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1
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Giunta-Stibb H, Hackett B. Interstitial lung disease in the newborn. J Perinatol 2025; 45:13-23. [PMID: 38956315 DOI: 10.1038/s41372-024-02036-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 05/30/2024] [Accepted: 06/18/2024] [Indexed: 07/04/2024]
Abstract
Although relatively rare, interstitial lung diseases may present with respiratory distress in the newborn period. Most commonly these include developmental and growth disorders, disorders of surfactant synthesis and homeostasis, pulmonary interstitial glycogenosis, and neuroendocrine cell hyperplasia of infancy. Although the diagnosis of these disorders is sometimes made based on clinical presentation and imaging, due to the significant overlap between disorders and phenotypic variability, lung biopsy or, increasingly genetic testing is needed for diagnosis. These diseases may result in significant morbidity and mortality. Effective medical treatment options are in some cases limited and/or invasive. The genetic basis for some of these disorders has been identified, and with increased utilization of exome and whole genome sequencing even before lung biopsy, further insights into their genetic etiologies should become available.
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Affiliation(s)
- Hannah Giunta-Stibb
- Divisions of Neonatology and Pulmonology, Department of Pediatrics, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA.
| | - Brian Hackett
- Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
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2
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Klubdaeng A, Tovichien P. Clinical approach for pulmonary alveolar proteinosis in children. World J Clin Cases 2024; 12:6339-6345. [PMID: 39464322 PMCID: PMC11438685 DOI: 10.12998/wjcc.v12.i30.6339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/02/2024] [Accepted: 07/10/2024] [Indexed: 09/04/2024] Open
Abstract
In this editorial, we discuss the clinical implications of the article by Zhang et al. Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by excessive surfactant accumulation in the alveoli. It is classified into four categories: Primary, secondary, congenital, and unclassified forms. Primary PAP is caused by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signaling, which is necessary for the clearance of surfactant by alveolar macrophages. It is further divided into autoimmune PAP, caused by anti-GM-CSF antibodies blocking alveolar macrophage activation, and hereditary PAP, resulting from mutations in genes encoding GM-CSF receptors. Secondary PAP develops due to conditions affecting the number or function of alveolar macrophages, such as infections, immunodeficiency, hematological disorders, or exposure to inhaled toxins. Congenital PAP is linked to mutations in genes involved in surfactant protein production. Notably, the causes of PAP differ between children and adults. Diagnostic features include a characteristic "crazy-paving" pattern on high-resolution computed tomography, accompanied by diffuse ground-glass opacities and interlobular septal thickening. The presence of PAP can be identified by the milky appearance of bronchoalveolar lavage fluid and histological evaluation. However, these methods cannot definitively determine the cause of PAP. Whole lung lavage remains the standard treatment, often combined with specific therapies based on the underlying cause.
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Affiliation(s)
- Anuvat Klubdaeng
- Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Prakarn Tovichien
- Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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3
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Borie R, Berteloot L, Kannengiesser C, Griese M, Cazes A, Crestani B, Hadchouel A, Debray MP. Rare genetic interstitial lung diseases: a pictorial essay. Eur Respir Rev 2024; 33:240101. [PMID: 39537246 PMCID: PMC11558537 DOI: 10.1183/16000617.0101-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/22/2024] [Indexed: 11/16/2024] Open
Abstract
The main monogenic causes of pulmonary fibrosis in adults are mutations in telomere-related genes. These mutations may be associated with extrapulmonary signs (hepatic, haematological and dermatological) and typically present radiologically as usual interstitial pneumonia or unclassifiable fibrosis. In children, the monogenic causes of pulmonary fibrosis are dominated by mutations in surfactant-related genes. These mutations are not associated with extrapulmonary signs and often manifest radiologically as unclassifiable fibrosis with cysts that can lead to chest wall deformities in adults. This review discusses these mutations, along with most of the monogenic causes of interstitial lung disease, including interferon-related genes, mutations in genes causing cystic lung disease, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lysinuric protein intolerance and lysosomal storage disorders, and their pulmonary and extrapulmonary manifestations.
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Affiliation(s)
- Raphael Borie
- Université Paris Cité, Inserm, PHERE, Paris, France
- Hôpital Bichat, APHP, Service de Pneumologie A, Centre constitutif du centre de référence des Maladies Pulmonaires Rares, FHU APOLLO, Paris, France
| | - Laureline Berteloot
- Service d'Imagerie Pédiatrique, Hôpital universitaire Necker-Enfants malades, Paris, France
- INSERM U1163, Paris, France
| | | | - Matthias Griese
- Department of Pediatric Pneumology, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, German Center for Lung Research, Munich, Germany
| | - Aurelie Cazes
- Département d'Anatomo-Pathologie, Hôpital Bichat, AP-HP, Paris, France
| | - Bruno Crestani
- Université Paris Cité, Inserm, PHERE, Paris, France
- Hôpital Bichat, APHP, Service de Pneumologie A, Centre constitutif du centre de référence des Maladies Pulmonaires Rares, FHU APOLLO, Paris, France
| | - Alice Hadchouel
- AP-HP, Hôpital Universitaire Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France
- INSERM U1151, Institut Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Marie Pierre Debray
- Service de Radiologie, Hopital Bichat, APHP, Université Paris Cité, Paris, France
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4
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Lettieri S, Bonella F, Marando VA, Franciosi AN, Corsico AG, Campo I. Pathogenesis-driven treatment of primary pulmonary alveolar proteinosis. Eur Respir Rev 2024; 33:240064. [PMID: 39142709 PMCID: PMC11322829 DOI: 10.1183/16000617.0064-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/28/2024] [Indexed: 08/16/2024] Open
Abstract
Pulmonary alveolar proteinosis (PAP) is a syndrome that results from the accumulation of lipoproteinaceous material in the alveolar space. According to the underlying pathogenetic mechanisms, three different forms have been identified, namely primary, secondary and congenital. Primary PAP is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling due to the presence of neutralising autoantibodies (autoimmune PAP) or GM-CSF receptor genetic defects (hereditary PAP), which results in dysfunctional alveolar macrophages with reduced phagocytic clearance of particles, cholesterol and surfactant. The serum level of GM-CSF autoantibody is the only disease-specific biomarker of autoimmune PAP, although it does not correlate with disease severity. In PAP patients with normal serum GM-CSF autoantibody levels, elevated serum GM-CSF levels is highly suspicious for hereditary PAP. Several biomarkers have been correlated with disease severity, although they are not specific for PAP. These include lactate dehydrogenase, cytokeratin 19 fragment 21.1, carcinoembryonic antigen, neuron-specific enolase, surfactant proteins, Krebs von Lungen 6, chitinase-3-like protein 1 and monocyte chemotactic proteins. Finally, increased awareness of the disease mechanisms has led to the development of pathogenesis-based treatments, such as GM-CSF augmentation and cholesterol-targeting therapies.
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Affiliation(s)
- Sara Lettieri
- Pneumology Unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Francesco Bonella
- Center for interstitial and rare lung diseases, Ruhrlandklinik, University of Essen, Essen, Germany
| | | | | | - Angelo Guido Corsico
- Pneumology Unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy
- Department of Internal Medicine, University of Pavia, Pavia, Italy
| | - Ilaria Campo
- Pneumology Unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy
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5
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Calder AD, Perucca G, Johnson SM, Pandey AR, Moshal K, Kusters MA. Lung infections in immunocompromised children. Pediatr Radiol 2024; 54:530-547. [PMID: 37589764 DOI: 10.1007/s00247-023-05735-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/18/2023]
Abstract
Pulmonary infection is the leading cause of infectious morbidity and mortality in children with immune defects. We provide a comprehensive review of lung infections in immunocompromised children, with a focus on imaging findings and imaging-based management. We include an overview of the immune defences of the respiratory tract, the aetiologies of immune defects in children, the features of specific infections and important differential diagnoses and describe diagnostic strategies using imaging and non-imaging-based techniques.
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Affiliation(s)
- Alistair D Calder
- Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
| | - Giulia Perucca
- Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK
| | - Sarah May Johnson
- Paediatric Infectious Diseases, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Ashwin R Pandey
- Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Karyn Moshal
- Paediatric Infectious Diseases, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Maaike A Kusters
- Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
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6
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Neehus AL, Carey B, Landekic M, Panikulam P, Deutsch G, Ogishi M, Arango-Franco CA, Philippot Q, Modaresi M, Mohammadzadeh I, Corcini Berndt M, Rinchai D, Le Voyer T, Rosain J, Momenilandi M, Martin-Fernandez M, Khan T, Bohlen J, Han JE, Deslys A, Bernard M, Gajardo-Carrasco T, Soudée C, Le Floc'h C, Migaud M, Seeleuthner Y, Jang MS, Nikolouli E, Seyedpour S, Begueret H, Emile JF, Le Guen P, Tavazzi G, Colombo CNJ, Marzani FC, Angelini M, Trespidi F, Ghirardello S, Alipour N, Molitor A, Carapito R, Mazloomrezaei M, Rokni-Zadeh H, Changi-Ashtiani M, Brouzes C, Vargas P, Borghesi A, Lachmann N, Bahram S, Crestani B, Fayon M, Galode F, Pahari S, Schlesinger LS, Marr N, Bogunovic D, Boisson-Dupuis S, Béziat V, Abel L, Borie R, Young LR, Deterding R, Shahrooei M, Rezaei N, Parvaneh N, Craven D, Gros P, Malo D, Sepulveda FE, Nogee LM, Aladjidi N, Trapnell BC, Casanova JL, Bustamante J. Human inherited CCR2 deficiency underlies progressive polycystic lung disease. Cell 2024; 187:390-408.e23. [PMID: 38157855 PMCID: PMC10842692 DOI: 10.1016/j.cell.2023.11.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 09/26/2023] [Accepted: 11/29/2023] [Indexed: 01/03/2024]
Abstract
We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.
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Affiliation(s)
- Anna-Lena Neehus
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France.
| | - Brenna Carey
- Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA
| | - Marija Landekic
- Department of Medicine, McGill University, Montreal, QC H3G 0B1, Canada
| | - Patricia Panikulam
- Molecular Basis of Altered Immune Homeostasis, INSERM U1163, Paris Cité University, Imagine Institute, Paris 75015, France
| | - Gail Deutsch
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
| | - Masato Ogishi
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
| | - Carlos A Arango-Franco
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia
| | - Quentin Philippot
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Mohammadreza Modaresi
- Pediatric Pulmonary and Sleep Medicine Department, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran; Pediatric Pulmonary Disease and Sleep Medicine Research Center, Children's Medical Center, Pediatric Center of Excellence, Tehran University of Medical Science, Tehran, Iran
| | - Iraj Mohammadzadeh
- Non-communicable Pediatric Diseases Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; USERN Office, Babol University of Medical Sciences, Babol, Iran
| | - Melissa Corcini Berndt
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Darawan Rinchai
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
| | - Tom Le Voyer
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Jérémie Rosain
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris 75015, France
| | - Mana Momenilandi
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Marta Martin-Fernandez
- Center for Inborn Errors of Immunity, Icahn School, New York, NY 10029, USA; Precision Immunology Institute, Icahn School, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School, New York, NY 10029, USA; Department of Pediatrics, Icahn School, New York, NY 10029, USA; Department of Microbiology, Icahn School, New York, NY 10029, USA
| | - Taushif Khan
- The Jackson Laboratory, Farmington, CT 06032, USA
| | - Jonathan Bohlen
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Ji Eun Han
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
| | - Alexandre Deslys
- Leukomotion Laboratory, Paris Cité University, INSERM UMR-S1151, CNRS UMR-S8253, Necker Hospital for Sick Children, Paris 75015, France
| | - Mathilde Bernard
- Leukomotion Laboratory, Paris Cité University, INSERM UMR-S1151, CNRS UMR-S8253, Necker Hospital for Sick Children, Paris 75015, France; Curie Institute, PSL Research University, CNRS, UMR144, Paris 75248, France; Pierre-Gilles de Gennes Institute, PSL Research University, Paris 75005, France
| | - Tania Gajardo-Carrasco
- Molecular Basis of Altered Immune Homeostasis, INSERM U1163, Paris Cité University, Imagine Institute, Paris 75015, France
| | - Camille Soudée
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Corentin Le Floc'h
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Mélanie Migaud
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Yoann Seeleuthner
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France
| | - Mi-Sun Jang
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover 30625, Germany
| | - Eirini Nikolouli
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover 30625, Germany
| | - Simin Seyedpour
- Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran; Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hugues Begueret
- Department of Pathology, Haut-Lévèque Hospital, CHU Bordeaux, Pessac 33604, France
| | | | - Pierre Le Guen
- Pulmonology Service, Bichat Hospital, AP-HP and Paris Cité University, INSERM U1152, PHERE, Paris 75018, France
| | - Guido Tavazzi
- Department of Surgical, Pediatric, and Diagnostic Sciences, University of Pavia, Pavia 27100, Italy; Anesthesia and Intensive Care, San Matteo Research Hospital, Pavia 27100, Italy
| | - Costanza Natalia Julia Colombo
- Anesthesia and Intensive Care, San Matteo Research Hospital, Pavia 27100, Italy; Experimental Medicine, University of Pavia, Pavia 27100, Italy
| | | | - Micol Angelini
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia 27100, Italy
| | - Francesca Trespidi
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia 27100, Italy
| | - Stefano Ghirardello
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia 27100, Italy
| | - Nasrin Alipour
- Molecular Immuno-Rheumatology Laboratory, INSERM UMR_S1109, GENOMAX Platform, Faculty of Medicine, OMICARE University Hospital Federation, Immunology and Hematology Research Center, Research Center in Biomedicine of Strasbourg (CRBS), Federation of Translational Medicine of Strasbourg (FMTS), University of Strasbourg, Strasbourg 67081, France; Interdisciplinary Thematic Institute (ITI) of Precision Medicine of Strasbourg, University of Strasbourg, Strasbourg 67081, France
| | - Anne Molitor
- Molecular Immuno-Rheumatology Laboratory, INSERM UMR_S1109, GENOMAX Platform, Faculty of Medicine, OMICARE University Hospital Federation, Immunology and Hematology Research Center, Research Center in Biomedicine of Strasbourg (CRBS), Federation of Translational Medicine of Strasbourg (FMTS), University of Strasbourg, Strasbourg 67081, France; Interdisciplinary Thematic Institute (ITI) of Precision Medicine of Strasbourg, University of Strasbourg, Strasbourg 67081, France
| | - Raphael Carapito
- Molecular Immuno-Rheumatology Laboratory, INSERM UMR_S1109, GENOMAX Platform, Faculty of Medicine, OMICARE University Hospital Federation, Immunology and Hematology Research Center, Research Center in Biomedicine of Strasbourg (CRBS), Federation of Translational Medicine of Strasbourg (FMTS), University of Strasbourg, Strasbourg 67081, France; Interdisciplinary Thematic Institute (ITI) of Precision Medicine of Strasbourg, University of Strasbourg, Strasbourg 67081, France; Immunology Laboratory, Biology Technical Platform, Biology Pole, New Civil Hospital, Strasbourg 67091, France
| | | | - Hassan Rokni-Zadeh
- Department of Medical Biotechnology, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
| | - Majid Changi-Ashtiani
- School of Mathematics, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Chantal Brouzes
- Laboratory of Onco-Hematology, Necker Hospital for Sick Children, Paris 75015, France
| | - Pablo Vargas
- Leukomotion Laboratory, Paris Cité University, INSERM UMR-S1151, CNRS UMR-S8253, Necker Hospital for Sick Children, Paris 75015, France; Curie Institute, PSL Research University, CNRS, UMR144, Paris 75248, France; Pierre-Gilles de Gennes Institute, PSL Research University, Paris 75005, France
| | - Alessandro Borghesi
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia 27100, Italy; School of Life Sciences, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland
| | - Nico Lachmann
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover 30625, Germany; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover 30625, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover 30625, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover 30625, Germany
| | - Seiamak Bahram
- Molecular Immuno-Rheumatology Laboratory, INSERM UMR_S1109, GENOMAX Platform, Faculty of Medicine, OMICARE University Hospital Federation, Immunology and Hematology Research Center, Research Center in Biomedicine of Strasbourg (CRBS), Federation of Translational Medicine of Strasbourg (FMTS), University of Strasbourg, Strasbourg 67081, France; Interdisciplinary Thematic Institute (ITI) of Precision Medicine of Strasbourg, University of Strasbourg, Strasbourg 67081, France; Immunology Laboratory, Biology Technical Platform, Biology Pole, New Civil Hospital, Strasbourg 67091, France
| | - Bruno Crestani
- Pulmonology Service, Bichat Hospital, AP-HP and Paris Cité University, INSERM U1152, PHERE, Paris 75018, France
| | - Michael Fayon
- Department of Pediatrics, Bordeaux Hospital, University of Bordeaux, 33000 Bordeaux, France; Cardiothoracic Research Center, U1045 INSERM, 33000 Bordeaux, France
| | - François Galode
- Department of Pediatrics, Bordeaux Hospital, University of Bordeaux, 33000 Bordeaux, France; Cardiothoracic Research Center, U1045 INSERM, 33000 Bordeaux, France
| | - Susanta Pahari
- Host-Pathogen Interactions and Population Health programs, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Larry S Schlesinger
- Host-Pathogen Interactions and Population Health programs, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Nico Marr
- Department of Human Immunology, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Institute of Translational Immunology, Brandenburg Medical School, Brandenburg 14770, Germany
| | - Dusan Bogunovic
- Center for Inborn Errors of Immunity, Icahn School, New York, NY 10029, USA; Precision Immunology Institute, Icahn School, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School, New York, NY 10029, USA; Department of Pediatrics, Icahn School, New York, NY 10029, USA; Department of Microbiology, Icahn School, New York, NY 10029, USA
| | - Stéphanie Boisson-Dupuis
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
| | - Vivien Béziat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
| | - Raphael Borie
- Pulmonology Service, Bichat Hospital, AP-HP and Paris Cité University, INSERM U1152, PHERE, Paris 75018, France
| | - Lisa R Young
- Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Robin Deterding
- Pediatric Pulmonary Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA
| | - Mohammad Shahrooei
- Dr. Shahrooei Laboratory, 22 Bahman St., Ashrafi Esfahani Blvd, Tehran, Iran; Clinical and Diagnostic Immunology, KU Leuven, Leuven 3000, Belgium
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity to Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Parvaneh
- Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
| | - Daniel Craven
- Division of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA
| | - Philippe Gros
- Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 2B4, Canada
| | - Danielle Malo
- Department of Medicine, McGill University, Montreal, QC H3G 0B1, Canada; Department of Human Genetics, McGill University, Montreal, QC H3G 0B1, Canada
| | - Fernando E Sepulveda
- Molecular Basis of Altered Immune Homeostasis, INSERM U1163, Paris Cité University, Imagine Institute, Paris 75015, France
| | - Lawrence M Nogee
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nathalie Aladjidi
- Pediatric Oncology Hematology Unit, Clinical Investigation Center (CIC), Multi-theme-CIC (CICP), University Hospital Bordeaux, Bordeaux 33000, France
| | - Bruce C Trapnell
- Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Departments of Medicine and Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA; Department of Pediatrics, Necker Hospital for Sick Children, Paris 75015, France.
| | - Jacinta Bustamante
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris 75015, France.
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7
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Purswani P, Hall G, Moorthy G, Mousallem T. Clinical implications of inherited chromosomally integrated HHV-6 in the setting of ADA-deficient severe combined immunodeficiency (SCID). THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:3553-3555.e1. [PMID: 37567344 DOI: 10.1016/j.jaip.2023.07.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/13/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023]
Affiliation(s)
- Pooja Purswani
- Department of Pediatrics, Duke University Medical Center, Durham, NC
| | - Geoffrey Hall
- Department of Pediatrics, Duke University Medical Center, Durham, NC
| | - Ganga Moorthy
- Department of Pediatrics, Duke University Medical Center, Durham, NC
| | - Talal Mousallem
- Department of Pediatrics, Duke University Medical Center, Durham, NC.
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8
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Murguia-Favela L, Suresh S, Wright NAM, Alvi S, Tehseen S, Hernandez-Trujillo V, Seroogy CM, Haddad E, Nieves D, Hershfield MS, Walter JE, Pettiford L, Kamani NR, Keller MD, Pham-Huy A, Grunebaum E. Long-Term Immune Reconstitution in ADA-Deficient Patients Treated With Elapegademase: A Real-World Experience. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1725-1733. [PMID: 36736953 DOI: 10.1016/j.jaip.2023.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 02/04/2023]
Abstract
BACKGROUND ADAGEN, a bovine-based enzyme replacement therapy (ERT), has been used to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). In 2018, ADAGEN was replaced by REVCOVI (elapegademase), a modified bovine recombinant protein. OBJECTIVE To determine the real-life long-term benefits of REVCOVI in ADA-SCID. METHODS Data on ERT, infectious and noninfectious complications, and metabolic and immune evaluations were collected from 17 patients with ADA-SCID treated for 6 months or more with REVCOVI. RESULTS Eleven patients had previously received ADAGEN for 16 to 324 months, whereas 6 patients were ERT-naive. REVCOVI was administered twice weekly at 0.4 mg/kg/wk in ERT-naive patients, whereas patients transitioning to REVCOVI from ADAGEN typically continued at the same frequency and equivalent dosing as ADAGEN, resulting in a significantly lower (P = .007) total REVCOVI dose in the transitioning group. REVCOVI treatment in the ERT-naive group led to the resolution of many clinical and laboratory complications of ADA deficiency, whereas there were no new adverse effects among the transitioning patients. REVCOVI treatment increased plasma ADA activity and decreased dAXP (which included deoxyadenosine mono-, di-, and tri phosphate) among most patients, effects that persisted throughout the 7- to 37-month treatment periods, except in 2 patients with incomplete adherence. Among some patients, after 0.5 to 6 months, injection frequency was reduced to once a week, while maintaining adequate metabolic profiles. All ERT-naive infants treated with REVCOVI demonstrated an increase in the number of CD4+ T and CD19+ B cells, although these counts remained stable but lower than normal in most transitioning patients. CONCLUSIONS REVCOVI is effective for the management of ADA-SCID.
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Affiliation(s)
- Luis Murguia-Favela
- Section of Hematology/Immunology, Department of Pediatrics, Alberta Children's Hospital and the University of Calgary, Calgary, Alberta, Canada
| | - Sneha Suresh
- Division of IHOPE, Department of Pediatrics, University of Alberta, Stollery Children's Hospital, Edmonton, Alberta, Canada
| | - Nicola A M Wright
- Section of Hematology/Immunology, Department of Pediatrics, Alberta Children's Hospital and the University of Calgary, Calgary, Alberta, Canada
| | - Saima Alvi
- Division of Pediatric Hematology/Oncology, Jim Pattison Children's Hospital, Saskatoon, Saskatchewan, Canada
| | - Sarah Tehseen
- Division of Hematology/Oncology and Transfusion Medicine, Jim Pattison Children's Hospital, Saskatoon, Saskatchewan, Canada
| | | | - Christine M Seroogy
- Division of Allergy, Immunology & Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison, Wis
| | - Elie Haddad
- Division of Immunology and Rheumatology, Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
| | - Daime Nieves
- Division of Pediatric Allergy and Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St Petersburg, Fla
| | - Michael S Hershfield
- Division of Medicine and Biochemistry, Duke University Medical Center, Durham, NC
| | - Jolan E Walter
- Division of Pediatric Allergy and Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St Petersburg, Fla
| | - Leah Pettiford
- Division of Allergy and Immunology, Children's National Hospital, Washington, DC
| | - Naynesh R Kamani
- Division of Allergy and Immunology, Children's National Hospital, Washington, DC
| | - Michael D Keller
- Division of Allergy and Immunology, Children's National Hospital, Washington, DC
| | - Anne Pham-Huy
- Division of Infectious Diseases, Immunology and Allergy, Children's Hospital Eastern Ontario, Ottawa, Ontario, Canada
| | - Eyal Grunebaum
- Division of Immunology and Allergy, The Hospital for Sick Children, Toronto, Ontario, Canada.
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9
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Grunebaum E, Booth C, Cuvelier GDE, Loves R, Aiuti A, Kohn DB. Updated Management Guidelines for Adenosine Deaminase Deficiency. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1665-1675. [PMID: 36736952 DOI: 10.1016/j.jaip.2023.01.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/23/2022] [Accepted: 01/07/2023] [Indexed: 02/04/2023]
Abstract
Inherited defects in the adenosine deaminase (ADA) gene typically cause severe combined immunodeficiency. In addition to infections, ADA-deficient patients can present with neurodevelopmental, behavioral, hearing, skeletal, lung, heart, skin, kidney, urogenital, and liver abnormalities. Some patients also suffer from autoimmunity and malignancies. In recent years, there have been remarkable advances in the management of ADA deficiency. Most ADA-deficient patients can be identified by newborn screening for severe combined immunodeficiency, which facilitates early diagnosis and treatment of asymptomatic infants. Most patients benefit from enzyme replacement therapy (ERT). Allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor or HLA-matched family member donor with no conditioning is currently the preferable treatment. When matched sibling donor or matched family member donor is not available, autologous ADA gene therapy with nonmyeloablative conditioning and ERT withdrawal, which is reported in recent studies to result in 100% overall survival and 90% to 95% engraftment, should be pursued. If gene therapy is not immediately available, ERT can be continued for a few years, although its excessive cost might be prohibitive. The recent improved outcome of hematopoietic cell transplantation using HLA-mismatched family-related donors or HLA-matched unrelated donors, after reduced-intensity conditioning, suggests that such procedures might also be considered rather than continuing ERT for prolonged periods. Long-term follow-up will further assist in determining the optimal treatment approach for ADA-deficient patients.
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Affiliation(s)
- Eyal Grunebaum
- Division of Immunology and Allergy, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Claire Booth
- Department of Paediatric Immunology and Gene Therapy, Great Ormond Street Hospital, London, United Kingdom
| | - Geoffrey D E Cuvelier
- Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Robyn Loves
- Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, and the Università Vita-Salute San Raffaele, Milan, Italy
| | - Donald B Kohn
- Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, Calif
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10
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Dąbrowska-Leonik N, Piątosa B, Słomińska E, Bohynikova N, Bernat-Sitarz K, Bernatowska E, Wolska-Kuśnierz B, Kałwak K, Kołtan S, Dąbrowska A, Goździk J, Ussowicz M, Pac M. National experience with adenosine deaminase deficiency related SCID in Polish children. Front Immunol 2023; 13:1058623. [PMID: 36685585 PMCID: PMC9853035 DOI: 10.3389/fimmu.2022.1058623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Introduction Deficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient's general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis. Material and methods We retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022. Results All patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy. Conclusions It is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID.
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Affiliation(s)
- Nel Dąbrowska-Leonik
- Department of Immunology, Children’s Memorial Health Institute, Warsaw, Poland,*Correspondence: Nel Dąbrowska-Leonik,
| | - Barbara Piątosa
- Histocompatibility Laboratory, Children’s Memorial Health Institute (IPCZD), Warsaw, Masovian, Poland
| | - Ewa Słomińska
- Biochemistry Department, Medical University of Gdansk, Gdansk, Poland
| | - Nadezda Bohynikova
- Department of Immunology, Children’s Memorial Health Institute, Warsaw, Poland
| | | | - Ewa Bernatowska
- Department of Immunology, Children’s Memorial Health Institute, Warsaw, Poland
| | | | - Krzysztof Kałwak
- Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wroclaw Medical University, Wroclaw, Poland
| | - Sylwia Kołtan
- Department of Pediatrics, Hematology and Oncology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Anna Dąbrowska
- Department of Pediatrics, Hematology and Oncology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Jolanta Goździk
- Department of Clinical Immunology and Transplantology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Marek Ussowicz
- Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wroclaw Medical University, Wroclaw, Poland
| | - Małgorzata Pac
- Department of Immunology, Children’s Memorial Health Institute, Warsaw, Poland
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11
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Gao X, Michel K, Griese M. Interstitial Lung Disease in Immunocompromised Children. Diagnostics (Basel) 2022; 13:diagnostics13010064. [PMID: 36611354 PMCID: PMC9818431 DOI: 10.3390/diagnostics13010064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The range of pulmonary complications beyond infections in pediatric immunocompromised patients is broad but not well characterized. Our goal was to assess the spectrum of disorders with a focus on interstitial lung diseases (ILD) in immunodeficient patients. METHODS We reviewed 217 immunocompromised children attending a specialized pneumology service during a period of 23 years. We assigned molecular diagnoses where possible and categorized the underlying immunological conditions into inborn errors of immunity or secondary immunodeficiencies according to the IUIS and the pulmonary conditions according to the chILD-EU classification system. RESULTS Among a wide array of conditions, opportunistic and chronic infections were the most frequent. ILD had a 40% prevalence. Of these children, 89% had a CT available, and 66% had a lung biopsy, which supported the diagnosis of ILD in 95% of cases. Histology was often lymphocyte predominant with the histo-pattern of granulomatous and lymphocytic interstitial lung disease (GLILD), follicular bronchiolitis or lymphocytic interstitial pneumonitis. Of interest, DIP, PAP and NSIP were also diagnosed. ILD was detected in several immunological disorders not yet associated with ILD. CONCLUSIONS Specialized pneumological expertise is necessary to manage the full spectrum of respiratory complications in pediatric immunocompromised patients.
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Affiliation(s)
| | | | - Matthias Griese
- Correspondence: ; Tel.: +49-89-4400-57870; Fax: +49-89-4400-57872
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12
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Gutierrez MJ, Nino G, Sun D, Restrepo-Gualteros S, Sadreameli SC, Fiorino EK, Wu E, Vece T, Hagood JS, Maglione PJ, Kurland G, Koumbourlis A, Sullivan KE. The lung in inborn errors of immunity: From clinical disease patterns to molecular pathogenesis. J Allergy Clin Immunol 2022; 150:1314-1324. [PMID: 36244852 PMCID: PMC9826631 DOI: 10.1016/j.jaci.2022.08.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 11/06/2022]
Abstract
In addition to being a vital organ for gas exchange, the lung is a crucial immune organ continuously exposed to the external environment. Genetic defects that impair immune function, called inborn errors of immunity (IEI), often have lung disease as the initial and/or primary manifestation. Common types of lung disease seen in IEI include infectious complications and a diverse group of diffuse interstitial lung diseases. Although lung damage in IEI has been historically ascribed to recurrent infections, contributions from potentially targetable autoimmune and inflammatory pathways are now increasingly recognized. This article provides a practical guide to identifying the diverse pulmonary disease patterns in IEI based on lung imaging and respiratory manifestations, and integrates this clinical information with molecular mechanisms of disease and diagnostic assessments in IEI. We cover the entire IEI spectrum, including immunodeficiencies and immune dysregulation with monogenic autoimmunity and autoinflammation, as well as recently described IEI with pulmonary manifestations. Although the pulmonary manifestations of IEI are highly relevant for all age groups, special emphasis is placed on the pediatric population, because initial presentations often occur during childhood. We also highlight the pivotal role of genetic testing in the diagnosis of IEI involving the lungs and the critical need to develop multidisciplinary teams for the challenging evaluation of these rare but potentially life-threatening disorders.
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Affiliation(s)
- Maria J Gutierrez
- Division of Pediatric Allergy, Immunology and Rheumatology, Johns Hopkins University, Baltimore, Md.
| | - Gustavo Nino
- Division of Pediatric Pulmonary and Sleep Medicine, Children's National Hospital, Washington, DC; Department of Pediatrics, George Washington University School of Medicine, Washington, DC
| | - Di Sun
- Division of Pediatric Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pa
| | - Sonia Restrepo-Gualteros
- Department of Pediatrics, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia; Division of Pediatric Pulmonology, Fundacion Hospital La Misericordia, Bogotá, Colombia
| | - Sarah C Sadreameli
- Division of Pediatric Pulmonology and Sleep Medicine, Johns Hopkins University, Baltimore, Md
| | - Elizabeth K Fiorino
- Departments of Science Education and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Eveline Wu
- Division of Pediatric Allergy, Immunology and Rheumatology, University of North Carolina, Chapel Hill, NC
| | - Timothy Vece
- Division of Pediatric Pulmonology, University of North Carolina, Chapel Hill, NC
| | - James S Hagood
- Division of Pediatric Pulmonology, University of North Carolina, Chapel Hill, NC
| | - Paul J Maglione
- Division of Allergy and Immunology, Boston University, Boston, Mass
| | - Geoffrey Kurland
- Division of Pediatric Pulmonology and Sleep Medicine, University of Pittsburgh, Pittsburgh, Pa
| | - Anastassios Koumbourlis
- Division of Pediatric Pulmonary and Sleep Medicine, Children's National Hospital, Washington, DC; Department of Pediatrics, George Washington University School of Medicine, Washington, DC
| | - Kathleen E Sullivan
- Division of Pediatric Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pa
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13
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Cuvelier GDE, Logan BR, Prockop SE, Buckley RH, Kuo CY, Griffith LM, Liu X, Yip A, Hershfield MS, Ayoub PG, Moore TB, Dorsey MJ, O'Reilly RJ, Kapoor N, Pai SY, Kapadia M, Ebens CL, Forbes Satter LR, Burroughs LM, Petrovic A, Chellapandian D, Heimall J, Shyr DC, Rayes A, Bednarski JJ, Chandra S, Chandrakasan S, Gillio AP, Madden L, Quigg TC, Caywood EH, Dávila Saldaña BJ, DeSantes K, Eissa H, Goldman FD, Rozmus J, Shah AJ, Vander Lugt MT, Thakar MS, Parrott RE, Martinez C, Leiding JW, Torgerson TR, Pulsipher MA, Notarangelo LD, Cowan MJ, Dvorak CC, Haddad E, Puck JM, Kohn DB. Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC. Blood 2022; 140:685-705. [PMID: 35671392 PMCID: PMC9389638 DOI: 10.1182/blood.2022016196] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/21/2022] [Indexed: 11/20/2022] Open
Abstract
Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.
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Affiliation(s)
- Geoffrey D E Cuvelier
- Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Brent R Logan
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI
| | - Susan E Prockop
- Stem Cell Transplant Service, Dana Farber Cancer Institute/Boston Children's Hospital, Boston, MA
| | | | - Caroline Y Kuo
- Division of Allergy, Immunology, Rheumatology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Linda M Griffith
- Division of Allergy, Immunology and Transplantation, National Institutes of Allergy, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD
| | - Xuerong Liu
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI
| | - Alison Yip
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | | | - Paul G Ayoub
- Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA
| | - Theodore B Moore
- Department of Pediatric Hematology-Oncology, Mattel Children's Hospital, University of California, Los Angeles, CA
| | - Morna J Dorsey
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | - Richard J O'Reilly
- Stem Cell Transplantation and Cellular Therapy, MSK Kids, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Neena Kapoor
- Division of Hematology, Oncology and Blood and Marrow Transplant, Children's Hospital, Los Angeles, CA
| | - Sung-Yun Pai
- Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Malika Kapadia
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA
| | - Christen L Ebens
- Division of Pediatric Blood and Marrow Transplant and Cellular Therapy, MHealth Fairview Masonic Children's Hospital, Minneapolis, MN
| | - Lisa R Forbes Satter
- Immunology, Allergy and Retrovirology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Lauri M Burroughs
- Fred Hutchinson Cancer Research Center, University of Washington, Department of Pediatrics and Seattle Children's Hospital, Seattle, WA
| | - Aleksandra Petrovic
- Fred Hutchinson Cancer Research Center, University of Washington, Department of Pediatrics and Seattle Children's Hospital, Seattle, WA
| | - Deepak Chellapandian
- Center for Cell and Gene Therapy for Non-Malignant Conditions, Johns Hopkins All Children's Hospital, St Petersburg, FL
| | - Jennifer Heimall
- Division of Allergy and Immunology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA
| | - David C Shyr
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Lucile Packard Children's Hospital, Stanford School of Medicine, Palo Alto, CA
| | - Ahmad Rayes
- Primary Children's Hospital, University of Utah, Salt Lake City, UT
| | | | - Sharat Chandra
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | | | - Alfred P Gillio
- Children's Cancer Institute, Hackensack University Medical Center, Hackensack, NJ
| | - Lisa Madden
- Methodist Children's Hospital of South Texas, San Antonio, TX
| | - Troy C Quigg
- Pediatric Blood and Marrow Transplant and Cellular Therapy Program, Helen DeVos Children's Hospital, Michigan State University College of Human Medicine, Grand Rapids, MI
| | - Emi H Caywood
- Nemours Children's Health, Thomas Jefferson University, Wilmington, DE
| | | | - Kenneth DeSantes
- Division of Pediatric Hematology-Oncology & Bone Marrow Transplant, University of Wisconsin, American Family Children's Hospital, Madison, WI
| | - Hesham Eissa
- Division of Pediatric Hematology-Oncology-BMT, Aurora, CO
| | - Frederick D Goldman
- Division of Pediatric Hematology and Oncology and Bone Marrow Transplant, University of Alabama at Birmingham, Birmingham, AL
| | - Jacob Rozmus
- British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Ami J Shah
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Lucile Packard Children's Hospital, Stanford School of Medicine, Palo Alto, CA
| | - Mark T Vander Lugt
- Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
| | - Monica S Thakar
- Fred Hutchinson Cancer Research Center, University of Washington, Department of Pediatrics and Seattle Children's Hospital, Seattle, WA
| | | | - Caridad Martinez
- Hematology/Oncology/BMT, Texas Children's Hospital, Baylor College of Medicine, Houston, TX
| | - Jennifer W Leiding
- Division of Allergy and Immunology, Johns Hopkins University, St Petersburg, FL
| | | | - Michael A Pulsipher
- Division of Pediatric Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute at the University of Utah Spencer Fox Eccles School of Medicine, Salt Lake City, UT
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD; and
| | - Morton J Cowan
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | - Christopher C Dvorak
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | - Elie Haddad
- Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine, University of Montreal, Montreal, QC, Canada
| | - Jennifer M Puck
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | - Donald B Kohn
- Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA
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14
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Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency. J Clin Immunol 2022; 42:975-985. [PMID: 35338423 PMCID: PMC8956456 DOI: 10.1007/s10875-022-01250-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 03/09/2022] [Indexed: 10/26/2022]
Abstract
BACKGROUND Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of immunity underlying an absence of blood myeloid mononuclear cells, intracerebral calcifications, and multiple infections. Only three unrelated patients have been reported. MATERIALS AND METHODS We studied an Argentinian child with multiple infectious diseases and severe pulmonary alveolar proteinosis (PAP). We performed whole-exome sequencing (WES) and characterized his condition by genetic, immunological, and clinical means. RESULTS The patient was born and lived in Argentina. He had a history of viral pulmonary diseases, disseminated disease due to bacillus Calmette-Guérin (BCG), PAP, and cerebral calcifications. He died at the age of 10 months from refractory PAP. WES identified two compound heterozygous variants in IRF8: c.55del and p.R111*. In an overexpression system, the p.R111* cDNA was loss-of-expression, whereas the c.55del cDNA yielded a protein with a slightly lower molecular weight than the wild-type protein. The mutagenesis of methionine residues downstream from c.55del revealed a re-initiation of translation. However, both variants were loss-of-function in a luciferase assay, suggesting that the patient had AR complete IRF8 deficiency. The patient had no blood monocytes or dendritic cells, associated with neutrophilia, and normal counts of NK and other lymphoid cell subsets. CONCLUSION We describe the fourth patient with AR complete IRF8 deficiency. This diagnosis should be considered in children with PAP, which is probably due to the defective development or function of alveolar macrophages.
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Chetty K, Houghton BC, Booth C. Gene Therapy for Inborn Errors of Immunity. Hematol Oncol Clin North Am 2022; 36:813-827. [DOI: 10.1016/j.hoc.2022.03.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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16
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Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency-Improved Outcomes in the Modern Era. J Clin Immunol 2022; 42:819-826. [PMID: 35288820 PMCID: PMC9166891 DOI: 10.1007/s10875-022-01238-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/21/2022] [Indexed: 10/29/2022]
Abstract
Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC-busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC-treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8-99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8-25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7-100.0%) and 79% (55-91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.
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Abstract
Primary immunodeficiencies (PIDs) have become a prime target for gene therapy given the morbidity, mortality, and the single gene etiology. Given that outcomes are better the earlier gene therapy is implemented, it is possible that fetal gene therapy may be an important future direction for the treatment of PIDs. In this chapter, the current treatments available for several PIDs will be reviewed, as well as the history and current status of gene therapy for PIDs. The possibility of in utero gene therapy as a possibility will then be discussed.
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Affiliation(s)
- Anne H Mardy
- Department of Obstetrics, Gynecology, and Reproductive Services, University of California, San Francisco, California
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18
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Tsui M, Min W, Ng S, Dobbs K, Notarangelo LD, Dror Y, Grunebaum E. The Use of Induced Pluripotent Stem Cells to Study the Effects of Adenosine Deaminase Deficiency on Human Neutrophil Development. Front Immunol 2021; 12:748519. [PMID: 34777360 PMCID: PMC8582638 DOI: 10.3389/fimmu.2021.748519] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/30/2021] [Indexed: 11/13/2022] Open
Abstract
Inherited defects that abrogate the function of the adenosine deaminase (ADA) enzyme and consequently lead to the accumulation of toxic purine metabolites cause profound lymphopenia and severe combined immune deficiency. Additionally, neutropenia and impaired neutrophil function have been reported among ADA-deficient patients. However, due to the rarity of the disorder, the neutrophil developmental abnormalities and the mechanisms contributing to them have not been characterized. Induced pluripotent stem cells (iPSC) generated from two unrelated ADA-deficient patients and from healthy controls were differentiated through embryoid bodies into neutrophils. ADA deficiency led to a significant reduction in the number of all early multipotent hematopoietic progenitors. At later stages of differentiation, ADA deficiency impeded the formation of granulocyte colonies in methylcellulose cultures, leading to a significant decrease in the number of neutrophils generated from ADA-deficient iPSCs. The viability and apoptosis of ADA-deficient neutrophils isolated from methylcellulose cultures were unaffected, suggesting that the abnormal purine homeostasis in this condition interferes with differentiation or proliferation. Additionally, there was a significant increase in the percentage of hyperlobular ADA-deficient neutrophils, and these neutrophils demonstrated significantly reduced ability to phagocytize fluorescent microspheres. Supplementing iPSCs and methylcellulose cultures with exogenous ADA, which can correct adenosine metabolism, reversed all abnormalities, cementing the critical role of ADA in neutrophil development. Moreover, chemical inhibition of the ribonucleotide reductase (RNR) enzyme, using hydroxyurea or a combination of nicotinamide and trichostatin A in iPSCs from healthy controls, led to abnormal neutrophil differentiation similar to that observed in ADA deficiency, implicating RNR inhibition as a potential mechanism for the neutrophil abnormalities. In conclusion, the findings presented here demonstrate the important role of ADA in the development and function of neutrophils while clarifying the mechanisms responsible for the neutrophil abnormalities in ADA-deficient patients.
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Affiliation(s)
- Michael Tsui
- Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.,The Institute of Medical Sciences, The University of Toronto, Toronto, ON, Canada
| | - Weixian Min
- Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Stephanie Ng
- The Institute of Medical Sciences, The University of Toronto, Toronto, ON, Canada.,Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Kerry Dobbs
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Yigal Dror
- The Institute of Medical Sciences, The University of Toronto, Toronto, ON, Canada.,Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.,Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
| | - Eyal Grunebaum
- Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.,The Institute of Medical Sciences, The University of Toronto, Toronto, ON, Canada.,Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
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19
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Kreins AY, Velasco HF, Cheong KN, Rao K, Veys P, Worth A, Gaspar HB, Booth C. Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience. J Clin Immunol 2021; 42:94-107. [PMID: 34654999 PMCID: PMC8821083 DOI: 10.1007/s10875-021-01145-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 09/27/2021] [Indexed: 12/15/2022]
Abstract
Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available.
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Affiliation(s)
- Alexandra Y Kreins
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,UCL Great Ormond Street Institute of Child Health, London, UK
| | - Helena F Velasco
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,Department of Pediatric Allergy and Immunology, Federal University of São Paolo, São Paolo, Brazil
| | - Kai-Ning Cheong
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,Department of Paediatric Rheumatology and Immunology, Hong Kong Children's Hospital, Hong Kong, Hong Kong
| | - Kanchan Rao
- UCL Great Ormond Street Institute of Child Health, London, UK.,Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Paul Veys
- UCL Great Ormond Street Institute of Child Health, London, UK.,Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Austen Worth
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,UCL Great Ormond Street Institute of Child Health, London, UK
| | - H Bobby Gaspar
- UCL Great Ormond Street Institute of Child Health, London, UK.,Orchard Therapeutics, London, UK
| | - Claire Booth
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. .,UCL Great Ormond Street Institute of Child Health, London, UK.
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20
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Vai S, Marin E, Cosso R, Saettini F, Bonanomi S, Cattoni A, Chiodini I, Persani L, Falchetti A. A Novel Germline Mutation of ADA2 Gene in Two "Discordant" Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype. Int J Mol Sci 2021; 22:8331. [PMID: 34361096 PMCID: PMC8348276 DOI: 10.3390/ijms22158331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/17/2022] Open
Abstract
Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up.
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Affiliation(s)
- Silvia Vai
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy; (S.V.); (E.M.); (I.C.); (L.P.)
| | - Erika Marin
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy; (S.V.); (E.M.); (I.C.); (L.P.)
| | - Roberta Cosso
- IRCCS, Istituto Auxologico Italiano, San Giuseppe Hospital, 28824 Verbania, Italy;
| | - Francesco Saettini
- Department of Pediatrics, Università degli Studi di Milano-Bicocca, Fondazione MBBM, San Gerardo Hospital, 20100 Monza, Italy; (F.S.); (S.B.); (A.C.)
| | - Sonia Bonanomi
- Department of Pediatrics, Università degli Studi di Milano-Bicocca, Fondazione MBBM, San Gerardo Hospital, 20100 Monza, Italy; (F.S.); (S.B.); (A.C.)
| | - Alessandro Cattoni
- Department of Pediatrics, Università degli Studi di Milano-Bicocca, Fondazione MBBM, San Gerardo Hospital, 20100 Monza, Italy; (F.S.); (S.B.); (A.C.)
| | - Iacopo Chiodini
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy; (S.V.); (E.M.); (I.C.); (L.P.)
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20122 Milan, Italy
| | - Luca Persani
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy; (S.V.); (E.M.); (I.C.); (L.P.)
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20122 Milan, Italy
| | - Alberto Falchetti
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20145 Milan, Italy; (S.V.); (E.M.); (I.C.); (L.P.)
- IRCCS, Istituto Auxologico Italiano, San Giuseppe Hospital, 28824 Verbania, Italy;
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21
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Wahjudi TD, Kutzner H, Bleeke M, Hoeger PH. Multicentric dermatofibrosarcoma protuberans in a child with severe combined immunodeficiency due to adenosine deaminase deficiency. Pediatr Dermatol 2021; 38:875-878. [PMID: 33931899 DOI: 10.1111/pde.14597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We report the case of a 4-year-old boy, post-human stem cell transplantation for severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency (ADA), who developed multiple dermatofibrosarcoma protuberans (DFSP). We hypothesize a role for chimerism leading to accumulation of toxic metabolites which can cause DNA strand breaks and inhibit lymphocyte activation. Patients with ADA-SCID should remain under lifelong dermatologic surveillance as DFSP lesions can be quite inconspicuous.
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Affiliation(s)
- Tatjana D Wahjudi
- Departments of Paediatrics, Catholic Children´s Hospital Wilhelmstift, Hamburg, Germany
| | - Heinz Kutzner
- Institute of Dermatopathology, Friedrichshafen, Germany
| | - Matthias Bleeke
- Divison of Paediatric Stem Cell Transplantation and Immunology, University Medical Center Eppendorf, Hamburg, Germany
| | - Peter H Hoeger
- Departments of Paediatrics, Catholic Children´s Hospital Wilhelmstift, Hamburg, Germany.,Department of Paediatric Dermatology, Catholic Children´s Hospital Wilhelmstift, Hamburg, Germany
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22
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Marchetti M, Faggiano S, Mozzarelli A. Enzyme Replacement Therapy for Genetic Disorders Associated with Enzyme Deficiency. Curr Med Chem 2021; 29:489-525. [PMID: 34042028 DOI: 10.2174/0929867328666210526144654] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 11/22/2022]
Abstract
Mutations in human genes might lead to loss of functional proteins, causing diseases. Among these genetic disorders, a large class is associated with the deficiency in metabolic enzymes, resulting in both an increase in the concentration of substrates and a loss in the metabolites produced by the catalyzed reactions. The identification of therapeutic actions based on small molecules represents a challenge to medicinal chemists because the target is missing. Alternative approaches are biology-based, ranging from gene and stem cell therapy, CRISPR/Cas9 technology, distinct types of RNAs, and enzyme replacement therapy (ERT). This review will focus on the latter approach that since the 1990s has been successfully applied to cure many rare diseases, most of them being lysosomal storage diseases or metabolic diseases. So far, a dozen enzymes have been approved by FDA/EMA for lysosome storage disorders and only a few for metabolic diseases. Enzymes for replacement therapy are mainly produced in mammalian cells and some in plant cells and yeasts and are further processed to obtain active, highly bioavailable, less degradable products. Issues still under investigation for the increase in ERT efficacy are the optimization of enzymes interaction with cell membrane and internalization, the reduction in immunogenicity, and the overcoming of blood-brain barrier limitations when neuronal cells need to be targeted. Overall, ERT has demonstrated its efficacy and safety in the treatment of many genetic rare diseases, both saving newborn lives and improving patients' life quality, and represents a very successful example of targeted biologics.
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Affiliation(s)
- Marialaura Marchetti
- Biopharmanet-TEC Interdepartmental Center, University of Parma, Parco Area delle Scienze, Bldg 33., 43124, Parma, Italy
| | - Serena Faggiano
- Department of Food and Drug, University of Parma, Parco Area delle Scienze 23/A, 43124, Parma, Italy
| | - Andrea Mozzarelli
- Institute of Biophysics, National Research Council, Via Moruzzi 1, 56124, Pisa, Italy
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23
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Rodriguez JA, Bang TJ, Restrepo CS, Green DB, Browne LP, Vargas D. Imaging Features of Primary Immunodeficiency Disorders. Radiol Cardiothorac Imaging 2021; 3:e200418. [PMID: 33969305 PMCID: PMC8098094 DOI: 10.1148/ryct.2021200418] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 11/10/2020] [Accepted: 12/01/2020] [Indexed: 06/12/2023]
Abstract
Primary immunodeficiency disorders (PIDs), which are humoral, combined, and innate defects of the immune system, are relatively uncommon and may go undiagnosed in patients experiencing recurrent infections, resulting in increased morbidity and mortality. PIDs are clinically characterized by a broad spectrum of disorders, including repeated infections, autoimmune disorders, lymphoproliferative diseases, congenital anomalies, and increased risk of malignancy. Cardiothoracic imaging plays a crucial role in the diagnosis of PIDs owing to the high rates of repeated respiratory infections leading to bronchiectasis and other forms of chronic lung disease. Although PIDs as a group may seem similar in terms of radiologic features and clinical manifestations, there are specific entities that are pertinent to each PID on an individual level. For example, patients with common variable immunodeficiency may develop a unique granulomatous lymphocytic interstitial lung disease, and Good syndrome is associated with thymoma. Familiarity with the imaging characteristics of these disorders may expedite diagnosis and prognostication, and better direct therapy. Reviewing the thoracic manifestations of all PIDs is beyond the scope of this article; thus, the focus herein is on discussing the thoracic manifestations of the most common PIDs and their imaging features. © RSNA, 2021An earlier incorrect version appeared online. This article was corrected on March 25, 2021.
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24
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Teke Kisa P, Arslan N. Inborn errors of immunity and metabolic disorders: current understanding, diagnosis, and treatment approaches. J Pediatr Endocrinol Metab 2021; 34:277-294. [PMID: 33675210 DOI: 10.1515/jpem-2020-0277] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 11/19/2020] [Indexed: 12/31/2022]
Abstract
Inborn errors of metabolism consist of a heterogeneous group of disorders with various organ systems manifestations, and some metabolic diseases also cause immunological disorders or dysregulation. In this review, metabolic diseases that affect the immunological system and particularly lead to primary immune deficiency will be reviewed. In a patient with frequent infections and immunodeficiency, the presence of symptoms such as growth retardation, abnormal facial appearance, heart, skeletal, lung deformities, skin findings, arthritis, motor developmental retardation, seizure, deafness, hepatomegaly, splenomegaly, impairment of liver function tests, the presence of anemia, thrombocytopenia and eosinophilia in hematological examinations should suggest metabolic diseases for the underlying cause. In some patients, these phenotypic findings may appear before the immunodeficiency picture. Metabolic diseases leading to immunological disorders are likely to be rare but probably underdiagnosed. Therefore, the presence of recurrent infections or autoimmune findings in a patient with a suspected metabolic disease should suggest that immune deficiency may also accompany the picture, and diagnostic examinations in this regard should be deepened.
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Affiliation(s)
- Pelin Teke Kisa
- Division of Pediatric Metabolism and Nutrition, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Nur Arslan
- Division of Pediatric Metabolism and Nutrition, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
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25
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Hetzel M, Ackermann M, Lachmann N. Beyond "Big Eaters": The Versatile Role of Alveolar Macrophages in Health and Disease. Int J Mol Sci 2021; 22:3308. [PMID: 33804918 PMCID: PMC8036607 DOI: 10.3390/ijms22073308] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/19/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023] Open
Abstract
Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be found as tissue resident macrophages tightly integrated into a variety of tissues in which they fulfill crucial and organ-specific functions. The lung harbors at least two macrophage populations: interstitial and alveolar macrophages, which occupy different niches and functions. In this review, we provide the latest insights into the multiple roles of alveolar macrophages while unraveling the distinct factors which can influence the ontogeny and function of these cells. Furthermore, we will highlight pulmonary diseases, which are associated with dysfunctional macrophages, concentrating on congenital diseases as well as pulmonary infections and impairment of immunological pathways. Moreover, we will provide an overview about different treatment approaches targeting macrophage dysfunction. Improved knowledge of the role of macrophages in the onset of pulmonary diseases may provide the basis for new pharmacological and/or cell-based immunotherapies and will extend our understanding to other macrophage-related disorders.
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Affiliation(s)
- Miriam Hetzel
- Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; (M.H.); (M.A.)
- REBIRTH Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
| | - Mania Ackermann
- Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; (M.H.); (M.A.)
- REBIRTH Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany
| | - Nico Lachmann
- REBIRTH Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625 Hannover, Germany
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Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2021; 20:765-778. [PMID: 33738330 PMCID: PMC7940710 DOI: 10.1016/j.omtm.2021.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/07/2021] [Indexed: 12/26/2022]
Abstract
Adenosine deaminase (ADA) deficiency is an inborn error of metabolism affecting multiple systems and causing severe combined immunodeficiency. We tested intravenous administration of recombinant adeno-associated virus (AAV) 2/8-ADA vector in ADA-deficient neonate and adult mice or as part of a bimodal approach comprised of rAAV treatment at birth followed by infusion of lentiviral vector (LV)-modified lineage-depleted bone marrow cells at 8 weeks. ADA−/− mice treated with rAAV and enzyme replacement therapy (ERT) for 30 days were rescued from the lethal pulmonary insufficiency, surviving out to 180 days without further treatment. rAAV vector copy number (VCN) was highest in liver, lung, and heart and was associated with near-normal ADA activity and thymocyte development. In the bimodal approach, rAAV-mediated ADA expression supported survival during the 4 weeks before infusion of the LV-modified bone marrow cells and during the engraftment period. Conditioning prior to infusion may have resulted in the replacement of rAAV marked cells in marrow and liver, with LV VCN 100- to 1,000-fold higher in hematopoietic tissue compared with rAAV VCN, and was associated with immune cell reconstitution. In conclusion, a bimodal approach may be an alternative for patients without reliable access to ERT before receiving a stem cell transplant or gene therapy.
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27
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Pulmonary Manifestations of Immunodeficiency and Immunosuppressive Diseases Other than Human Immunodeficiency Virus. Pediatr Clin North Am 2021; 68:103-130. [PMID: 33228927 DOI: 10.1016/j.pcl.2020.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Immune deficiencies may alter normal lung function and protective mechanisms, resulting in a myriad of pulmonary manifestations. Primary immunodeficiencies involve multiple branches of the immune system, and defects may predispose to recurrent upper and lower respiratory infections by common pathogens; opportunistic infections; and autoimmune, inflammatory, and malignant processes that may result in interstitial pneumonias. Secondary immunodeficiencies may result from neoplasms or their treatment, organ transplant and immunosuppression, and from autoimmune diseases and their treatments. Primary and secondary immunodeficiencies and their pulmonary manifestations may be difficult to diagnose and treat. A multidisciplinary approach to evaluation is essential.
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Hadchouel A, Drummond D, Abou Taam R, Lebourgeois M, Delacourt C, de Blic J. Alveolar proteinosis of genetic origins. Eur Respir Rev 2020; 29:29/158/190187. [PMID: 33115790 DOI: 10.1183/16000617.0187-2019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/21/2020] [Indexed: 12/18/2022] Open
Abstract
Pulmonary alveolar proteinosis (PAP) is a rare form of chronic interstitial lung disease, characterised by the intra-alveolar accumulation of lipoproteinaceous material. Numerous conditions can lead to its development. Whereas the autoimmune type is the main cause in adults, genetic defects account for a large part of cases in infants and children. Even if associated extra-respiratory signs may guide the clinician during diagnostic work-up, next-generation sequencing panels represent an efficient diagnostic tool. Exome sequencing also allowed the discovery of new variants and genes involved in PAP. The aim of this article is to summarise our current knowledge of genetic causes of PAP.
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Affiliation(s)
- Alice Hadchouel
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France .,INSERM U1151, Institut Necker Enfants Malades, Paris, France.,Université de Paris, Faculté de Médecine, Paris, France
| | - David Drummond
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France
| | - Rola Abou Taam
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France
| | - Muriel Lebourgeois
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France
| | - Christophe Delacourt
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France.,INSERM U1151, Institut Necker Enfants Malades, Paris, France.,Université de Paris, Faculté de Médecine, Paris, France
| | - Jacques de Blic
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France
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29
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Gennery AR. The challenges presented by haematopoietic stem cell transplantation in children with primary immunodeficiency. Br Med Bull 2020; 135:4-15. [PMID: 32676650 DOI: 10.1093/bmb/ldaa017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/13/2020] [Accepted: 05/21/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION OR BACKGROUND For many primary immunodeficiencies (PIDs), haematopoietic stem cell transplantation (HSCT) offers treatment to cure disease. However, patients with PID present a unique set of challenges when considering HSCT. SOURCES OF DATA Review of recent literature. AREAS OF AGREEMENT The most significant recent impact on successful outcome is introduction of newborn screening programmes for diagnosis of severe combined immunodeficiency-wider adoption of screening in an increasing number of countries will see further improvements. Other PIDs have better outcomes when treated earlier, before development of co-morbidities-early referral for consideration of HSCT is important. Evolution of conditioning regimens is improving short- and long-term toxicities-targeted busulfan and low-toxicity myeloablative treosulfan regimens deliver good survival with reduced short-term toxicities. AREAS OF CONTROVERSY The most radical development, still in clinical trials, is the use of mono-antibody-based conditioning, which eliminates the requirement for chemotherapy and is likely to become much more important in HSCT for non-malignant disease in the future. GROWING POINTS Multidisciplinary working for optimum care is essential. AREAS TIMELY FOR DEVELOPING RESEARCH International collaborations are important to learn about rare presentations and complications, and to formulate the most effective and safe treatment strategies.
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Affiliation(s)
- A R Gennery
- Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Newcastle upon Tyne NE1 4LP, UK.,Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
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30
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Bush A, Pabary R. Pulmonary alveolarproteinosis in children. Breathe (Sheff) 2020; 16:200001. [PMID: 32684993 PMCID: PMC7341618 DOI: 10.1183/20734735.0001-2020] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 03/01/2020] [Indexed: 12/15/2022] Open
Abstract
Pulmonary alveolar proteinosis (PAP) is an umbrella term for a wide spectrum of conditions that have a very characteristic appearance on computed tomography. There is outlining of the secondary pulmonary lobules on the background of ground-glass shadowing and pathologically, filling of the alveolar spaces with normal or abnormal surfactant. PAP is rare and the common causes in children are very different from those seen in adults; autoimmune PAP is rare and macrophage blockade not described in children. There are many genetic causes of PAP, the best known of which are mutations in the genes encoding surfactant protein (SP)-B, SP-C, thyroid transcription factor 1, ATP-binding cassette protein 3, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α- and β- chains. PAP may also be a manifestation of rheumatological and metabolic disease, congenital immunodeficiency, and haematological malignancy. Precise diagnosis of the underlying cause is essential in planning treatment, as well as for genetic counselling. The evidence base for treatment is poor. Some forms of PAP respond well to whole-lung lavage, and autoimmune PAP, which is much commoner in adults, responds to inhaled or subcutaneous GM-CSF. Emerging therapies based on studies in murine models of PAP include stem-cell transplantation for GM-CSF receptor mutations. EDUCATIONAL AIMS To understand when to suspect that a child has pulmonary alveolar proteinosis (PAP) and how to confirm that this is the cause of the presentation.To show that PAP is an umbrella term for conditions characterised by alveolar filling by normal or abnormal surfactant, and that this term is the start, not the end, of the diagnostic journey.To review the developmental differences in the spectrum of conditions that may cause PAP, and specifically to understand the differences between causes in adults and children.To discuss when to treat PAP with whole-lung lavage and/or granulocyte-macrophage colony-stimulating factor, and review potential promising new therapies.
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Affiliation(s)
- Andrew Bush
- Imperial College, London, UK
- Royal Brompton Harefield NHS Foundation Trust, London, UK
| | - Rishi Pabary
- Imperial College, London, UK
- Royal Brompton Harefield NHS Foundation Trust, London, UK
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31
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Murguia-Favela L, Min W, Loves R, Leon-Ponte M, Grunebaum E. Comparison of elapegademase and pegademase in ADA-deficient patients and mice. Clin Exp Immunol 2020; 200:176-184. [PMID: 31989577 DOI: 10.1111/cei.13420] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2020] [Indexed: 01/08/2023] Open
Abstract
The absence of adenosine deaminase (ADA) causes severe combined immune deficiency (SCID), which has been treated with PEGylated bovine-extracted ADA (ADAGEN). ADAGEN was recently replaced by a PEGylated recombinant bovine ADA, expressed in Escherichia coli (elapegademase, ELA-ADA). Limited information on ELA-ADA is available. ADA enzymatic activity of ELA-ADA and ADAGEN was assessed in vitro at diverse dilutions. ADA activity and immune reconstitution in an ADA-SCID patient treated with ELA-ADA were compared with age-matched patients previously treated with ADAGEN. ADA activity and thymus reconstitution were evaluated in ADA-deficient mice following ELA-ADA or ADAGEN administered from 7 days postpartum. In vitro, ADA activity of ELA-ADA and ADAGEN were similar at all dilutions. In an ADA-SCID patient, ELA-ADA treatment led to a marked increase in trough plasma ADA activity, which was 20% higher than in a patient previously treated with ADAGEN. A marked increase in T cell numbers and generation of naive T cells was evident following 3 months of ELA-ADA treatment, while T cell numbers increased following 4 months in 3 patients previously treated with ADAGEN. T cell proliferations stimulation normalized and thymus shadow became evident following ELA-ADA treatment. ADA activity was significantly increased in the blood of ADA-deficient mice following ELA-ADA compared to ADAGEN, while both treatments improved the mice weights, the weight, number of cells in their thymus and thymocyte subpopulations. ELA-ADA has similar in- vitro and possibly better in-vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution.
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Affiliation(s)
- L Murguia-Favela
- Section of Hematology and Immunology, Department of Pediatrics, Alberta Children's Hospital and University of Calgary, Calgary, Canada
| | - W Min
- Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Canada
| | - R Loves
- Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Canada
| | - M Leon-Ponte
- Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Canada
| | - E Grunebaum
- Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Canada.,Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada
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32
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Morbidity in an adenosine deaminase-deficient patient during 27 years of enzyme replacement therapy. Clin Immunol 2020; 211:108321. [DOI: 10.1016/j.clim.2019.108321] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/21/2019] [Accepted: 12/03/2019] [Indexed: 11/30/2022]
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33
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Chest Radiographs for Distinguishing ADA-SCID from Other Forms of SCID. J Clin Immunol 2019; 40:259-266. [PMID: 31858364 DOI: 10.1007/s10875-019-00733-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 11/11/2019] [Indexed: 02/01/2023]
Abstract
PURPOSE Early differentiation of adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID) from other forms of SCID may initiate appropriate treatment interventions with the aim of metabolic detoxification and improved outcome. Our hypothesis was that previously described radiological features (inferior scapular angle squaring and spurring and costochondral cupping) can differentiate ADA-SCID from other forms of SCID. METHODS Chest radiographs at clinical presentation between 2000 and 2017 of children with ADA-SCID were retrospectively included, provided that the radiological features were assessable. Random chest radiographs of children with other forms of SCID were included for comparison. Three paediatric radiologists (2 senior, 1 junior) assessed the radiographs for the specific radiological features and stated their diagnosis (ADA-SCID or non-ADA-SCID). An optimal threshold for test performance was defined using a ROC curve. RESULTS Thirty-six patients with ADA-SCID and twenty-five patients with non-ADA-SCID were included (median age 3.8 months). The optimal threshold for test performance was at approximately < 7 months old: sensitivity 91.7%, specificity 80.7%, interreader agreement was k = 0.709, AUC 0.862. The positive likelihood ratio for scapular squaring, scapular spur, and costochondral cupping was 4.0, 54.6 and 7.8, respectively. The test was valid when performed by both senior and junior paediatric radiologists. CONCLUSION Radiological features such as scapular spurring, scapular squaring and costochondral cupping can reliably differentiate between ADA-SCID and other forms of SCID. This is true for children aged approximately < 7 months, and this is reliable when assessed by both senior and junior paediatric radiologists.
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34
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Xu X, Negandhi J, Min W, Tsui M, Post M, Harrison RV, Grunebaum E. Early Enzyme Replacement Therapy Improves Hearing and Immune Defects in Adenosine Deaminase Deficient-Mice. Front Immunol 2019; 10:416. [PMID: 30918508 PMCID: PMC6424861 DOI: 10.3389/fimmu.2019.00416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 02/18/2019] [Indexed: 12/24/2022] Open
Abstract
Background: Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). Additionally, ADA-deficient patients suffer from hearing impairment. We hypothesized that ADA-deficient (-/-) mice also exhibit hearing abnormalities and that ERT from an early age will improve the hearing and immune defects in these mice. Methods: Auditory brainstem evoked responses, organ weights, thymocytes numbers, and subpopulations, lymphocytes in peripheral blood as well as T lymphocytes in spleen were analyzed in ADA-/- and ADA-proficient littermate post-partum (pp). The cochlea was visualized by scanning electron microscopy (SEM). The effects of polyethylene glycol conjugated ADA (PEG-ADA) ERT or 40% oxygen initiated at 7 days pp on the hearing and immune abnormalities were assessed. Results: Markedly abnormal hearing thresholds responses were found in ADA-/- mice at low and medium tone frequencies. SEM demonstrated extensive damage to the cochlear hair cells of ADA-/- mice, which were splayed, short or missing, correlating with the hearing deficits. The hearing defects were not reversed when hypoxia in ADA-/- mice was corrected. Progressive immune abnormalities were detected in ADA-/- mice from 4 days pp, initially affecting the thymus followed by peripheral lymphocytes and T cells in the spleen. ERT initiated at 7 days pp significantly improved the hearing of ADA-/- mice as well as the number of thymocytes and T lymphocytes, although not all normalized. Conclusions: ADA deficiency is associated with hearing deficits and damage to cochlear hair cells. Early initiation of ERT improves the hearing and immune abnormalities.
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Affiliation(s)
- Xiaobai Xu
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Jaina Negandhi
- Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Weixian Min
- Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Michael Tsui
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Martin Post
- Translational Medicine Program, Hospital for Sick Children, Toronto, ON, Canada.,Department of Laboratory Medicine & Pathology, Hospital for Sick Children, Toronto, ON, Canada
| | - Robert V Harrison
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada.,Department of Otolaryngology, University of Toronto, Toronto, ON, Canada
| | - Eyal Grunebaum
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.,Division of Immunology and Allergy, Hospital for Sick Children, Toronto, ON, Canada
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35
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Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol 2019; 143:852-863. [PMID: 30194989 PMCID: PMC6688493 DOI: 10.1016/j.jaci.2018.08.024] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 08/07/2018] [Accepted: 08/28/2018] [Indexed: 12/29/2022]
Abstract
Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.
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Affiliation(s)
- Donald B Kohn
- Department of Microbiology, Immunology and Molecular Genetics, and the Division of Hematology & Oncology, Department of Pediatrics, David Geffen School of Medicine University of California, Los Angeles, Calif
| | - Michael S Hershfield
- Department of Medicine and Biochemistry, Duke University Medical Center, Durham, NC
| | - Jennifer M Puck
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, Calif
| | - Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, and Università Vita Salute San Raffaele, Milan, Italy
| | - Annaliesse Blincoe
- Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
| | - H Bobby Gaspar
- Infection, Immunity, Inflammation, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Eyal Grunebaum
- Division of Immunology and Allergy, and the Department of Pediatrics, Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
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36
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Dorsey MJ, Puck JM. Newborn Screening for Severe Combined Immunodeficiency in the United States: Lessons Learned. Immunol Allergy Clin North Am 2018; 39:1-11. [PMID: 30466767 DOI: 10.1016/j.iac.2018.08.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In the United States, significant improvement in diagnosis and outcomes for children affected with severe combined immunodeficiency has followed institution of newborn screening using an assay to measure T-cell receptor excision circles in newborn dried blood spot specimens. Key to this outcome is the avoidance of infectious complications in infants with severe combined immunodeficiency.
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Affiliation(s)
- Morna J Dorsey
- Department of Pediatrics, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA 94158, USA.
| | - Jennifer M Puck
- Department of Pediatrics, University of California San Francisco, Box 3118, 555 Mission Bay Boulevard South, Rm SC-252K, San Francisco, CA 94143, USA
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37
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Flinn AM, Gennery AR. Adenosine deaminase deficiency: a review. Orphanet J Rare Dis 2018; 13:65. [PMID: 29690908 PMCID: PMC5916829 DOI: 10.1186/s13023-018-0807-5] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 04/12/2018] [Indexed: 04/07/2023] Open
Abstract
Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable affects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental affects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency. Three treatment options are currently available. Initial treatment with enzyme replacement therapy may alleviate acute symptoms and enable partial immunological reconstitution, but treatment is life-long, immune reconstitution is incomplete, and the reconstituted immune system may nullify the effects of the enzyme replacement. Hematopoietic stem cell transplant has long been established as the treatment of choice, particularly where a matched sibling or well matched unrelated donor is available. More recently, the use of gene addition techniques to correct the genetic defect in autologous haematopoietic stem cells treatment has demonstrated immunological and clinical efficacy. This article reviews the biology, clinical presentation, diagnosis and treatment of ADA-deficiency.
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Affiliation(s)
- Aisling M Flinn
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.,Great North Children's Hospital, Clinical Resource Building, Floor 4, Block 2, Queen Victoria Road, NE1 4LP, Newcastle upon Tyne, UK
| | - Andrew R Gennery
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. .,Great North Children's Hospital, Clinical Resource Building, Floor 4, Block 2, Queen Victoria Road, NE1 4LP, Newcastle upon Tyne, UK.
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38
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Kim VHD, Murguia-Favela L, Grunebaum E. Adenosine deaminase deficiency: current treatments and emerging therapeutics. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2018.1418660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Vy Hong-Diep Kim
- Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada
| | - Luis Murguia-Favela
- Section of Hematology and Immunology, Department of Pediatrics, Alberta Children’s Hospital and University of Calgary, Calgary, Canada
| | - Eyal Grunebaum
- Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada
- Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Canada
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39
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Tanaka-Kubota M, Shinozaki K, Miyamoto S, Yanagimachi M, Okano T, Mitsuiki N, Ueki M, Yamada M, Imai K, Takagi M, Agematsu K, Kanegane H, Morio T. Hematopoietic stem cell transplantation for pulmonary alveolar proteinosis associated with primary immunodeficiency disease. Int J Hematol 2017; 107:610-614. [PMID: 29185156 DOI: 10.1007/s12185-017-2375-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 11/23/2017] [Accepted: 11/24/2017] [Indexed: 01/27/2023]
Abstract
Pulmonary alveolar proteinosis (PAP) is a rare disorder that is characterized by the excessive accumulation of surfactant-like materials in the alveoli, leading to hypoxemic respiratory failure. We describe two Japanese infants with PAP associated with hypogammaglobulinemia and monocytopenia. These patients may have underlying primary immunodeficiency (PID) and were successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT). This report indicates that allogeneic HSCT may provide a curative treatment for PAP associated with PID.
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Affiliation(s)
- Mari Tanaka-Kubota
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Koji Shinozaki
- Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Japan
| | - Satoshi Miyamoto
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Masakatsu Yanagimachi
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Tsubasa Okano
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Noriko Mitsuiki
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Masahiro Ueki
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masafumi Yamada
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kohsuke Imai
- Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Masatoshi Takagi
- Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kazunaga Agematsu
- Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Japan.,Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan
| | - Hirokazu Kanegane
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Tomohiro Morio
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
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40
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Bradford KL, Moretti FA, Carbonaro-Sarracino DA, Gaspar HB, Kohn DB. Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations. J Clin Immunol 2017; 37:626-637. [PMID: 28842866 DOI: 10.1007/s10875-017-0433-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 08/07/2017] [Indexed: 12/18/2022]
Abstract
Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T- B- NK-), thus underscoring the importance of functional purine metabolism for the development of the immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID.
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Affiliation(s)
- Kathryn L Bradford
- Department of Pediatrics, University of California, Los Angeles (UCLA), 3163 Terasaki Life Science Bldg., 610 Charles E. Young Drive East, Los Angeles, CA, 90095, USA
| | - Federico A Moretti
- Centre for Immunodeficiency, Molecular Immunology Unit, University College London Institute of Child Health, London, UK
| | | | - Hubert B Gaspar
- Centre for Immunodeficiency, Molecular Immunology Unit, University College London Institute of Child Health, London, UK
| | - Donald B Kohn
- Department of Pediatrics, University of California, Los Angeles (UCLA), 3163 Terasaki Life Science Bldg., 610 Charles E. Young Drive East, Los Angeles, CA, 90095, USA.
- Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA.
- Department of Molecular & Medical Pharmacology, UCLA University of California, Los Angeles, CA, USA.
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41
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Long-Term Outcome of Adenosine Deaminase-Deficient Patients-a Single-Center Experience. J Clin Immunol 2017; 37:582-591. [PMID: 28748310 DOI: 10.1007/s10875-017-0421-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 07/10/2017] [Indexed: 12/19/2022]
Abstract
PURPOSE Inherited defects in the adenosine deaminase (ADA) enzyme can cause severe combined immune deficiency (SCID) and systemic abnormalities. Management options for ADA-deficient patients include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy (GT). Here, we describe the long-term benefits of these treatments. METHODS Survival, infections, systemic sequelae, and laboratory assessments were recorded for all ADA-deficient SCID patients, managed at a single center since 1985, who survived 5 or more years following treatment. RESULTS Of 20 ADA-deficient patients, the 8 (40%) who survived 5 or more years (range 6-29.5 years, median 14 years) were included in the study. Among the long-term survivors, two patients were treated exclusively with ERT, five underwent HSCT (three from HLA-matched sibling donors, two from HLA-mismatched related donors), and one received GT. The long-term survivors often suffered from recurrent respiratory infections; however, opportunistic infections occurred in only one patient. Systemic sequelae included lung disease such as bronchiectasis and asthma (four patients), neurologic abnormalities (six patients), metabolic disturbances (two patients), allergy and autoimmunity (six patients), and neoplasms (three patients). Normal CD4+ T cell numbers and function, as well as antibody production, were usually observed after HSCT and GT, but not after ERT. Late deaths occurred in two patients at 15 and 25 years after HSCT, respectively, and were attributed to respiratory failure. CONCLUSIONS ADA-deficient patients commonly suffer from long-term complications, emphasizing the need for improved management and for multi-disciplinary follow-up.
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Litvack ML, Wigle TJ, Lee J, Wang J, Ackerley C, Grunebaum E, Post M. Alveolar-like Stem Cell-derived Myb(-) Macrophages Promote Recovery and Survival in Airway Disease. Am J Respir Crit Care Med 2017; 193:1219-29. [PMID: 26730942 DOI: 10.1164/rccm.201509-1838oc] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
RATIONALE Abnormal alveolar macrophages (AM) are found in chronic obstructive pulmonary disease, asthma, cystic fibrosis, and adenosine deaminase deficiency (ADA(-/-)). There is no specific treatment strategy to compensate for these innate immune abnormalities. Recent findings suggest AMs are of early embryonic or fetal origin. Pluripotent stem cells (PSCs) as a source of embryonic-derived AMs for therapeutic use in acute and chronic airway diseases has yet to be investigated. OBJECTIVES To determine if embryonic Myb(-/-) alveolar-like macrophages have therapeutic value on pulmonary transplantation in acute and chronic airway diseases. METHODS Directed differentiation of murine PSCs was used in factor-defined media to produce expandable embryonic macrophages conditioned to an alveolar-like phenotype with granulocyte-macrophage colony-stimulating factor. AMs were partially depleted in mice to create an acute lung injury. To model a chronic lung disease, ADA(-/-) mice were used. Alveolar-like macrophages were intratracheally transplanted to the injured animals and therapeutic potential was determined. MEASUREMENTS AND MAIN RESULTS The differentiation protocol is highly efficient and adaptable to human PSCs. The PSC macrophages are phenotypically like AMs both functionally and by ligand marker characterization. They engulf bacteria and apoptotic cells and are better phagocytes than bone marrow-derived macrophages. In vivo, these macrophages remain in healthy airways for at least 4 weeks, can engulf neutrophils during acute lung injury, enhance pulmonary tissue repair, and promote survival in ADA(-/-) mice. Animals receiving the macrophages do not develop abnormal pathology or teratomas. CONCLUSIONS PSCs are a reliable source to produce therapeutically active alveolar-like macrophages to treat airway disease.
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Affiliation(s)
| | | | - Joyce Lee
- 1 Program of Physiology and Experimental Medicine
| | - Jinxia Wang
- 1 Program of Physiology and Experimental Medicine
| | - Cameron Ackerley
- 1 Program of Physiology and Experimental Medicine.,2 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Eyal Grunebaum
- 3 Developmental and Stem Cell Biology Program, and.,2 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Martin Post
- 1 Program of Physiology and Experimental Medicine.,4 Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and
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Sokolic R, Candotti F. Gene therapy for the treatment of adenosine deaminase-deficient severe combined immune deficiency. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1325360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Robert Sokolic
- Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States of America
- Division of Hematology/Oncology, University Medicine Foundation, Providence, RI
| | - Fabio Candotti
- Immunology and Allergy Service, Department of Medicine Centre Hospitalier, Universitaire Vaudois, Lausanne, Switzerland
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Dorsey M, Puck J. Newborn Screening for Severe Combined Immunodeficiency in the US: Current Status and Approach to Management. Int J Neonatal Screen 2017; 3:15. [PMID: 31304419 PMCID: PMC6625796 DOI: 10.3390/ijns3020015] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
In the US, the assay of T cell receptor excision circles (TRECs) in newborn dried blood spot specimens to detect severe combined immunodeficiency (SCID) was first piloted in 2008 in the state of Wisconsin. It has been rapidly adopted with 49 states and Puerto Rico now either routinely screening all newborns or planning to do so in 2017. Advances in SCID NBS over the last 9 years have revolutionized the ability to detect SCID and has led to profound improvement in outcomes of affected children.
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Affiliation(s)
- Morna Dorsey
- Department of Pediatrics, Division of Allergy, Immunology and Bone Marrow Transplant, University of California San Francisco, San Francisco, CA 94158, USA
- Correspondence: ; Tel.: +1-415-476-3086
| | - Jennifer Puck
- Smith Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA
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Al-Haidary AS, Alotaibi W, Alhaider SA, Al-Saleh S. A newly identified novel variant in the CSF2RA gene in a child with pulmonary alveolar proteinosis: a case report. J Med Case Rep 2017; 11:122. [PMID: 28464852 PMCID: PMC5414320 DOI: 10.1186/s13256-017-1285-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 04/05/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The congenital form of pulmonary alveolar proteinosis due to colony stimulating factor 2 receptor alpha gene mutations is a rare disease with only a few cases reported worldwide. In this study we report a new case of pulmonary alveolar proteinosis with a novel variant in colony stimulating factor 2 receptor alpha gene. CASE PRESENTATION A 5-year-old Saudi boy presented with a history of progressive dyspnea over 6 months; he was diagnosed as having pulmonary alveolar proteinosis. A molecular study revealed a novel variation in colony stimulating factor 2 receptor alpha gene. His clinical condition showed significant improvement after whole lung lavage. CONCLUSIONS This case has the typical presentation of congenital pulmonary alveolar proteinosis due to colony stimulating factor 2 receptor alpha defect with a novel variant in this gene likely to be pathogenic.
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Affiliation(s)
- Adel S Al-Haidary
- Department of Pediatrics, King Fahad Medical City, P.O. Box 59046, Riyadh, 11525, Saudi Arabia.
| | - Wadha Alotaibi
- Department of Pediatrics, King Fahad Medical City, P.O. Box 59046, Riyadh, 11525, Saudi Arabia
| | - Sami A Alhaider
- Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Suhail Al-Saleh
- The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, ON, Canada
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Dorsey MJ, Dvorak CC, Cowan MJ, Puck JM. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening. J Allergy Clin Immunol 2017; 139:733-742. [PMID: 28270365 PMCID: PMC5385855 DOI: 10.1016/j.jaci.2017.01.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/20/2017] [Accepted: 01/20/2017] [Indexed: 12/30/2022]
Abstract
Severe combined immunodeficiency (SCID) is characterized by severely impaired T-cell development and is fatal without treatment. Newborn screening (NBS) for SCID permits identification of affected infants before development of opportunistic infections and other complications. Substantial variation exists between treatment centers with regard to pretransplantation care, and transplantation protocols for NBS identified infants with SCID, as well as infants with other T-lymphopenic disorders detected by using NBS. We developed approaches to management based on the study of infants identified by means of NBS for SCID who received care at the University of California, San Francisco (UCSF). From August 2010 through October 2016, 32 patients with NBS-identified SCID and leaky SCID from California and other states were treated, and 42 patients with NBS-identified non-SCID T-cell lymphopenia were followed. Our center's approach supports successful outcomes; systematic review of our practice provides a framework for diagnosis and management, recognizing that more data will continue to shape best practices.
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Affiliation(s)
- Morna J Dorsey
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, San Francisco, Calif.
| | - Christopher C Dvorak
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, San Francisco, Calif
| | - Morton J Cowan
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, San Francisco, Calif
| | - Jennifer M Puck
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, San Francisco, Calif
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Xu X, Tailor CS, Grunebaum E. Gene therapy for primary immune deficiencies: a Canadian perspective. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2017; 13:14. [PMID: 28261277 PMCID: PMC5327566 DOI: 10.1186/s13223-017-0184-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 02/11/2017] [Indexed: 12/11/2022]
Abstract
The use of gene therapy (GT) for the treatment of primary immune deficiencies (PID) including severe combined immune deficiency (SCID) has progressed significantly in the recent years. In particular, long-term studies have shown that adenosine deaminase (ADA) gene delivery into ADA-deficient hematopoietic stem cells that are then transplanted into the patients corrects the abnormal function of the ADA enzyme, which leads to immune reconstitution. In contrast, the outcome was disappointing for patients with X-linked SCID, Wiskott-Aldrich syndrome and chronic granulomatous disease who received GT followed by autologous gene corrected transplantations, as many developed hematological malignancies. The malignancies were attributed to the predilection of the viruses used for gene delivery to integrated at oncogenic areas. The availability of safer and more efficient self-inactivating lentiviruses for gene delivery has reignited the interest in GT for many PID that are now in various stages of pre-clinical studies and clinical trials. Moreover, advances in early diagnosis of PID and gene editing technology coupled with enhanced abilities to generate and manipulate stem cells ex vivo are expected to further contribute to the benefit of GT for PID. Here we review the past, the present and the future of GT for PID, with particular emphasis on the Canadian perspective.
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Affiliation(s)
- Xiaobai Xu
- Developmental and Stem Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, ON Canada
| | | | - Eyal Grunebaum
- Developmental and Stem Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, ON Canada
- Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON Canada
- University of Toronto, Toronto, ON Canada
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How We Manage Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA SCID). J Clin Immunol 2017; 37:351-356. [DOI: 10.1007/s10875-017-0373-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 01/31/2017] [Indexed: 10/20/2022]
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Sauer AV, Hernandez RJ, Fumagalli F, Bianchi V, Poliani PL, Dallatomasina C, Riboni E, Politi LS, Tabucchi A, Carlucci F, Casiraghi M, Carriglio N, Cominelli M, Forcellini CA, Barzaghi F, Ferrua F, Minicucci F, Medaglini S, Leocani L, la Marca G, Notarangelo LD, Azzari C, Comi G, Baldoli C, Canale S, Sessa M, D’Adamo P, Aiuti A. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Sci Rep 2017; 7:40136. [PMID: 28074903 PMCID: PMC5225479 DOI: 10.1038/srep40136] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 11/23/2016] [Indexed: 02/03/2023] Open
Abstract
Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency.
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Affiliation(s)
- Aisha V. Sauer
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Raisa Jofra Hernandez
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesca Fumagalli
- Neurology Unit, Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Veronica Bianchi
- Dulbecco Telethon Institute at Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Chiara Dallatomasina
- Psychological Service, Neurological Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Elisa Riboni
- Psychological Service, Neurological Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Letterio S. Politi
- Imaging Core and Neuroradiology Unit, Head and Neck Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Antonella Tabucchi
- Department of Medical Biotechnologies, University of Siena, Italy
- U.O.C. Clinical Pathology, AOUS, Siena, Italy
| | - Filippo Carlucci
- Department of Medical Biotechnologies, University of Siena, Italy
- U.O.C. Clinical Pathology, AOUS, Siena, Italy
| | - Miriam Casiraghi
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Nicola Carriglio
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Carlo Alberto Forcellini
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Federica Barzaghi
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Francesca Ferrua
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Fabio Minicucci
- Neurophysiology Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefania Medaglini
- Neurophysiology Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Letizia Leocani
- Neurophysiology Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giancarlo la Marca
- Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Lucia D. Notarangelo
- Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy
| | - Chiara Azzari
- Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Giancarlo Comi
- Psychological Service, Neurological Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Cristina Baldoli
- Neuroradiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sabrina Canale
- Multimedica hospital, Neurological Rehabilitation, Limbiate, Italy
| | - Maria Sessa
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Neurology Unit, Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Patrizia D’Adamo
- Dulbecco Telethon Institute at Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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50
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Whitmore KV, Gaspar HB. Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency. Front Immunol 2016; 7:314. [PMID: 27579027 PMCID: PMC4985714 DOI: 10.3389/fimmu.2016.00314] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 08/02/2016] [Indexed: 11/24/2022] Open
Abstract
Adenosine deaminase (ADA) deficiency is best known as a form of severe combined immunodeficiency (SCID) that results from mutations in the gene encoding ADA. Affected patients present with clinical and immunological manifestations typical of a SCID. Therapies are currently available that can target these immunological disturbances and treated patients show varying degrees of clinical improvement. However, there is now a growing body of evidence that deficiency of ADA has significant impact on non-immunological organ systems. This review will outline the impact of ADA deficiency on various organ systems, starting with the well-understood immunological abnormalities. We will discuss possible pathogenic mechanisms and also highlight ways in which current treatments could be improved. In doing so, we aim to present ADA deficiency as more than an immunodeficiency and suggest that it should be recognized as a systemic metabolic disorder that affects multiple organ systems. Only by fully understanding ADA deficiency and its manifestations in all organ systems can we aim to deliver therapies that will correct all the clinical consequences.
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Affiliation(s)
- Kathryn V. Whitmore
- Molecular and Cellular Immunology Section, UCL Institute of Child Health, University College London, London, UK
| | - Hubert B. Gaspar
- Molecular and Cellular Immunology Section, UCL Institute of Child Health, University College London, London, UK
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