (AD) were identified: (1) diagnosis of X-linked agammaglobulinemia (XLA), (2) recurrent airway infections (2.5/year), and (3) the presence of AD at baseline. Signs of AD progression were detected in 5 of 11 patients with XLA and in 17 of 80 of the other patients with PAD. Of the 22 patients who progressed, 17 had pre-existent AD scores ≥7.0%. Increased AD scores were related to poorer forced expiratory volume in 1 second values and chronic cough. Common variable immunodeficiency and increased CD4 effector/memory cells were risk factors for an interstitial lung disease (ILD) score ≥13.0%. ILD ≥13.0% occurred in 12 of 80 patients. Signs of ILD progression were detected in 8 of 80 patients, and 4 of 8 patients showing progression had pre-existent ILD scores ≥13.0%., Conclusion: We identified risk factors that distinguished patients with PAD at risk for AD and ILD presence and progression, which could guide future screening frequency; however, independent and preferably prospective validation is needed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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45. Humoral and cellular immunogenicity, effectiveness and safety of COVID-19 mRNA vaccination in patients with pediatric rheumatic diseases: A prospective cohort study.

Author

Hamad Saied M, van Straalen JW, de Roock S, Verduyn Lunel FM, de Wit J, de Rond LGH, Van Nieuwenhove E, Vastert BJ, van Montfrans JM, van Royen-Kerkhof A, de Joode-Smink GCJ, Swart JF, Wulffraat NM, and Jansen MHA

Subjects
Child, Humans, Antibodies, Viral, Immunogenicity, Vaccine, Prospective Studies, Rheumatic Diseases, RNA, Messenger, SARS-CoV-2, Vaccination, Arthritis, Juvenile complications, COVID-19 prevention & control, COVID-19 Vaccines administration & dosage
Abstract

Objectives: To evaluate immunogenicity, effectiveness and safety of COVID-19 vaccination in patients with pediatric autoimmune inflammatory rheumatic disease (pedAIIRD)., Methods: A prospective cohort study was performed at the pediatric rheumatology department of the Wilhelmina Children's Hospital in Utrecht, the Netherlands. Vaccination dates, COVID-19 cases and vaccine-related adverse events (AEs) were registered for all pedAIIRD patients during regular clinic visits from March 2021 - August 2022. SARS-CoV-2 IgG antibody levels and T-cell responses were measured from serum samples after vaccination, and clinical and drug therapy data were collected from electronic medical records. Rate of COVID-19 disease was compared between vaccinated and unvaccinated patients in a time-varying Cox regression analysis., Results: A total of 157 patients were included in this study and 88 % had juvenile idiopathic arthritis (JIA). One hundred thirty-seven patients were fully vaccinated, of which 47 % used biological agents at the time of vaccination, and 20 patients were unvaccinated. Geometric mean concentrations (GMCs) of post-vaccine antibody levels against SARS-CoV-2 were above the threshold for positivity in patients who did and did not use biological agents at the time of vaccination, although biological users demonstrated significantly lower antibody levels (adjusted GMC ratio: 0.38, 95 % CI: 0.21 - 0.70). T-cell responses were adequate in all but two patients (9 %). The adjusted rate of reported COVID-19 was significantly lower for fully vaccinated patients compared to non-vaccinated patients (HR: 0.53, 95 % CI: 0.29 - 0.97). JIA disease activity scores were not significantly different after vaccination, and no serious AEs were reported., Conclusions: COVID-19 mRNA vaccines were immunogenic (both cellular and humoral), effective and safe in a large cohort of pedAIIRD patients despite their use of immunosuppressive medication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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46. Neurological phenotype of adenosine deaminase 2 deficient patients: a cohort study.

Author

Verschoof MA, van Meenen LCC, Andriessen MVE, Brinkman DMC, Kamphuis S, Kuijpers TW, Leavis HL, Legger GE, Mulders-Manders CM, de Pagter APJ, Rutgers A, van Well GTJ, Coutinho JM, Hak AE, van Montfrans JM, and Klouwer FCC

Subjects
Humans, Child, Preschool, Adenosine Deaminase genetics, Cohort Studies, Intercellular Signaling Peptides and Proteins genetics, Tumor Necrosis Factor-alpha, Phenotype, Stroke etiology, Ischemic Attack, Transient complications, Brain Ischemia complications, Ischemic Stroke complications
Abstract

Background and Purpose: Patients with adenosine deaminase 2 (ADA2) deficiency can present with various neurological manifestations due to vasculopathies and autoinflammation. These include ischaemic and hemorrhagic stroke, but less clearly defined neurological symptoms have also been reported., Methods: In this cohort study, patients with confirmed ADA2 deficiency from seven university hospitals in the Netherlands were included. The frequency and recurrence rates of neurological manifestations before and after initiation of tumor necrosis factor α (TNF-α) inhibiting therapy were analyzed., Results: Twenty-nine patients were included with a median age at presentation of 5 years (interquartile range 1-17). Neurological manifestations occurred in 19/29 (66%) patients and were the presenting symptom in 9/29 (31%) patients. Transient ischaemic attack (TIA)/ischaemic stroke occurred in 12/29 (41%) patients and was the presenting symptom in 8/29 (28%) patients. In total, 25 TIAs/ischaemic strokes occurred in 12 patients, one after initiation of TNF-α inhibiting therapy and one whilst switching between TNF-α inhibitors. None was large-vessel occlusion stroke. Two hemorrhagic strokes occurred: one aneurysmatic subarachnoid hemorrhage and one spontaneous intracerebral hemorrhage. Most neurological symptoms, including cranial nerve deficits, vertigo, ataxia and seizures, were caused by TIAs/ischaemic strokes and seldom recurred after initiation of TNF-α inhibiting therapy., Conclusions: Neurological manifestations, especially TIA/ischaemic stroke, are common in patients with ADA2 deficiency and frequently are the presenting symptom. Because it is a treatable cause of young stroke, for which antiplatelet and anticoagulant therapy are considered contraindicated, awareness amongst neurologists and pediatricians is important. Screening for ADA2 deficiency in young patients with small-vessel ischaemic stroke without an identified cause should be considered., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Published
2024
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47. Antibody deficiencies in children are associated with prematurity and a family history of infections.

Author

Koenen MH, van Montfrans JM, Prevaes SMPJ, van Engelen MP, van der Vries E, Boes M, Sanders EAM, Bogaert D, and Verhagen LM

Subjects
Humans, Child, Child, Preschool, Quality of Life, Prospective Studies, Genetic Predisposition to Disease, Respiratory Tract Infections diagnosis, Respiratory Tract Infections epidemiology, Primary Immunodeficiency Diseases
Abstract

Background: Recurrent respiratory tract infections (rRTIs) frequently affect young children and are associated with antibody deficiencies. We investigated the prevalence of and epidemiological risk factors associated with antibody deficiencies in young children with rRTIs and their progression over time, and linked these to prospectively measured RTI symptoms., Methods: We included children <7 years with rRTIs in a prospective cohort study. Patient characteristics associated with antibody deficiencies were identified using multivariable logistic regression analysis., Results: We included 146 children with a median age of 3.1 years. Daily RTI symptoms were monitored in winter in n = 73 children and repeated immunoglobulin level measurements were performed in n = 45 children. Antibody deficiency was diagnosed in 56% and associated with prematurity (OR 3.17 [1.15-10.29]) and a family history of rRTIs (OR 2.37 [1.11-5.15]). Respiratory symptoms did not differ between children with and without antibody deficiencies. During follow-up, antibody deficiency diagnosis remained unchanged in 67%, while 18% of children progressed to a more severe phenotype., Conclusion: Immune maturation and genetic predisposition may lie at the basis of antibody deficiencies commonly observed in early life. Because disease severity did not differ between children with and without antibody deficiency, we suggest symptom management can be similar for all children with rRTIs., Impact: An antibody deficiency was present in 56% of children <7 years with recurrent respiratory tract infections (rRTIs) in a Dutch tertiary hospital setting. Prematurity and a family history of rRTIs were associated with antibody deficiencies, suggesting that immune maturation and genetic predisposition may lie at the basis of antibody deficiencies in early life. RTI symptoms did not differ between children with and without antibody deficiency, suggesting that symptom management can be similar for all children with rRTIs, irrespective of humoral immunological deficiencies. During follow-up, 18% of children progressed to a more severe phenotype, emphasizing that early diagnosis is warranted to prevent long-term morbidity and increase quality of life., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Published
2023
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48. Clinical Symptoms, Laboratory Parameters and Long-Term Follow-up in a National DADA2 Cohort.

Author

Andriessen MVE, Legger GE, Bredius RGM, van Gijn ME, Hak AE, Muller PCEH, Kamphuis S, Klouwer FCC, Kuijpers TW, Leavis HL, Nierkens S, Rutgers A, van der Veken LT, van Well GTJ, Mulders-Manders CM, and van Montfrans JM

Subjects
Humans, Adult, Adenosine Deaminase genetics, Follow-Up Studies, Retrospective Studies, Intercellular Signaling Peptides and Proteins genetics, Mutation genetics, Stroke, Lymphohistiocytosis, Hemophagocytic
Abstract

Deficiency of adenosine deaminase-2 (DADA2) is an autosomal recessive autoinflammatory disease with an extremely variable disease presentation. This paper provides a comprehensive overview of the Dutch DADA2 cohort. We performed a retrospective cohort study in 29 ADA2-deficient patients from 23 families with a median age at inclusion of 26 years. All patients had biallelic pathogenic variants in the ADA2 gene. The most common clinical findings included cutaneous involvement (79.3%), (hepato)splenomegaly (70.8%) and recurrent infections (58.6%). Stroke was observed in 41.4% of the patients. The main laboratory abnormalities were hypogammaglobulinemia and various cytopenias. Patients presented most often with a mixed phenotype involving vasculopathy, immunodeficiency and hematologic manifestations (62.1%). In this cohort, malignancies were reported in eight patients (27.6%), of whom five presented with a hematologic malignancy and two with a basal cell carcinoma. Four patients developed hemophagocytic lymphohistiocytosis (HLH) or an HLH-like episode, of whom three passed away during or shortly after the occurrence of HLH. TNF-inhibitors (TNFi) were effective in treating vasculopathy-associated symptoms and preventing stroke, but were hardly effective in the treatment of hematologic manifestations. Three patients underwent hematopoietic cell transplantation and two of them are doing well with complete resolution of DADA2-related symptoms. The overall mortality in this cohort was 17.2%. In conclusion, this cohort describes the clinical, genetic and laboratory findings of 29 Dutch DADA2 patients. We describe the occurrence of HLH as a life-threatening disease complication and report a relatively high incidence of malignancies and mortality., (© 2023. The Author(s).)

Published
2023
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49. Meningococcal ACWY conjugate vaccine immunogenicity and safety in adolescents with juvenile idiopathic arthritis and inflammatory bowel disease: A prospective observational cohort study.

Author

Ohm M, van Straalen JW, Zijlstra M, de Joode-Smink G, Sellies AJ, Swart JF, Vastert SJ, van Montfrans JM, Bartels M, van Royen-Kerkhof A, Wildenbeest JG, Lindemans CA, Wolters VM, Wennink RAW, de Boer JH, Knol MJ, Heijstek MW, Sanders EAM, Verduyn-Lunel FM, Berbers GAM, Wulffraat NM, and Jansen MHA

Subjects
Adolescent, Humans, Antibodies, Bacterial, Immunogenicity, Vaccine, Prospective Studies, Vaccines, Conjugate adverse effects, Arthritis, Juvenile drug therapy, Meningococcal Infections prevention & control, Meningococcal Vaccines adverse effects
Abstract

Background: Immunogenicity to meningococcal serogroup ACWY (MenACWY) conjugate vaccine has not been studied in immunocompromised minors with juvenile idiopathic arthritis (JIA) or inflammatory bowel disease (IBD). We determined immunogenicity of a MenACWY-TT vaccine in JIA and IBD patients at adolescent age and compared results to data from aged-matched healthy controls (HCs)., Methods: We performed a prospective observational cohort study in JIA and IBD patients (14-18 years old), who received a MenACWY vaccination during a nationwide catch-up campaign (2018-2019) in the Netherlands. Primary aim was to compare MenACWY polysaccharide-specific serum IgG geometric mean concentrations (GMCs) in patients with HCs and secondary between patients with or without anti-TNF therapy. GMCs were determined before and 3-6, 12, and 24 months postvaccination and compared with data from HCs at baseline and 12 months postvaccination. Serum bactericidal antibody (SBA) titers were determined in a subset of patients at 12 months postvaccination., Results: We included 226 JIA and IBD patients (66 % and 34 % respectively). GMCs were lower for MenA and MenW (GMC ratio 0·24 [0·17-0·34] and 0·16 [0·10-0·26] respectively, p < 0·01) in patients compared to HCs at 12 months postvaccination. Anti-TNF users had lower MenACWY GMCs postvaccination compared with those without anti-TNF (p < 0·01). The proportion protected (SBA ≥ 8) for MenW was reduced in anti-TNF users (76 % versus 92 % in non-anti-TNF and 100 % in HCs, p < 0.01)., Conclusion: The MenACWY conjugate vaccine was immunogenic in the vast majority of JIA and IBD patients at adolescent age, but seroprotection was lower in patients using anti-TNF agents. Therefore, an extra booster MenACWY vaccination should be considered., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Published
2023
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50. Development of a primary care screening algorithm for the early detection of patients at risk of primary antibody deficiency.

Author

Messelink MA, Berbers RM, van Montfrans JM, Ellerbroek PM, Gladiator A, Welsing PMJ, and Leavis H

Abstract

Background: Primary antibody deficiencies (PAD) are characterized by a heterogeneous clinical presentation and low prevalence, contributing to a median diagnostic delay of 3-10 years. This increases the risk of morbidity and mortality from undiagnosed PAD, which may be prevented with adequate therapy. To reduce the diagnostic delay of PAD, we developed a screening algorithm using primary care electronic health record (EHR) data to identify patients at risk of PAD. This screening algorithm can be used as an aid to notify general practitioners when further laboratory evaluation of immunoglobulins should be considered, thereby facilitating a timely diagnosis of PAD., Methods: Candidate components for the algorithm were based on a broad range of presenting signs and symptoms of PAD that are available in primary care EHRs. The decision on inclusion and weight of the components in the algorithm was based on the prevalence of these components among PAD patients and control groups, as well as clinical rationale., Results: We analyzed the primary care EHRs of 30 PAD patients, 26 primary care immunodeficiency patients and 58,223 control patients. The median diagnostic delay of PAD patients was 9.5 years. Several candidate components showed a clear difference in prevalence between PAD patients and controls, most notably the mean number of antibiotic prescriptions in the 4 years prior to diagnosis (5.14 vs. 0.48). The final algorithm included antibiotic prescriptions, diagnostic codes for respiratory tract and other infections, gastro-intestinal complaints, auto-immune symptoms, malignancies and lymphoproliferative symptoms, as well as laboratory values and visits to the general practitioner., Conclusions: In this study, we developed a screening algorithm based on a broad range of presenting signs and symptoms of PAD, which is suitable to implement in primary care. It has the potential to considerably reduce diagnostic delay in PAD, and will be validated in a prospective study. Trial registration The consecutive prospective study is registered at clinicaltrials.gov under NCT05310604., (© 2023. The Author(s).)

Published
2023
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