Publications

 

Publications

  • Correction: Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT. Journal of clinical immunology Marsh, R. A., Leiding, J. W., Logan, B. R., Griffith, L. M., Arnold, D. E., Haddad, E., Falcone, E. L., Yin, Z., Patel, K., Arbuckle, E., Bleesing, J. J., Sullivan, K. E., Heimall, J., Burroughs, L. M., Skoda-Smith, S., Chandrakasan, S., Yu, L. C., Oshrine, B. R., Cuvelier, G. D., Thakar, M. S., Chen, K., Teira, P., Shenoy, S., Phelan, R., Forbes, L. R., Martinez, C., Chellapandian, D., Davila Saldana, B. J., Shah, A. J., Weinacht, K. G., Joshi, A., Boulad, F., Quigg, T. C., Dvorak, C. C., Grossman, D., Torgerson, T., Graham, P., Prasad, V., Knutsen, A., Chong, H., Miller, H., de la Morena, M. T., DeSantes, K., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Stenger, E., Pai, S., Routes, J. M., Puck, J. M., Kapoor, N., Pulsipher, M. A., Malech, H. L., Parikh, S., Kang, E. M., submitted on behalf of the Primary Immune Deficiency Treatment Consortium 2020

    Abstract

    The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

    View details for DOI 10.1007/s10875-020-00852-0

    View details for PubMedID 32860171

  • Insight into the Pediatric and Adult Dichotomy of COVID-19: Age-Related Differences in the Immune Response to SARS-CoV-2 infection. Pediatric pulmonology Fialkowski, A., Gernez, Y., Arya, P., Weinacht, K. G., Bernard Kinane, T., Yonker, L. M. 2020

    Abstract

    The difference in morbidity and mortality between adult and pediatric COVID-19 infections is dramatic. Understanding pediatric-specific acute and delayed immune responses to SARS-CoV-2 is critical for the development of vaccination strategies, immune-targeted therapies, and treatment and prevention of MIS-C. The goal of this review is to highlight research developments in understanding of the immune responses to SARS-CoV-2 infections, with a specific focus on age-related immune responses. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ppul.24981

    View details for PubMedID 32710693

  • Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia. Blood advances Bosticardo, M., Pala, F., Calzoni, E., Delmonte, O. M., Dobbs, K., Gardner, C. L., Sacchetti, N., Kawai, T., Garabedian, E. K., Draper, D., Bergerson, J. R., DeRavin, S. S., Freeman, A. F., Gungor, T., Hartog, N., Holland, S. M., Kohn, D. B., Malech, H. L., Markert, M. L., Weinacht, K. G., Villa, A., Seet, C. S., Montel-Hagen, A., Crooks, G. M., Notarangelo, L. D. 2020; 4 (12): 2611–16

    Abstract

    The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34+ cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. We observed a similar defect in a patient carrying a null IL2RG mutation. In contrast, CD34+ cells from a patient carrying a missense IL2RG mutation reached full T-cell maturation, although cell numbers were significantly lower than in controls. CD34+ cells from patients carrying RAG mutations were able to differentiate to CD4+CD8+ cells, but not to CD3+TCRalphabeta+ cells. Finally, normal T-cell differentiation was observed in a patient with complete DiGeorge syndrome, consistent with the extra-hematopoietic nature of the defect. The ATO system may help determine whether T-cell deficiency reflects hematopoietic or thymic intrinsic abnormalities and define the exact stage at which T-cell differentiation is blocked.

    View details for DOI 10.1182/bloodadvances.2020001730

    View details for PubMedID 32556283

  • Excellent Outcomes Following Hematopoietic Cell Transplantation for Wiskott-Aldrich Syndrome: A PIDTC Report. Blood Burroughs, L., Petrovic, A., Brazauskas, R., Liu, X., Griffith, L. M., Ochs, H. D., Bleesing, J., Edwards, S., Dvorak, C. C., Chaudhury, S., Prockop, S., Quinones, R., Goldman, F., Quigg, T., Chandrakasan, S., Smith, A. R., Parikh, S. H., Davila Saldana, B. J., Thakar, M. S., Phelan, R., Shenoy, S., Forbes, L. R., Martinez, C. A., Chellapandian, D., Shereck, E., Miller, H., Kapoor, N., Barnum, J. L., Chong, H., Shyr, D., Chen, K., Abu-Arja, R. F., Shah, A., Weinacht, K., Moore, T. B., Joshi, A., DeSantes, K., Gillio, A. P., Cuvelier, G. D., Keller, M. D., Rozmus, J., Torgerson, T. R., Pulsipher, M. A., Haddad, E., Sullivan, K., Logan, B. R., Kohn, D. B., Puck, J. M., Notarangelo, L. D., Pai, S., Rawlings, D., Cowan, M. J. 2020

    Abstract

    Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. Here we report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers between 2005 and 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs. ≥5 years old at the time of HCT (94% vs. 66%, overall p=0.0008). OS was excellent regardless of donor type even in cord blood recipients (90%). Conditioning intensity did not impact OS, but was associated with donor T-cell and myeloid engraftment post-HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early post-HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) versus low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005 compared to prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution following either myeloablative or busulfan-containing reduced intensity conditioning. (www.clinicaltrials.gov NCT02064933.).

    View details for DOI 10.1182/blood.2019002939

    View details for PubMedID 32268350

  • A Case of G6PC3 Congenital Neutropenia, Misdiagnosed As Evans Syndrome Camacho, J., Brar, R., Chapman, C., Fernandez-Pol, S., Weinacht, K., Gernez, Y. SPRINGER/PLENUM PUBLISHERS. 2020: S131–S132
  • Autosomal Dominant JAK1 Gain-Of-Function Mutation Drives Myelopoiesis and Dysregulated T Helper Responses Leading To Severe Allergic Inflammation That Is Clinically Responsive To Ruxolitinib Biggs, C., Lin, E., Del Bel, K. L., Orben, F., Ragotte, R., Saferali, A., Mostafavi, S., Weinacht, K., de Bruin, L., Sharma, M., Shopsowitz, K., McKinnon, M. L., Vercauteren, S., Notarangelo, L., Lynn, F., Turvey, S. SPRINGER/PLENUM PUBLISHERS. 2020: S120
  • Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey. Frontiers in immunology Chan, A. Y., Leiding, J. W., Liu, X., Logan, B. R., Burroughs, L. M., Allenspach, E. J., Skoda-Smith, S., Uzel, G., Notarangelo, L. D., Slatter, M., Gennery, A. R., Smith, A. R., Pai, S., Jordan, M. B., Marsh, R. A., Cowan, M. J., Dvorak, C. C., Craddock, J. A., Prockop, S. E., Chandrakasan, S., Kapoor, N., Buckley, R. H., Parikh, S., Chellapandian, D., Oshrine, B. R., Bednarski, J. J., Cooper, M. A., Shenoy, S., Davila Saldana, B. J., Forbes, L. R., Martinez, C., Haddad, E., Shyr, D. C., Chen, K., Sullivan, K. E., Heimall, J., Wright, N., Bhatia, M., Cuvelier, G. D., Goldman, F. D., Meyts, I., Miller, H. K., Seidel, M. G., Vander Lugt, M. T., Bacchetta, R., Weinacht, K. G., Andolina, J. R., Caywood, E., Chong, H., de la Morena, M. T., Aquino, V. M., Shereck, E., Walter, J. E., Dorsey, M. J., Seroogy, C. M., Griffith, L. M., Kohn, D. B., Puck, J. M., Pulsipher, M. A., Torgerson, T. R. 2020; 11: 239

    Abstract

    Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.

    View details for DOI 10.3389/fimmu.2020.00239

    View details for PubMedID 32153572

  • Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT. Journal of clinical immunology Marsh, R. A., Leiding, J. W., Logan, B. R., Griffith, L. M., Arnold, D. E., Haddad, E., Falcone, E. L., Yin, Z., Patel, K., Arbuckle, E., Bleesing, J. J., Sullivan, K. E., Heimall, J., Burroughs, L. M., Skoda-Smith, S., Chandrakasan, S., Yu, L. C., Oshrine, B. R., Cuvelier, G. D., Thakar, M. S., Chen, K., Teira, P., Shenoy, S., Phelan, R., Forbes, L. R., Chellapandian, D., Davila Saldana, B. J., Shah, A. J., Weinacht, K. G., Joshi, A., Boulad, F., Quigg, T. C., Dvorak, C. C., Grossman, D., Torgerson, T., Graham, P., Prasad, V., Knutsen, A., Chong, H., Miller, H., de la Morena, M. T., DeSantes, K., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Stenger, E., Pai, S., Routes, J. M., Puck, J. M., Kapoor, N., Pulsipher, M. A., Malech, H. L., Parikh, S., Kang, E. M., submitted on behalf of the Primary Immune Deficiency Treatment Consortium 2019

    Abstract

    INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p=0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p=0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p=0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p=0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p=0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2years following allogeneic HCT.CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

    View details for DOI 10.1007/s10875-019-00659-8

    View details for PubMedID 31376032

  • Severe autoinflammation in four patients with C-terminal variants in CDC42 successfully treated with IL-1beta inhibition. The Journal of allergy and clinical immunology Gernez, Y., de Jesus, A. A., Alsaleem, H., Macaubas, C., Roy, A., Lovell, D., Jagadeesh, K. A., Alehashemi, S., Erdman, L., Grimley, M., Talarico, S., Bacchetta, R., Lewis, D. B., Canna, S. W., Laxer, R. M., Mellins, E. D., Goldbach-Mansky, R., Weinacht, K. G. 2019

    Abstract

    Four patients with novel variants in the C-terminal domain of CDC42, severe autoinflammation, constitutive elevation of serum interleukin 18, and predisposition to macrophage activation syndrome respond to treatment with interleukin-1beta signaling inhibition.

    View details for DOI 10.1016/j.jaci.2019.06.017

    View details for PubMedID 31271789

  • Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Bucciol, G., Nicholas, S. K., Calvo, P., Cant, A., Edgar, J. M., Espanol, T., Ferrua, F., Galicchio, M., Gennery, A. R., Hadzic, N., Hanson, I., Kusminsky, G., Lange, A., Lanternier, F., Mahlaoui, N., Moshous, D., Nademi, Z., Neven, B., Oleastro, M., Porta, F., Quarello, P., Silva, M., Slatter, M. A., Soncini, E., Stefanowicz, M., Tandoi, F., Teisseyre, M., Torgerson, T. R., Veys, P., Weinacht, K. G., Wolska-Kusnierz, B., Pirenne, J., de la Morena, M., Meyts, I. 2019; 143 (5): 1952-+