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Wang Y, Yuan X, Wang T, Wei W, Wu S, Hou H. Comprehensive evaluation of immune dysregulation in secondary hemophagocytic lymphohistiocytosis. Virulence 2024; 15:2342276. [PMID: 38629410 PMCID: PMC11028026 DOI: 10.1080/21505594.2024.2342276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 04/08/2024] [Indexed: 04/19/2024] Open
Abstract
Host immune dysfunction plays a crucial role in the onset, progression, and outcome of hemophagocytic lymphohistiocytosis (HLH). This study aimed to comprehensively evaluate the peripheral immune profiles in patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), and explore their predictive value for patient prognosis. A total of 77 patients with sHLH were enrolled in this study, with 31 of them experiencing mortality. Flow cytometry was used to assess the percentages, absolute numbers, and phenotypes of lymphocyte subsets. Simultaneously, cytokine levels and routine laboratory indicators were also collected. In sHLH patients, lymphocyte subset absolute numbers were significantly impaired, accompanied by T cell hyperactivation, B cell hyperactivation, and increased plasmablast proliferation. Prognostic analysis revealed that lower CD8+ T cell percentages, elevated APTT, IL-6, IL-10 levels, and increased CD4+CD28null T cell proportions were associated with poor patient outcomes. The study demonstrates dysregulation in the counts and phenotypes of lymphocyte subsets in sHLH patients. Several key factors, including IL-6, IL-10, APTT, and various T cell percentages, have potential as prognostic markers and therapeutic targets in sHLH.
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Affiliation(s)
- Yun Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xu Yuan
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wei
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiji Wu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyan Hou
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Duong VT, Lee D, Kim YH, Oh SO. Functional role of UNC13D in immune diseases and its therapeutic applications. Front Immunol 2024; 15:1460882. [PMID: 39469717 PMCID: PMC11513310 DOI: 10.3389/fimmu.2024.1460882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 09/24/2024] [Indexed: 10/30/2024] Open
Abstract
UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced.
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Affiliation(s)
- Van-Thanh Duong
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Dongjun Lee
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Yun Hak Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
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Gawhale S, Tambolkar S, Tamhankar P, Tandur BS, Verma S. Hemophagocytic Lymphohistiocytosis in Association With Neuroblastoma Amplified Sequence (NBAS) Gene Variants: A Report of a Rare Case. Cureus 2024; 16:e69690. [PMID: 39429260 PMCID: PMC11489862 DOI: 10.7759/cureus.69690] [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: 08/14/2024] [Accepted: 09/18/2024] [Indexed: 10/22/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a multisystem involvement, hyperinflammatory state with rapid progression and a poor outcome. However, HLH may rarely present with signs and symptoms isolated to the central nervous system (CNS). Thus, we discuss this case, which presented with CNS symptoms and worsened over time with multisystem involvement, an inflammatory storm, and required immunomodulation. Whole exome sequencing performed on genomic DNA extracted from peripheral blood showed a novel finding that the patient was likely compound heterozygous for the following two novel variants of uncertain significance in the neuroblastoma amplified sequence (NBAS) gene (chr2:g.15461289C>T) or c.2251G>A (p.Asp751Asn) on Exon 21 and (chr2:g.15467334A>G) or c.2092T>C (p.Tyr698His) on Exon 19 (genomic coordinates in the GRCh37 format, transcript ID: NM_015909.4). The NBAS gene is needed for cytotoxic degranulation in natural killer (NK) cells and mutation of which dysregulates lytic vesicle transport, thus leading to the hyperinflammatory state. To the best of our knowledge and according to the available literature, this NBAS gene is a rarely documented cause of primary HLH.
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Affiliation(s)
- Siddhi Gawhale
- Pediatrics, Dr. D.Y. Patil Medical College, Hospital and Research Center, Dr. D.Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Sampada Tambolkar
- Paediatrics, Dr. D.Y. Patil Medical College, Hospital and Research Center, Dr. D.Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Parag Tamhankar
- Pediatrics, Dr. D.Y. Patil Medical College, Hospital and Research Center, Dr. D.Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Balasubramanya S Tandur
- Pediatrics, Dr. D.Y. Patil Medical College, Hospital and Research Center, Dr. D.Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Sarita Verma
- Pediatric Oncology, King Edward Memorial Hospital, Pune, IND
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Papazachariou A, Ioannou P. Hemophagocytic Lymphohistiocytosis Triggered by Herpes Simplex Virus 1 and 2: A Narrative Review. Hematol Rep 2024; 16:487-503. [PMID: 39189243 PMCID: PMC11348265 DOI: 10.3390/hematolrep16030047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/13/2024] [Accepted: 07/22/2024] [Indexed: 08/28/2024] Open
Abstract
Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome characterized by an uncontrolled hyperinflammatory reaction. HLH is classified into primary (familial) and secondary (acquired). Secondary HLH is commonly triggered by infections, with viral infections being a leading cause. Its epidemiology and clinical features in cases associated with herpes simplex virus 1 and 2 remain underexplored. This study aimed to review all previously described cases of HSV-1 or -2-triggered HLH and provide information about this syndrome's epidemiology, microbiology, clinical characteristics, treatment, and outcomes. Methods: A narrative review was performed based on a search in PubMed, the Cochrane Library, and Scopus. Studies published until 27 April 2024 providing relevant data for HLH due to HSV 1 and 2 in humans were included. Results: We identified 29 eligible studies reporting HLH due to HSV 1 and 2, involving 34 patients. Half of them were adults, and half were neonates. Fever and splenomegaly were the most common clinical findings. Most patients were diagnosed with HSV-1 (64.7%), with PCR being the primary diagnostic method. The median duration of in-hospital treatment was 21 days, with acyclovir and steroids being the mainstays of therapy. The overall mortality rate was 41.2%, and AST levels emerged as an independent predictor of mortality. Conclusions: Our findings underscore the need for heightened awareness surrounding HLH triggered by HSV 1 and 2 and the importance of prompt diagnosis and tailored treatment approaches.
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Affiliation(s)
- Andria Papazachariou
- Department of Internal Medicine, University Hospital of Heraklion, 71500 Heraklion, Greece
| | - Petros Ioannou
- Department of Internal Medicine, University Hospital of Heraklion, 71500 Heraklion, Greece
- School of Medicine, University of Crete, 71003 Heraklion, Greece
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Alradhi SI, Almanjomi F, Alamr F, Alwakid I, Alrashidi M, Alkhelaif M. Clinical Presentations, Diagnosis, and Genetic Features of Hemophagocytic Lymphohistiocytosis: A Single Institutional Experience With the Saudi Population. Cureus 2024; 16:e61879. [PMID: 38978926 PMCID: PMC11228410 DOI: 10.7759/cureus.61879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2024] [Indexed: 07/10/2024] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, potentially fatal condition caused by high immune activation. The present study aimed to identify the clinical manifestations, geographic distribution, and associated pathogenic genetic mutations of HLH in Saudi Arabia. Method A retrospective cross-sectional study was conducted at King Fahad Medical City (KFMC), with a total of 59 patients diagnosed with HLH in the period between 2006 and 2018. All genetic results and clinical and biochemical data were retrieved and statistically analyzed using IBM SPSS Statistics for Windows, Version 25 (Released 2017; IBM Corp., Armonk, New York, United States). Results The results revealed that 48 patients (81.4%) had 15 pathogenic mutations of primary HLH whereas 8 (13.6%) patients had no genetic mutation. The most common variant mutation identified was c.1430C>T of the STXBP2 gene (42.4% of total patients), followed by c.1122G>A of the PRF1 gene (10.2% of patients), which demonstrated a distinctive geographic and tribal association. Patients with RAB27A mutation tend to present at an older age than the others with a median age of presentation of 5.5 months vs 2 months for patients with PRF1 mutations. No significant differences in clinical features were observed among the various groups. Conclusion This study highlights the incidence of genetic mutations among the Saudi population with HLH. The STXBP2 is the most common mutation followed by PRF1 mutations, many mutation variants are associated with a distinctive tribal and geographic association.
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Affiliation(s)
- Sami I Alradhi
- Pediatric Hematology and Oncology, Maternity and Children Hospital, Dammam, SAU
| | | | - Fahad Alamr
- College of Medicine, Al-Baha University, Al-Baha, SAU
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Rodrigues CM, Carvalho AC, Ventura S, Domingues ÂP, Silva A, Ministro P. Persistent Fever after COVID-19 Vaccination in a Patient with Ulcerative Colitis: A Call for Attention. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2024; 31:129-135. [PMID: 38572438 PMCID: PMC10987068 DOI: 10.1159/000530834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 02/06/2023] [Indexed: 04/05/2024]
Abstract
The development of vaccinations has been game-changing in the ongoing effort to combat the COVID-19 pandemic. Until now, adverse effects are being reported at low frequency, including thrombocytopenia and myocarditis. Careful monitoring for any suspicious symptoms and signs following vaccination is necessary. We report a case of hemophagocytic lymphohistiocytosis (HLH) after mRNA COVID-19 vaccine in a 23-year-old female with ulcerative colitis. Diagnosis was made according to HLH-2004 criteria and the patient was treated with dexamethasone with response. Our report aimed to draw attention to the potential relation between COVID-19 vaccines and HLH and the necessity of continued surveillance, especially in at-risk populations such as those with underlying immune dysregulation.
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Affiliation(s)
| | | | - Sofia Ventura
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | | | - Américo Silva
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | - Paula Ministro
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
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Li X, Wirtz T, Weber T, Lebedin M, Lowenstein ED, Sommermann T, Zach A, Yasuda T, de la Rosa K, Chu VT, Schulte JH, Müller I, Kocks C, Rajewsky K. Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis. Sci Immunol 2024; 9:eadi0042. [PMID: 38306418 DOI: 10.1126/sciimmunol.adi0042] [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: 03/30/2023] [Accepted: 01/11/2024] [Indexed: 02/04/2024]
Abstract
Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, often fatal immune deficiency characterized by severe systemic hyperinflammation. Although allogeneic bone marrow transplantation can be curative, more effective therapies are urgently needed. FHL is caused by inactivating mutations in proteins that regulate cellular immunity. Here, we used an adeno-associated virus-based CRISPR-Cas9 system with an inhibitor of nonhomologous end joining to repair such mutations in potentially long-lived T cells ex vivo. Repaired CD8 memory T cells efficiently cured lethal hyperinflammation in a mouse model of Epstein-Barr virus-triggered FHL2, a subtype caused by perforin-1 (Prf1) deficiency. Furthermore, repair of PRF1 and Munc13-4 (UNC13D)-whose deficiency causes the FHL subtype FHL3-in mutant memory T cells from two critically ill patients with FHL restored T cell cytotoxicity. These results provide a starting point for the treatment of genetic T cell immune dysregulation syndromes with repaired autologous T cells.
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Affiliation(s)
- Xun Li
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Tristan Wirtz
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Timm Weber
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Mikhail Lebedin
- Immune Mechanisms and Human Antibodies, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
| | - Elijah D Lowenstein
- Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Thomas Sommermann
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Andreas Zach
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
| | - Tomoharu Yasuda
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Kathrin de la Rosa
- Immune Mechanisms and Human Antibodies, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
- Center of Biological Design, Berlin Institute of Health (BIH) at Charité, 13125 Berlin, Germany
| | - Van Trung Chu
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
- Genome Engineering & Disease Models, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Johannes H Schulte
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
| | - Ingo Müller
- Division of Pediatric Stem Cell Transplantation and Immunology, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Christine Kocks
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
- Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Klaus Rajewsky
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
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Nagaraj CB, Brightman DS, Rea H, Wakefield E, Harkavy NVG, Dyer L, Zhang W. Detection of a novel gross deletion in the UNC13D gene ends the diagnostic odyssey for a family with familial hemophagocytic lymphohistiocytosis 3. BMC Pediatr 2024; 24:34. [PMID: 38212754 PMCID: PMC10782673 DOI: 10.1186/s12887-023-04510-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 12/26/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND Familial hemophagocytic lymphohistiocytosis (FHL) is an immunological disorder characterized by overactivation of macrophages and T lymphocytes. This autosomal recessive condition has been characterized into multiple types depending on the genetic etiology. FHL type 3 is associated with bi-allelic pathogenic variants in the UNC13D gene. CASE PRESENTATION We present a 12-year diagnostic odyssey for a family with FHL that signifies the advances of FHL genetic testing in a clinical genetic diagnostic laboratory setting. We describe the first case of a large UNC13D gross deletion in trans to a nonsense variant in a family with FHL3, which may have been mediated by Alu elements within introns 12 and 25 of the UNC13D gene. CONCLUSIONS This case highlights the importance of re-evaluating past genetic testing for a patient and family as test technology evolves in order to end a diagnostic odyssey.
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Affiliation(s)
- Chinmayee B Nagaraj
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Diana S Brightman
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH, 45229, USA
| | - Hannah Rea
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH, 45229, USA
| | - Emily Wakefield
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH, 45229, USA
| | - Nina V G Harkavy
- Department of OB/GYN, Columbia University Vagelos College of Physicians and Surgeons, New York City, NY, USA
| | - Lisa Dyer
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Wenying Zhang
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Rosado FG, Gopal P. Laboratory Features and Pathology of Cytokine Storm Syndromes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:43-58. [PMID: 39117807 DOI: 10.1007/978-3-031-59815-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
The laboratory diagnosis of cytokine storm syndromes (CSSs), i.e., hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), is often challenging. The laboratory features using routinely available tests lack specificity, whereas confirmatory testing is available in only few laboratories in the United States. The disease mechanisms are still largely unclear, particularly in adults. In this chapter, the pathogenesis of CSSs, their associated laboratory findings, and recommended diagnostic strategies are reviewed.
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Affiliation(s)
- Flavia G Rosado
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Purva Gopal
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Mansour R, El-Hassan R, El-Orfali Y, Saidu A, Al-Kalamouni H, Chen Q, Benamar M, Dbaibo G, Hanna-Wakim R, Chatila TA, Massaad MJ. The opposing effects of two gene defects in STX11 and SLP76 on the disease in a patient with an inborn error of immunity. J Allergy Clin Immunol 2023; 152:1597-1606. [PMID: 37595757 DOI: 10.1016/j.jaci.2023.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/03/2023] [Accepted: 08/10/2023] [Indexed: 08/20/2023]
Abstract
BACKGROUND Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect. OBJECTIVE We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death. METHODS Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting. T-cell proliferation and F-actin levels were studied by flow cytometry. RESULTS The patient harbored 2 homozygous deletions in STX11 (c.369_370del, c.374_376del; p.V124fs60∗) previously associated with familial hemophagocytic lymphohistiocytosis and a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) that resulted in an approximately 85% decrease in SLP76 levels and absent T-cell proliferation. The patient's heterozygous family members showed an approximately 50% decrease in SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells did not express SLP76 and had decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reconstitution of J14 cells with T256I mutant SLP76 resulted in low protein expression and abnormal extracellular signal-regulated kinase phosphorylation and F-actin polymerization after T-cell receptor activation compared with normal expression and J14 function when wild-type SLP76 was introduced. CONCLUSIONS The hypomorphic mutation in SLP76 tones down the hyperinflammation due to STX11 deletion, resulting in a combined immunodeficiency that overshadows the hemophagocytic lymphohistiocytosis phenotype. To our knowledge, this study represents the first report of the opposing effects of 2 gene defects on the disease in a patient with an inborn error of immunity.
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Affiliation(s)
- Rana Mansour
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rana El-Hassan
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Youmna El-Orfali
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Adam Saidu
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Habib Al-Kalamouni
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Qian Chen
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Mehdi Benamar
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Ghassan Dbaibo
- Department of Biochemistry, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon; Research Center of Excellence in Immunity and Infections, American University of Beirut, Beirut, Lebanon
| | - Rima Hanna-Wakim
- Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon
| | - Talal A Chatila
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Michel J Massaad
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon; Research Center of Excellence in Immunity and Infections, American University of Beirut, Beirut, Lebanon.
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11
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Xin X, Wang N, Zhang Y. Hemophagocytic lymphohistiocytosis with a hemizygous PRF1 c.674G>A mutation. Am J Med Sci 2023; 366:387-394. [PMID: 37467895 DOI: 10.1016/j.amjms.2023.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/23/2023] [Accepted: 07/14/2023] [Indexed: 07/21/2023]
Abstract
Hemophagocytic lymphohistiocytosis(HLH) is a rare highly-fatal disease presenting with fever, hepatosplenomegaly, and pancytopenia and has a poor prognosis. Homozygous or semi-zygous or complex heterozygous variants can cause familial HLH and heterozygous carriers are frequently seen in secondary HLH. A 42-year-old male patient was admitted to the hospital for persistent fever, fatigue, and splenomegaly. Investigations revealed hypertriglyceridemia, hyperlactatemia dehydrogenaseemia, hyperferritinemia, and elevated levels of soluble cluster of differentiation 25. We found a heterozygous mutation of PRF1: c.674G>A (p.R225Q) through next-generation sequencing technology of hemophagocytic-lymphohistiocytosis-related genes. After a brief remission with dexamethasone and etoposide-based therapy, the disease relapsed quickly, and an allogeneic hematopoietic stem cell transplant was performed to achieve complete remission. To date, the patient's condition was in complete remission. Our study detected a rare missense mutation in the PRF1 gene in a patient with HLH disease and the c.674G>A mutation may be rated as a possible pathogenic variant.
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Affiliation(s)
- Xiangke Xin
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Na Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yicheng Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Diorio C, Teachey DT, Canna SW. Cytokine Storm Syndromes in Pediatric Patients. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1636-1644. [PMID: 36990432 DOI: 10.1016/j.jaip.2023.03.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
Cytokine storm syndromes (CSS) represent a diverse group of disorders characterized by severe overactivation of the immune system. In the majority of patients, CSS arise from a combination of host factors, including genetic risk and predisposing conditions, and acute triggers such as infections. CSS present differently in adults than in children, who are more likely to present with monogenic forms of these disorders. Individual CSS are rare, but in aggregate represent an important cause of severe illness in both children and adults. We present 3 rare, illustrative cases of CSS in pediatric patients that describe the spectrum of CSS.
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Affiliation(s)
- Caroline Diorio
- Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Immune Dysregulation Frontier Program, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
| | - David T Teachey
- Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Immune Dysregulation Frontier Program, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa
| | - Scott W Canna
- Immune Dysregulation Frontier Program, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa
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13
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Brain MRI Findings of Hemophagocytic Lymphohistiocytosis With a Heterozygous PRF1 Gene Mutation Masquerading As CLIPPERS: A Case Report. Cureus 2023; 15:e36787. [PMID: 36998916 PMCID: PMC10043984 DOI: 10.7759/cureus.36787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2023] [Indexed: 03/30/2023] Open
Abstract
Familial hemophagocytic lymphohistiocytosis is a rare and potentially life-threatening genetic condition characterized by unsuppressed immune activation and hypercytokinemia. Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is a central nervous system inflammatory disorder characterized by punctate and curvilinear gadolinium-enhancing lesions in the brainstem, cerebellum, and spinal cord, which responds well to corticosteroid treatment. Hemophagocytic lymphohistiocytosis has been known to mimic CLIPPERS on neuroimaging, and patients previously diagnosed with CLIPPERS may carry familial hemophagocytic lymphohistiocytosis-related gene mutations that serve as predisposing factors. In this article, we describe a case initially diagnosed with CLIPPERS based on characteristic magnetic resonance imaging features and clinical course, who was later diagnosed with hemophagocytic lymphohistiocytosis based on a heterozygous familial hemophagocytic lymphohistiocytosis-associated PRF1 gene mutation.
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14
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Gupta S, Agrawal A. Dendritic cells in inborn errors of immunity. Front Immunol 2023; 14:1080129. [PMID: 36756122 PMCID: PMC9899832 DOI: 10.3389/fimmu.2023.1080129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 01/06/2023] [Indexed: 01/24/2023] Open
Abstract
Dendritic cells (DCs) are crucial cells for initiating and maintaining immune response. They play critical role in homeostasis, inflammation, and autoimmunity. A number of molecules regulate their functions including synapse formation, migration, immunity, and induction of tolerance. A number of IEI are characterized by mutations in genes encoding several of these molecules resulting in immunodeficiency, inflammation, and autoimmunity in IEI. Currently, there are 465 Inborn errors of immunity (IEI) that have been grouped in 10 different categories. However, comprehensive studies of DCs have been reported in only few IEI. Here we have reviewed biology of DCs in IEI classified according to recently published IUIS classification. We have reviewed DCs in selected IEI in each group category and discussed in depth changes in DCs where significant data are available regarding role of DCs in clinical and immunological manifestations. These include severe immunodeficiency diseases, antibody deficiencies, combined immunodeficiency with associated and syndromic features, especially disorders of synapse formation, and disorders of immune regulation.
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Affiliation(s)
- Sudhir Gupta
- Division of Basic and Clinical Immunology, University of California, Irvine, CA, United States
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15
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Alsohime F, Temsah MH, Alotaibi RM, Alhalabi RM, AlEnezy S, Yousef AA, Alzaydi AM, Inany HS, Al-Eyadhy A, Almazyad M, Alharbi A, Alsoqati AA, Andijani A, Abu Ghazal M, El Masri K, Doussouki M, Butt RF, Alshehri S, Alsatrawi M, Macarambon J, Hasan GM, Alsultan A. Presentations and outcomes of familial hemophagocytic lymphohistiocytosis in the pediatric intensive care units (PICUs). Front Pediatr 2023; 11:1152409. [PMID: 37144147 PMCID: PMC10151775 DOI: 10.3389/fped.2023.1152409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/30/2023] [Indexed: 05/06/2023] Open
Abstract
Objectives We aimed to describe Familial Hemophagocytic Lymphohistiocytosis (F-HLH) patients' clinical features, intensive care courses, and outcomes. Methods Multi-center retrospective cohort study of pediatric patients diagnosed with F-HLH from 2015 to 2020 in five tertiary centers in Saudi Arabia. Patients were classified as F-HLH based on their genetic confirmation of known mutation or on their clinical criteria, which include a constellation of abnormalities, early disease onset, recurrent HLH in the absence of other causes, or a family history of HLH. Results Fifty-eight patients (28 male, 30 female), with a mean age of 21.0 ± 33.9 months, were included. The most common principal diagnosis was hematological or immune dysfunction (39.7%), followed by cardiovascular dysfunction in 13 (22.4%) patients. Fever was the most common clinical presentation in 27.6%, followed by convulsions (13.8%) and bleeding (13.8%). There were 20 patients (34.5%) who had splenomegaly, and more than 70% of patients had hyperferritinemia >500 mg/dl, hypertriglyceridemia >150 mg/dl and hemophagocytosis in bone marrow biopsy. Compared to deceased patients 18 (31%), survivors had significantly lower PT (p = 041), bilirubin level of <34.2 mmol/L (p = 0.042), higher serum triglyceride level (p = 0.036), and lesser bleeding within the initial 6 h of admission (p = 0.004). Risk factors for mortality included requirements of higher levels of hemodynamic (61.1% vs. 17.5%, p = 0.001) and respiratory (88.9% vs. 37.5%, p < 0.001) support, and positive fungal cultures (p = 0.046). Conclusions Familial HLH still represents a challenge in the pediatric critical care setting. Earlier diagnosis and prompt initiation of appropriate treatment could improve F-HLH survival.
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Affiliation(s)
- Fahad Alsohime
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Pediatric Intensive Care Unit, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Mohamad-Hani Temsah
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Pediatric Intensive Care Unit, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
- Prince Abdullah bin Khaled Coeliac Disease Research Chair, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Correspondence: Mohamad-Hani Temsah
| | - Rawan M. Alotaibi
- College of Medicine, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Reham M. Alhalabi
- College of Medicine, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Sarah AlEnezy
- College of Medicine, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Aly Abdelrahman Yousef
- Division of Pediatric Critical Care, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
- Department of Pediatrics, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Abdullah Mohammed Alzaydi
- Division of Pediatric Critical Care, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Hussam Sameer Inany
- Division of Pediatric Critical Care, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Ayman Al-Eyadhy
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Pediatric Intensive Care Unit, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Mohammed Almazyad
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Pediatric Intensive Care Unit, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Ali Alharbi
- Pediatric Critical Care Division, Specialized Children Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Abdulaziz Abdullah Alsoqati
- Pediatric Critical Care Division, Specialized Children Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Abdurahman Andijani
- Pediatric Critical Care Division, Specialized Children Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mohammed Abu Ghazal
- Pediatric Critical Care Division, Specialized Children Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Kamal El Masri
- Pediatric Intensive Care Unit, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Maher Doussouki
- Pediatric Hematology & Oncology Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Raheel Farooq Butt
- Pediatric Critical Care Division, King Saud Medical City, Riyadh, Saudi Arabia
| | - Saleh Alshehri
- Pediatric Critical Care Division, King Saud Medical City, Riyadh, Saudi Arabia
| | - Mohammed Alsatrawi
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Pediatric Intensive Care Unit, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Jaramia Macarambon
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Gamal M. Hasan
- Pediatric Department, Assiut Faculty of Medicine, Assiut University, Assiut, Egypt
- Pediatric Department, Pediatric Intensive Care Unit, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Abdulrahman Alsultan
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Oncology Center, King Saud University Medical City, Riyadh, Saudi Arabia
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16
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Sadeghalvad M, Rezaei N. Immunodeficiencies. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00004-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Cooray S, Sabanathan S, Hacohen Y, Worth A, Eleftheriou D, Hemingway C. Treatment Strategies for Central Nervous System Effects in Primary and Secondary Haemophagocytic Lymphohistiocytosis in Children. Curr Treat Options Neurol 2022. [DOI: 10.1007/s11940-022-00705-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Abstract
Purpose of Review
This review presents an appraisal of current therapeutic options for the treatment of central nervous system haemophagocytic lymphohistiocytosis (CNS-HLH) in the context of systemic disease, as well as when CNS features occur in isolation. We present the reader with a diagnostic approach to CNS-HLH and commonly used treatment protocols. We discuss and evaluate newer treatments on the horizon.
Recent Findings
Mortality is high in patients who do not undergo HSCT, and while larger studies are required to establish benefit in many treatments, a number of new treatments are currently being evaluated. Alemtuzumab is being used as a first-line treatment for CNS-HLH in a phase I/II multicentre prospective clinical trial as an alternative to traditional HLH-1994 and 2004 protocols. It has also been used successfully as a second-line agent for the treatment of isolated CNS-HLH that is refractory to standard treatment. Ruxolitinib and emapalumab are new immunotherapies that block the Janus kinase—Signal Transducer and Activator of Transcription (JAK-STAT) pathway that have shown efficacy in refractory HLH, including for CNS-HLH disease.
Summary
Treatment of CNS-HLH often requires HLH-94 or 2004 protocols followed by haematopoietic stem cell transplantation (HSCT) to maintain remission, although relapse can occur, particularly with reduced intensity conditioning if donor chimerism falls. CNS features have been shown to improve or stabilise following HSCT in CNS-HLH in the context of systemic disease and in isolated CNS-HLH. Encouraging reports of early cohort studies suggest alemtuzumab and the Janus kinase (JAK) inhibitor ruxolitinib offer potential salvage therapy for relapsed and refractory CNS-HLH. Newer immunotherapies such as tocilizumab and natalizumab have been shown to be beneficial in sporadic cases. CNS-HLH due to primary gene defects may be amenable to gene therapy in the future.
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Ivanova ME, Lukoyanova N, Malhotra S, Topf M, Trapani JA, Voskoboinik I, Saibil HR. The pore conformation of lymphocyte perforin. SCIENCE ADVANCES 2022; 8:eabk3147. [PMID: 35148176 PMCID: PMC8836823 DOI: 10.1126/sciadv.abk3147] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 12/17/2021] [Indexed: 05/05/2023]
Abstract
Perforin is a pore-forming protein that facilitates rapid killing of pathogen-infected or cancerous cells by the immune system. Perforin is released from cytotoxic lymphocytes, together with proapoptotic granzymes, to bind to a target cell membrane where it oligomerizes and forms pores. The pores allow granzyme entry, which rapidly triggers the apoptotic death of the target cell. Here, we present a 4-Å resolution cryo-electron microscopy structure of the perforin pore, revealing previously unidentified inter- and intramolecular interactions stabilizing the assembly. During pore formation, the helix-turn-helix motif moves away from the bend in the central β sheet to form an intermolecular contact. Cryo-electron tomography shows that prepores form on the membrane surface with minimal conformational changes. Our findings suggest the sequence of conformational changes underlying oligomerization and membrane insertion, and explain how several pathogenic mutations affect function.
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Affiliation(s)
- Marina E. Ivanova
- Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet St, London WC1E 7HX, UK
- Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Natalya Lukoyanova
- Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet St, London WC1E 7HX, UK
| | - Sony Malhotra
- Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet St, London WC1E 7HX, UK
- Scientific Computing Department, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Fermi Ave, Harwell, Didcot OX11 0QX, UK
| | - Maya Topf
- Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet St, London WC1E 7HX, UK
- Centre for Structural Systems Biology, Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Joseph A. Trapani
- Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia
| | - Ilia Voskoboinik
- Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia
| | - Helen R. Saibil
- Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet St, London WC1E 7HX, UK
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Familial Hemophagocytic Lymphohistiocytosis Secondary to PRF1 Mutation. Case Rep Hematol 2022; 2021:7213939. [PMID: 35003815 PMCID: PMC8731261 DOI: 10.1155/2021/7213939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/17/2021] [Indexed: 12/03/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that causes systemic inflammation which can progress to multiorgan failure and death. Symptoms and signs commonly seen in HLH include high fever, hepatosplenomegaly, pancytopenia, and hypertriglyceridemia. This report describes the 8-month clinical course of a 17-year-old male with G6PD deficiency who presented with intermittent high fever of unknown origin for 8 months accompanied by pancytopenia and bilateral lower limb weakness. A pathogenic homozygous missense mutation (c.1081A > T p.(Arg361Trp)) in the PRF1 gene was detected by whole exome sequencing (WES). The brain and the whole spine MRI showed leptomeningeal enhancement at different levels involving both the brain and the spine. Therefore, a diagnosis of familial HLH type 2 with CNS involvement was confirmed. Accordingly, treatment with dexamethasone, cyclosporin, and etoposide in addition to intrathecal methotrexate and hydrocortisone was given. The patient showed a dramatic response with significant neurological improvement of the bilateral lower limb weakness. Genetic analysis has helped the patient's family with appropriate genetic counselling. This case highlights the importance of immediate treatment with immunosuppressants and the high clinical suspicion of physicians regarding HLH in areas where consanguinity is common.
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20
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Fávero Vanraes L, Beckers V, Van Berkel K, Gucciardo L, Faron G. Haemophagocytic lymphohistiocytosis during pregnancy: a case presentation and literature review. CASE REPORTS IN PERINATAL MEDICINE 2022; 11:20210004. [PMID: 40041215 PMCID: PMC11800670 DOI: 10.1515/crpm-2021-0004] [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: 01/10/2021] [Revised: 12/12/2021] [Accepted: 02/10/2022] [Indexed: 03/06/2025]
Abstract
Objectives Haemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disorder of the immune system that typically occurs in the paediatric population. Diagnosing this rare disease in the adult population is challenging, particularly during pregnancy. Case presentation We present a case of a gravid patient developing HLH at week 13 of gestation undergoing a medical termination of pregnancy at 27 weeks due to anhydramnios and associated stopped foetal growth. Conclusions Disease triggers could vary from a simple viral infection to the pregnancy as such causing the disorder. Treatment should benefit the mother and limit the foetal harm.
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Affiliation(s)
- Larissa Fávero Vanraes
- Department of Gynaecology and Obstetrics, Vrije Universiteit Brussel, Brussels Health Campus, Brussels, Belgium
| | - Veerle Beckers
- Division of Haematology, Department of Internal Medicine, Vrije Universiteit Brussel, Brussels Health Campus, Brussels, Belgium
| | - Kim Van Berkel
- Department of Medical Genetics, Vrije Universiteit Brussel, Brussels Health Campus, Brussels, Belgium
| | - Leonardo Gucciardo
- Division of Prenatal Medicine and Obstetrics, Department of Gynaecology and Obstetrics, Vrije Universiteit Brussel, Brussels Health Campus, Brussels, Belgium
| | - Gilles Faron
- Division of Prenatal Medicine and Obstetrics, Department of Gynaecology and Obstetrics, Vrije Universiteit Brussel, Brussels Health Campus, Brussels, Belgium
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21
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A Young Boy With Hemophagocytic Lymphohistiocytosis Presenting With Vaccine-Related Granulomatous Dermatitis: A Case Report and Literature Review. Am J Dermatopathol 2021; 43:e267-e272. [PMID: 34797807 DOI: 10.1097/dad.0000000000002075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Cutaneous eruptions associated with hemophagocytic lymphohistiocytosis (HLH) have been reported in 6%-63% of patients. Clinical findings of these skin lesions vary widely and include maculopapular rashes, ulcers, and violaceous nodules. Corresponding histologic findings are also variable and are considered nonspecific. We report the case of a 4-year-old boy who initially developed a widespread popular-pustular rash 2 weeks after his 12-month measles, mumps, and rubella vaccinations. These resolved with scarring then recurred following his 24-month vaccinations. Multiple skin biopsies were negative for infectious organisms and showed a granulomatous infiltrate with perforation and necrobiosis. The differential diagnosis included perforating granuloma annulare, infection, or rheumatoid nodules. At the age of 4, he developed fever, hepatosplenomegaly, pancytopenia and other laboratory abnormalities, requiring hospitalization. A number of studies were performed including biopsies of bone marrow and liver. Molecular testing revealed 2 mutations in UNC13D known to be associated with familial HLH. His prior cutaneous lesions were likely caused by immune dysregulation exacerbated by immunizations because of underlying familial HLH. This case illustrates the importance of recognizing an unusual cutaneous manifestation of a rare disease to arrive at an earlier diagnosis in a pediatric patient. Although cutaneous eruptions usually develop concurrently with other systemic symptoms of HLH, preceding unusual skin lesions may be the first indication of this rare disease.
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22
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Escaron C, Ralph E, Bibi S, Visser J, Aricò M, Rao K, Veys P, Gilmour K. Diagnosis of HLH: two siblings, two distinct genetic causes. Clin Exp Immunol 2021; 207:205-207. [PMID: 35020838 PMCID: PMC8982960 DOI: 10.1093/cei/uxab019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 02/03/2023] Open
Abstract
This report highlights case of two siblings who developed haemophagocytic lymphohystiocytosis due to distinct genetic abnormalities. Though their presentation was clinically similar, the cases demonstrate that a shared genetic diagnosis among siblings cannot be assumed.
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Affiliation(s)
- Claire Escaron
- Immunology Laboratory, Great Ormond Street Hospital, London, UK
| | - Elizabeth Ralph
- Immunology Laboratory, Great Ormond Street Hospital, London, UK,Correspondence: Elizabeth Ralph, Immunology Laboratory, Great Ormond Street Hospital, London, UK.
| | - Shahnaz Bibi
- Genetics Laboratory, Great Ormond Street Hospital, London, UK
| | - Johannes Visser
- Department of Paediatric Oncology, Addenbrookes Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Maurizio Aricò
- Azienda Ospedaliero-Universitaria Consorziale Policlinico Bari, Children Hospital 13 Giovanni XXIII, Bari, Italy
| | - Kanchan Rao
- Department of Bone Marrow Transplant, Great Ormond Street Hospital for Children, London, UK
| | - Paul Veys
- Department of Bone Marrow Transplant, Great Ormond Street Hospital for Children, London, UK
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23
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Lin CH, Shih YH, Chen TC, Chou CW, Hsu CY, Teng CLJ. A Decade of Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: Does the Outcome Improve? J Clin Med 2021; 10:jcm10215114. [PMID: 34768633 PMCID: PMC8584765 DOI: 10.3390/jcm10215114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/29/2021] [Accepted: 10/29/2021] [Indexed: 11/30/2022] Open
Abstract
To investigate the potential treatment evolution and outcome improvement, we retrospectively compared clinical characteristics, therapeutic strategies, treatment responses, and overall survival (OS) in patients diagnosed and treated with lymphoma-associated HLH between 2004–2012 (n = 30) and 2013–2021 (n = 26). Our study showed that the clinical characteristics of lymphoma-associated HLH did not substantially change over the past two decades. However, more patients diagnosed in 2013–2021 were tested for Epstein–Barr virus than those diagnosed in 2004–2012 (69.3% vs. 33.3%; p = 0.021). In addition, Eastern Cooperative Oncology Group performance status 3–4 (hazard ratio (HR): 5.38; 95% confidence intervals (CI): 2.49–11.61; p < 0.001) and jaundice (HR: 2.91; 95% CI: 1.37–6.18; p = 0.006) were poor prognostic factors for lymphoma-associated HLH. With a comparable response rate of lymphoma treatment, patients treated in 2013–2021 had a numerically greater median OS than those treated in 2004–2012 (23.6 ± 19.8 vs. 9.7 ± 4.5 months). However, the difference was not statistically significant (p = 0.334). In conclusion, early diagnosis and tailored treatments that balance efficacy and adverse events remain the key to obtaining a better outcome in lymphoma-associated HLH.
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Affiliation(s)
- Cheng-Hsien Lin
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-H.L.); (Y.-H.S.); (T.-C.C.); (C.-W.C.)
- College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan
| | - Yu-Hsuan Shih
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-H.L.); (Y.-H.S.); (T.-C.C.); (C.-W.C.)
- College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan
| | - Tsung-Chih Chen
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-H.L.); (Y.-H.S.); (T.-C.C.); (C.-W.C.)
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Cheng-Wei Chou
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-H.L.); (Y.-H.S.); (T.-C.C.); (C.-W.C.)
- College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan
| | - Chiann-Yi Hsu
- Biostatistics Task Force, Taichung Veterans General Hospital, Taicung 40705, Taiwan;
| | - Chieh-Lin Jerry Teng
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-H.L.); (Y.-H.S.); (T.-C.C.); (C.-W.C.)
- College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan
- Department of Life Science, Tunghai University, Taichung 407224, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Correspondence:
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Kikuchi A, Singh K, Gars E, Ohgami RS. Pathology updates and diagnostic approaches to hemophagocytic lymphohistiocytosis. Histopathology 2021; 80:616-626. [PMID: 34716920 DOI: 10.1111/his.14591] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/29/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a complex, often under-recognized hyperinflammatory immune dysregulation syndrome arising in a diverse range of clinical scenarios and conditions. The accurate and timely diagnosis of HLH is crucial for patient survival, and usually requires a high level of clinical suspicion. The histologic corollary to clinical HLH - hemophagocytosis - is neither necessary nor sufficient for the diagnosis of HLH, as it may be seen in a variety of reactive conditions and may be absent in true HLH. Nevertheless, the finding of hemophagocytosis in specific clinical situations should prompt consideration of HLH and further testing to exclude the condition. While traditionally described in bone marrow, identification of hemophagocytosis in other tissues, including lymphoid, splenic, liver, or neural tissue, can be an important asset to the overall recognition of HLH. In this review we discuss the underlying pathophysiology and etiologies of HLH, morphologic aspects of hemophagocytosis and its associated histologic findings in different tissues, and give a brief overview of diagnostic criteria and clinical evaluation.
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Affiliation(s)
- Alexander Kikuchi
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Kunwar Singh
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Eric Gars
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Robert S Ohgami
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
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Pai TS, Stancampiano FF, Rivera C. Hemophagocytic Lymphohistiocytosis for the Internist and Other Primary Care Providers. J Prim Care Community Health 2021; 12:21501327211053756. [PMID: 34704505 PMCID: PMC8554543 DOI: 10.1177/21501327211053756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) syndrome is a hyperinflammatory state that leads to life-threatening, disproportionate activation of the immune system and may be confused for and concomitantly exist with sepsis. However, its treatment differs from sepsis, requiring early initiation of immunosuppressive treatment. While HLH syndrome is more commonly diagnosed in children, internists and other primary care providers must be familiar with the diagnosis and treatment of adult patients with HLH in the hospital and outpatient setting. In this article, we review the essentials that an internist and other primary care providers managing adult HLH patients should know.
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Affiliation(s)
| | | | - Candido Rivera
- Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA
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26
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Hosaka S, Kido T, Imagawa K, Fukushima H, Morio T, Nonoyama S, Takada H. Vaccination for Patients with Inborn Errors of Immunity: a Nationwide Survey in Japan. J Clin Immunol 2021; 42:183-194. [PMID: 34704141 DOI: 10.1007/s10875-021-01160-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/11/2021] [Indexed: 01/23/2023]
Abstract
We conducted a nationwide survey of inborn errors of immunity (IEI) in Japan for the second time in 10 years, focusing on protective measures for IEI patients against infectious diseases. Questionnaires were sent to various medical departments nationwide, and a total of 1307 patients were reported. The prevalence of IEI was 2.2 patients per 100,000 population, which was comparable with the previous nationwide study. The most common disease category was autoinflammatory disorders (25%), followed by antibody deficiencies (24%) and congenital defects of phagocyte number or function (16%). We found that a significant number of patients received contraindicated vaccines, principally because the patients were not diagnosed with IEI by the time of the vaccination. Regarding diseases for which BCG vaccination is contraindicated, 43% of patients had actually received BCG, of which 14% developed BCG-related infections. BCG-related infections were mainly observed among patients with CGD and MSMD. In order to prevent IEI patients from receiving inadequate vaccines, continuous education to parents and physicians is needed, along with the expansion of newborn screening, but efforts to screen IEI at the site of vaccination also remain important.
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Affiliation(s)
- Sho Hosaka
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
| | - Takahiro Kido
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hiroko Fukushima
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Tomohiro Morio
- Department of Pediatrics, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
| | - Shigeaki Nonoyama
- Department of Pediatrics, National Defense Medical College, Saitama, Japan
| | - Hidetoshi Takada
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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Wilson C, Lee WI, Cook MC, Smyth L, Talaulikar D. Correlation of haemophagocytosis with clinical criteria of haemophagocytic lymphohistiocytosis and recommendations for bone marrow reporting. Pathology 2021; 54:434-441. [PMID: 34711415 DOI: 10.1016/j.pathol.2021.07.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/18/2021] [Accepted: 07/28/2021] [Indexed: 10/20/2022]
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a rare condition resulting from a dysregulated inflammatory response. Currently there are no guidelines on the reporting of haemophagocytosis on bone marrow biopsy (BM) and lack of evidence on correlation between haemophagocytosis with the clinical diagnostic criteria for HLH. We aimed to assess if the amount of haemophagocytosis identified in the BM correlates with HLH-2004 criteria. Secondary aims were to evaluate inter-observer variability in reporting haemophagocytosis, and to formulate recommendations for screening in bone marrow specimens. A retrospective review of bone marrow biopsies from adult patients under investigation for HLH was undertaken independently by two haematopathologists who were blinded to the original biopsy report. The average number of actively haemophagocytic cells in each slide were quantified. Cases with discordance pertaining to the degree of haemophagocytosis were reviewed by both assessors to reach a consensus. Sixty-two specimens from 59 patients were available for assessment. An underlying haematological condition was identified in 34 cases (58%). There was a significant association between the amount of haemophagocytosis identified on the aspirate samples and the number of HLH-2004 criteria met (p<0.0001). In patients where haemophagocytosis was present (n=31), there was a correlation between the amount of haemophagocytosis and ferritin (p=0.041). Based on our review, we have made recommendations for the reporting of BM haemophagocytosis. Our findings indicate that the amount of haemophagocytosis present on BM samples correlates with the number of HLH-2004 criteria. We found marked interobserver variability which we anticipate can be rectified with our recommendations for reporting.
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Affiliation(s)
- C Wilson
- Haematology Department, Canberra Hospital, Garran, ACT, Australia
| | - W I Lee
- Immunology Department, Canberra Hospital, Garran, ACT, Australia
| | - M C Cook
- Immunology Department, Canberra Hospital, Garran, ACT, Australia; Australian National University Medical School, Acton, ACT, Australia
| | - L Smyth
- Australian National University Medical School, Acton, ACT, Australia
| | - D Talaulikar
- Haematology Department, Canberra Hospital, Garran, ACT, Australia; Australian National University Medical School, Acton, ACT, Australia.
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Kelkar MG, Bargir UA, Malik-Yadav R, Gupta M, Dalvi A, Jodhawat N, Shinde S, Madkaikar MR. CD8 + T Cells Exhibit an Exhausted Phenotype in Hemophagocytic Lymphohistiocytosis. J Clin Immunol 2021; 41:1794-1803. [PMID: 34389889 DOI: 10.1007/s10875-021-01109-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/22/2021] [Indexed: 12/31/2022]
Abstract
PURPOSE Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome mainly caused by uncontrolled activation of antigen presenting cells and CD8 T cells. CD8 T cell exhaustion is a known phenomenon in chronic viral infections and cancer. However, the role of T cell exhaustion is not yet identified in HLH in the background of persistent inflammation. So, currently, we have characterized the CD8 T cells using flow cytometry to understand the phenomenon of exhaustion in these cells in HLH. METHODS We have comprehensively evaluated lymphocyte subsets and characterized CD8 T cells using immunophenotypic markers like PD1, TIM3, LAG3, Ki67, Granzyme B, etc. in a cohort of 21 HLH patients. Effector cytokine secretion and degranulation by CD8 T cells are also studied. RESULTS Our findings indicate skewed lymphocyte subsets and aberrantly activated CD8 T cells in HLH. CD8 T cells exhibit significantly increased expression of PD1, TIM3, and LAG3 prominently in primary HLH as compared to controls. PD1 + CD8 T cells express elevated levels of Granzyme B and Ki67. Moreover, CD8 T cells are hypofunctional as evidenced by significantly reduced cytokine secretion and compromised CD107a degranulation. CONCLUSION The study has revealed that CD8 + cytotoxic T lymphocytes from HLH patients exhibited high expression of exhaustion markers with overall impaired function. To the best of our understanding, this is the first report suggesting functional exhaustion of CD8 T cells in both primary and secondary HLH. Future studies to understand the association of exhaustion with disease outcome are needed for its probable therapeutic implementation.
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Affiliation(s)
- Madhura G Kelkar
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India
| | - Umair Ahmad Bargir
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India
| | - Reetika Malik-Yadav
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India
| | - Maya Gupta
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India
| | - Aparna Dalvi
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India
| | - Neha Jodhawat
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India
| | - Shweta Shinde
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India
| | - Manisha R Madkaikar
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology (NIIH), 13th Floor, NMS Building, KEM Hospital Campus, Parel, , Mumbai, 400012, India.
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Bi SH, Jiang LL, Dai LY, Wang LL, Liu GH, Teng RJ. Familial hemophagocytic lymphohistiocytosis type 2 in a female Chinese neonate: A case report and review of the literature. World J Clin Cases 2021; 9:6056-6066. [PMID: 34368327 PMCID: PMC8316947 DOI: 10.12998/wjcc.v9.i21.6056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/06/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare genetic disorder presenting with fever, hepatosplenomegaly, and pancytopenia secondary to perforin-1 (PRF1) mutation. FLH2 has been described in Chinese but usually presents after 1 year old. We describe a female Chinese neonate with FHL2 secondary to compound heterozygous PRF1 mutation with symptom onset before 1 mo old. We review Chinese FHL2 patients in the literature for comparison. CASE SUMMARY A 15-d-old female neonate was referred to our hospital for persistent fever and thrombocytopenia with diffuse petechiae. She was born to a G5P3 mother at 39 wk and 4 d via cesarean section secondary to breech presentation. No resuscitation was required at birth. She was described to be very sleepy with poor appetite since birth. She developed a fever up to 39.5°C at 7 d of life. Leukocytosis, anemia, and thrombocytopenia were detected at a local medical facility. CONCLUSION A literature review identified 75 Chinese FHL2 patients, with only five presenting in the first year of life. Missense and frameshift mutations are the most common PRF1 mutations in Chinese, with 24.8% having c.1349C>T followed by 11.6% having c.65delC. The c.658G>C mutation has only been reported once in the literature and our case suggests it can be pathogenic, at least in the presence of another pathogenic mutation such as c.1066C>T.
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Affiliation(s)
- Shao-Hua Bi
- Division of Neonatology, Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei 230022, Anhui Province, China
| | - Liang-Liang Jiang
- Department of Pediatric Neurology, Anhui Provincial Children's Hospital, Hefei 230022, Anhui Province, China
| | - Li-Ying Dai
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei 230022, Anhui Province, China
| | - Li-Li Wang
- Division of Neonatology, Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Guang-Hui Liu
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei 230022, Anhui Province, China
| | - Ru-Jeng Teng
- Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, WI 53226, United States
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Ahmari AA, Alsmadi O, Sheereen A, Elamin T, Jabr A, El-Baik L, Alhissi S, Saud BA, Al-Awwami M, Fawaz IA, Ayas M, Siddiqui K, Hawwari A. Genetic and clinical characteristics of pediatric patients with familial hemophagocytic lymphohistiocytosis. Blood Res 2021; 56:86-101. [PMID: 34083498 PMCID: PMC8246041 DOI: 10.5045/br.2021.2020308] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 05/02/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Our study was designed to investigate the frequencies and distributions of familial hemophagocytic lymphohistiocytosis (FHL) associated genes in Saudi patients. METHODS FHL associated gene screening was performed on 87 Saudi patients who were diagnosed with hemophagocytic lymphohistiocytosis (HLH) between 1995 and 2014. The clinical and biochemical profiles were also retrospectively captured and analyzed. RESULTS Homozygous mutations and mono-allelic variants were identified in 66 (75.9%) and 3 (3.5%) of the study participants, respectively. STXBP2 was the most frequently mutated gene (36% of patients) and mutations in STXBP2 and STX11 accounted for 58% of all FHL cases and demonstrated a specific geographical pattern. Patients in the FHL group presented at a significantly younger age than those belonging to the unknown-genetics group (median, 3.9 vs. 9.4 mo; P=0.005). The presenting clinical features were similar among the various genetic groups and the 5-year overall survival (OS) was 55.4% with a 5.6 year median follow-up. Patients with PRF1 mutations had a significantly poorer 5-year OS (21.4%, P =0.008) and patients undergoing hematopoietic stem cell transplant (72.4%) had a significantly better 5-year OS (66.5% vs. 0%, P =0.001). CONCLUSION Our study revealed the predominance of the STXBP2 mutations in Saudi patients with FHL. A genetic diagnosis was possible in 80% of the cohort and our data showed improved survival in FHL patients who underwent hematopoietic stem cell transplant.
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Affiliation(s)
- Ali Al Ahmari
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
- College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
| | - Osama Alsmadi
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
- Cell Therapy, Applied Genomics, King Hussein Cancer Center, Amman, Jordan, Arabia
| | - Atia Sheereen
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Tanziel Elamin
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Amal Jabr
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Lina El-Baik
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Safa Alhissi
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Bandar Al Saud
- Department of Pediatric Allergy/Immunology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Moheeb Al-Awwami
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ibrahim Al Fawaz
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
- College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
| | - Mouhab Ayas
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
- College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
| | - Khawar Siddiqui
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
| | - Abbas Hawwari
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City Hospital, Al-Ahsa, Saudi Arabia
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Kim YR, Kim DY. Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. Blood Res 2021; 56:S17-S25. [PMID: 33935031 PMCID: PMC8094004 DOI: 10.5045/br.2021.2020323] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.
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Affiliation(s)
- Yu Ri Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dae-Young Kim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
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Liu XY, Nie YB, Chen XJ, Gao XH, Zhai LJ, Min FL. Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report. World J Clin Cases 2021; 9:2289-2295. [PMID: 33869605 PMCID: PMC8026822 DOI: 10.12998/wjcc.v9.i10.2289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 01/19/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Familial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (PRF1) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review.
CASE SUMMARY We report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation.
CONCLUSION The delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.
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Affiliation(s)
- Xin-Yi Liu
- Department of Hematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Yan-Bo Nie
- Gene Sequencing Laboratory, Tianjin SINO-US-Diagnostics Co.Ltd, Tianjin 300000, China
| | - Xue-Jing Chen
- Flow Cytometry Laboratory, Tianjin SINO-US-Diagnostics Co.Ltd, Tianjin 300000, China
| | - Xiao-Hui Gao
- Department of Hematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Li-Jia Zhai
- Department of Hematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Feng-Ling Min
- Department of Hematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
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Patel V, Udwadia-Hegde A, Hajirnis O, Nemani T, Pandrowala A, Desai M, Geetha TS, Ramprasad V, Kashikar R. A Rare Neurological Presentation of Familial Hemophagocytic Lymphohistiocytosis. JOURNAL OF PEDIATRIC NEUROLOGY 2021. [DOI: 10.1055/s-0040-1712471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
AbstractIn this case report, we described a 15-year-old boy who presented with intermittent episodes of ataxia and diplopia since 6.5 years of age. Extensive workup done over several years was negative. Brain biopsy showed a neuroinflammatory disorder, and hence, differential diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, central nervous system (CNS) lymphoma, and small vessel CNS vasculitis were considered. A final diagnosis of familial hemophagocytic lymphohistiocytosis was made when the patient developed episodes of prolonged fever with pancytopenia much later in the course of illness and genetic workup revealed pathogenic mutations in the PRF1 gene.
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Affiliation(s)
- Vishal Patel
- Department of Pediatric Neurology, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India
| | - Anaita Udwadia-Hegde
- Department of Pediatric Neurology, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India
| | - Omkar Hajirnis
- Synapses Child Neurology & Development Center, Thane, Maharashtra, India
| | - Tarishi Nemani
- Department of Pediatric Neurology, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India
| | - Ambreen Pandrowala
- Department of Immunology, Narayana Health SRCC Children's Hospital, Mumbai, Maharashtra, India
| | - Mukesh Desai
- Department of Immunology, Narayana Health SRCC Children's Hospital, Mumbai, Maharashtra, India
| | - Thenral S. Geetha
- Department of Genetics, MedGenome Labs Ltd, Bangalore, Karnataka, India
| | - Vedam Ramprasad
- Department of Genetics, MedGenome Labs Ltd, Bangalore, Karnataka, India
| | - Ritu Kashikar
- Department of Radiology, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India
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Smits BM, van Montfrans J, Merrill SA, van de Corput L, van Gijn M, de Vries A, van den Bos C, Abbink F, van der Molen RG, Dors N, Lindemans C, Boelens JJ, Nierkens S. A Minimal Parameter Set Facilitating Early Decision-making in the Diagnosis of Hemophagocytic Lymphohistiocytosis. J Clin Immunol 2021; 41:1219-1228. [PMID: 33779897 PMCID: PMC8310853 DOI: 10.1007/s10875-021-01005-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 02/23/2021] [Indexed: 12/11/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation syndrome characterized by uncontrolled immune cell activation. Timely diagnosis is important, since early treatment can improve survival rates. However, completing all assessments needed to reach ≥5 positive criteria out of the 8 HLH-2004 criteria can be time consuming and may delay timely initiation of treatment. Hence, we applied a data-driven approach to identify a minimal parameter set for early decision-making towards the initiation of HLH-specific treatment. We retrospectively evaluated 165 patients from five Dutch tertiary hospitals with suspected HLH. Sixteen pHLH (median age 0.5 years) and 70 sHLH patients (median age 8.7 years) were identified using the HLH-2004 criteria. Clustering analysis and multi-receiver operator characteristics were used to identify parameters distinctive of HLH. The presence of either increased ferritin, cytopenia in ≥2 lineages, or splenomegaly distinguished HLH from non-HLH cases with a negative predictive value of 100%. A minimal parameter set consisting of 2 major criteria (phagocytosis and splenomegaly) and 3 minor criteria (cytopenia, increased ferritin, and increased triglycerides/low fibrinogen) predicted HLH with 95% (88-99) sensitivity and 94% (86-98) specificity. This finding was replicated in an independent retrospective validation cohort of 109 US patients (n = 109). By dividing a subset of the HLH-2004 criteria into major and minor criteria, this strategy uses the evaluation of less than 5 criteria to quickly identify patients with HLH. When confirmed in a prospective setting, this approach could be of value for timely diagnosis and treatment of HLH.
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Affiliation(s)
- Bas M Smits
- Center of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.,Department of Pediatric Immunology and Infectious Diseases, UMC Utrecht, Utrecht, The Netherlands
| | - Joris van Montfrans
- Department of Pediatric Immunology and Infectious Diseases, UMC Utrecht, Utrecht, The Netherlands
| | - Samuel A Merrill
- Division of Hematology/Oncology, West Virginia University, Morgantown, WV, USA
| | - Lisette van de Corput
- Center of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Mariëlle van Gijn
- Center of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.,Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Andrica de Vries
- Department of Pediatric Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Cor van den Bos
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.,Department of Pediatric Oncology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Floor Abbink
- Department of Pediatric Oncology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Renate G van der Molen
- Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Natasja Dors
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.,Department of Pediatric Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Jaap J Boelens
- Center of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.,Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.,Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stefan Nierkens
- Center of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands. .,Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
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Chu R, van Eeden C, Suresh S, Sligl WI, Osman M, Cohen Tervaert JW. Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis. Int J Mol Sci 2021; 22:2967. [PMID: 33803997 PMCID: PMC8001312 DOI: 10.3390/ijms22062967] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/12/2021] [Accepted: 03/10/2021] [Indexed: 12/15/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.
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Affiliation(s)
- Raymond Chu
- Division of Rheumatology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON K1H 7W9, Canada;
| | - Charmaine van Eeden
- Division of Rheumatology, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (M.O.)
| | - Sneha Suresh
- Division of IHOPE, Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 1C9, Canada;
| | - Wendy I. Sligl
- Department of Critical Care Medicine and Division of Infectious Diseases, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Mohammed Osman
- Division of Rheumatology, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (M.O.)
| | - Jan Willem Cohen Tervaert
- Division of Rheumatology, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (M.O.)
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Shabrish S, Kelkar M, Yadav RM, Bargir UA, Gupta M, Dalvi A, Aluri J, Kulkarni M, Shinde S, Sawant-Desai S, Kambli P, Hule G, Setia P, Jodhawat N, Gaikwad P, Dhawale A, Nambiar N, Gowri V, Pandrowala A, Taur P, Raj R, Uppuluri R, Sharma R, Kini P, Sivasankaran M, Munirathnam D, Vedam R, Vignesh P, Banday A, Rawat A, Aggarwal A, Poddar U, Girish M, Chaudhary A, Sampagar A, Jayaraman D, Chaudhary N, Shah N, Jijina F, Chandrakla S, Kanakia S, Arora B, Sen S, Lokeshwar M, Desai M, Madkaikar M. The Spectrum of Clinical, Immunological, and Molecular Findings in Familial Hemophagocytic Lymphohistiocytosis: Experience From India. Front Immunol 2021; 12:612583. [PMID: 33746956 PMCID: PMC7973116 DOI: 10.3389/fimmu.2021.612583] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 02/04/2021] [Indexed: 11/26/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation characterized by hyperactivation of the immune system, excessive cytokine secretion and severe systemic inflammation. HLH is classified as familial (FHL) when associated with mutations in PRF1, UNC13D, STX11, and STXBP2 genes. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. This study is a retrospective analysis of 101 molecularly characterized FHL patients over the last 10 years from 20 different referral centers in India. FHL2 and FHL3 together accounted for 84% of cases of FHL in our cohort. Patients belonging to different FHL subtypes were indistinguishable based on clinical and biochemical parameters. However, flow cytometry-based assays viz. perforin expression and degranulation assay were found to be specific and sensitive in diagnosis and classification of FHL patients. Molecular characterization of respective genes revealed 76 different disease-causing mutations including 39 (51%) novel mutations in PRF1, UNC13D, STX11, and STXBP2 genes. Overall, survival was poor (28%) irrespective of the age of onset or the type of mutation in our cohort. Altogether, this article sheds light on the current scenario of FHL in India. Our data reveal a wide genetic heterogeneity of FHL in the Indian population and confirms the poor prognosis of FHL. This study also emphasizes that though mutational analysis is important for diagnostic confirmation of FHL, flow cytometry based assays help significantly in rapid diagnosis and functional validation of novel variants identified.
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Affiliation(s)
- Snehal Shabrish
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Madhura Kelkar
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Reetika Malik Yadav
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Umair Ahmed Bargir
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Maya Gupta
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Aparna Dalvi
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Jahnavi Aluri
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Manasi Kulkarni
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Shweta Shinde
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Sneha Sawant-Desai
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Priyanka Kambli
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Gouri Hule
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Priyanka Setia
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Neha Jodhawat
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Pallavi Gaikwad
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Amruta Dhawale
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Nayana Nambiar
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
| | - Vijaya Gowri
- Department of Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Ambreen Pandrowala
- Department of Bone Marrow Transplant, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Prasad Taur
- Department of Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Revathi Raj
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Chennai, India
| | - Ramya Uppuluri
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Chennai, India
| | - Ratna Sharma
- Comprehensive Thalassemia Care, Pediatric Hematology-Oncology & Bone Marrow Transplantation Centre, Mumbai, India
| | - Pranoti Kini
- Comprehensive Thalassemia Care, Pediatric Hematology-Oncology & Bone Marrow Transplantation Centre, Mumbai, India
| | - Meena Sivasankaran
- Department of Pediatric Hemato-Oncology, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India
| | | | - Ramprasad Vedam
- Medgenome Labs Pvt Ltd., Narayana Health City, Bommasandra, India
| | - Pandiarajan Vignesh
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Aaqib Banday
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Amita Aggarwal
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Ujjal Poddar
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Meenakshi Girish
- Department of Pediatrics, All India Institute of Medical Sciences, Nagpur, India
| | - Abhijit Chaudhary
- Department of Pediatrics, All India Institute of Medical Sciences, Nagpur, India
| | | | - Dharani Jayaraman
- Department of Pediatrics, Sri Ramchandra Institute of Higher Education and Research, Chennai, India
| | - Narendra Chaudhary
- Department of Pediatrics, All India Institute of Medical Sciences, Bhopal, India
| | | | | | - S Chandrakla
- Department of Haematology, Seth G. S. Medical College and King Edward Memorial Hospital, Mumbai, India
| | - Swati Kanakia
- Lilavati Hospital and Research Centre, Mumbai, India
| | - Brijesh Arora
- Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, India
| | - Santanu Sen
- Kokilaben Dhirubai Ambani Hospital, Mumbai, India
| | | | - Mukesh Desai
- Department of Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Manisha Madkaikar
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research-National Institute of Immunohaematology, Mumbai, India
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De Rose DU, Coppola M, Gallini F, Maggio L, Vento G, Rigante D. Overview of the rarest causes of fever in newborns: handy hints for the neonatologist. J Perinatol 2021; 41:372-382. [PMID: 32719496 DOI: 10.1038/s41372-020-0744-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 06/23/2020] [Accepted: 07/17/2020] [Indexed: 12/17/2022]
Abstract
Neonatal causes of fever are a major source of concern for clinicians. If fever is combined with organ-specific sterile inflammatory manifestations the suspicion of autoinflammatory disorders should be considered, and the list of such conditions starting in the neonatal period includes chronic infantile neurological cutaneous articular syndrome, mevalonate kinase deficiency, deficiency of the interleukin-1 receptor antagonist, otulipenia, STING-associated vasculopathy with onset in infancy and Blau syndrome. Other causes of noninfectious fever that can rarely occur in newborns are Kawasaki disease, Behçet's disease, and hemophagocytic lymphohistiocytosis. Diagnosis of these exceptionally rare disorders is challenging for neonatologists. An early recognition of these complex diseases might lead to use more specific or rational drugs preventing permanent consequences. This review focuses on the rarest causes of fever occurring in the neonatal age with the aim of portraying many protean clinical pictures associated with fever and reviewing the potential available treatments.
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Affiliation(s)
- Domenico Umberto De Rose
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
- Department of Medical and Surgical Neonatology, "Bambino Gesù" Children's Hospital IRCCS, Rome, Italy.
| | - Maria Coppola
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Francesca Gallini
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luca Maggio
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Vento
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Donato Rigante
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
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Almalky M, Saleh SHA, Baz EG, Fakhr AE. Novel mutation in perforin gene causing familial hemophagocytic lymphohistiocytosis type 2 in an Egyptian infant: case report. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020. [DOI: 10.1186/s43042-020-00067-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathological immune activation characterized by clinical signs and symptoms of extreme inflammation. It results from the uninhibited proliferation and activation of cells of the macrophage lineage and leads to the production of excess amounts of pro-inflammatory cytokines. The familial form of HLH disease is due to mutations in several genes necessary for natural killer (NK) cell and T cell granule-mediated cytotoxic function. These genes are involved in sorting, trafficking, docking, and fusion of cytotoxic granules containing granzymes A and B and perforin to the cell membrane of the target cell (using the proteins LYST, AP-3 complex, Rab27a, Munc 13–4, Munc 18–2, syntaxin 11). Defect in any of those proteins results in defective cytotoxicity. Consequently, genes included in these steps play valuable roles in the pathogenesis of familial HLH disease including perforin (PRF1) gene in which defect causes familial HLH type 2 (FHL2).
Case presentation
A 2-year-old boy suffered from hepatosplenomegaly and fever. He fulfilled the required criteria for the diagnosis of HLH according to HLH-2004 diagnostic criteria. We screened the patient for the presence of mutations in the coding exons and of PRF1 gene by PCR amplification of genomic DNA followed by direct sequencing of the PCR products. We report a novel homozygous deletion/insertion frameshift mutation in PRF1 gene (M28393: exon 2: c.536delAinsCG p.F178fs). We treated him with HLH 2004 protocol of treatment and showed a remarkable response with resolution of fever and decrement in the size of hepatosplenomegaly.
Conclusions
Our study discovered a novel frameshift mutation in PRF1 gene in an infant with HLH disease, and it is the first report of this type of mutation in Egyptian patients with this disease.
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Eguizabal C, Herrera L, Inglés-Ferrándiz M, Izpisua Belmonte JC. Treating primary immunodeficiencies with defects in NK cells: from stem cell therapy to gene editing. Stem Cell Res Ther 2020; 11:453. [PMID: 33109263 PMCID: PMC7590703 DOI: 10.1186/s13287-020-01964-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 10/05/2020] [Indexed: 12/29/2022] Open
Abstract
Primary immunodeficiency diseases (PIDs) are rare diseases that are characterized by genetic mutations that damage immunological function, defense, or both. Some of these rare diseases are caused by aberrations in the normal development of natural killer cells (NKs) or affect their lytic synapse. The pathogenesis of these types of diseases as well as the processes underlying target recognition by human NK cells is not well understood. Utilizing induced pluripotent stem cells (iPSCs) will aid in the study of human disorders, especially in the PIDs with defects in NK cells for PID disease modeling. This, together with genome editing technology, makes it possible for us to facilitate the discovery of future therapeutics and/or cell therapy treatments for these patients, because, to date, the only curative treatment available in the most severe cases is hematopoietic stem cell transplantation (HSCT). Recent progress in gene editing technology using CRISPR/Cas9 has significantly increased our capability to precisely modify target sites in the human genome. Among the many tools available for us to study human PIDs, disease- and patient-specific iPSCs together with gene editing offer unique and exceptional methodologies to gain deeper and more thorough understanding of these diseases as well as develop possible alternative treatment strategies. In this review, we will discuss some immunodeficiency disorders affecting NK cell function, such as classical NK deficiencies (CNKD), functional NK deficiencies (FNKD), and PIDs with involving NK cells as well as strategies to model and correct these diseases for further study and possible avenues for future therapies.
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Affiliation(s)
- C Eguizabal
- Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
- Research Unit, Basque Center for Blood Transfusion and Human Tissues, Osakidetza, Galdakao, Spain.
| | - L Herrera
- Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Research Unit, Basque Center for Blood Transfusion and Human Tissues, Osakidetza, Galdakao, Spain
| | - M Inglés-Ferrándiz
- Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Research Unit, Basque Center for Blood Transfusion and Human Tissues, Osakidetza, Galdakao, Spain
| | - J C Izpisua Belmonte
- Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 93027, USA
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van Eeden C, Khan L, Osman MS, Cohen Tervaert JW. Natural Killer Cell Dysfunction and Its Role in COVID-19. Int J Mol Sci 2020; 21:E6351. [PMID: 32883007 PMCID: PMC7503862 DOI: 10.3390/ijms21176351] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/27/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022] Open
Abstract
When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.
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Affiliation(s)
| | | | | | - Jan Willem Cohen Tervaert
- Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (L.K.); (M.S.O.)
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41
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McLean J, Katebian R, Suh E, Mirza K, Amin S. Neonatal Hemophagocytic Lymphohistiocytosis. Neoreviews 2020; 20:e316-e325. [PMID: 31261095 DOI: 10.1542/neo.20-6-e316] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is extremely rare in the neonatal period. The incidence of neonatal HLH is not confirmed and may range from 1 in 50,000 to 150,000. The incidence varies based on ethnicity, particularly in populations in which consanguinity is common. HLH is associated with a high fatality rate and poor prognosis, making it important to recognize and diagnose it early. This review will concentrate primarily on the diagnosis and management of neonatal HLH.
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Affiliation(s)
| | | | | | - Kamran Mirza
- Pathology, Loyola University Medical Center, Chicago, IL
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Lee WI, Talaulikar D, Cook MC. Retrospective single-centre analysis of diagnostic approach to adult-onset haemophagocytic lymphohistiocytosis. Intern Med J 2020; 51:939-947. [PMID: 32388900 DOI: 10.1111/imj.14891] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/10/2020] [Accepted: 04/27/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder with a poor prognosis characterised by substantial immune activation leading to end-organ failure. In childhood, genetic defects that impair cytotoxic function of natural killer cells and T cells. (HLH) are often identified. In adults, clinical manifestations are similar to those observed in children but the aetiology is often unclear. AIMS To evaluate whether poor prognosis for adult HLH is in part due to lack of awareness of the disorder, which results in incomplete investigation and failure to implement timely treatment. METHODS We performed a retrospective case series of adult-onset HLH in a tertiary hospital in Australia. We evaluated clinical characteristics, treatment and outcome, and related these to application of standard diagnostic criteria for HLH. RESULTS In our centre, incomplete assessment of HLH criteria was common. Serum ferritin was the criterion most commonly assessed. Hyperferritinaemia ≥10 000 μg/L was highly sensitive in detecting patients with adult-onset HLH; however, the majority of patients who had hyperferritinaemia ≥10 000 μg/L did not have adult-onset HLH. CONCLUSION The present study highlights the importance of comprehensive application of diagnostic criteria to improve accuracy and timelines of the diagnosis of adult onset HLH.
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Affiliation(s)
- Wei-I Lee
- Department of Immunology, Canberra Hospital, Australia
| | | | - Matthew C Cook
- Department of Immunology, Canberra Hospital, Australia.,Centre for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
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Yarwood R, Hellicar J, Woodman PG, Lowe M. Membrane trafficking in health and disease. Dis Model Mech 2020; 13:13/4/dmm043448. [PMID: 32433026 PMCID: PMC7197876 DOI: 10.1242/dmm.043448] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Membrane trafficking pathways are essential for the viability and growth of cells, and play a major role in the interaction of cells with their environment. In this At a Glance article and accompanying poster, we outline the major cellular trafficking pathways and discuss how defects in the function of the molecular machinery that mediates this transport lead to various diseases in humans. We also briefly discuss possible therapeutic approaches that may be used in the future treatment of trafficking-based disorders. Summary: This At a Glance article and poster summarise the major intracellular membrane trafficking pathways and associated molecular machineries, and describe how defects in these give rise to disease in humans.
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Affiliation(s)
- Rebecca Yarwood
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - John Hellicar
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Philip G Woodman
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Martin Lowe
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
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44
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Liao CH, Lee NC, Jou ST, Chiang BL, Yu HH. UNC13D mutation presenting as fulminant familial hemophagocytic lymphohistiocytosis. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2020; 53:1039-1041. [PMID: 32327331 DOI: 10.1016/j.jmii.2020.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 03/13/2020] [Accepted: 04/05/2020] [Indexed: 11/25/2022]
Affiliation(s)
- Chun-Hua Liao
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Shiann-Tarng Jou
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Bor-Luen Chiang
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsin-Hui Yu
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan.
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45
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Gomez R, Maakaron J, Baiocchi R. Macrophage Activation Syndrome Versus Hemophagocytic Lymphohistiocytosis: A Diagnostic Dilemma in a Patient With Still's Disease and Epstein-Barr Virus Viremia. J Hematol 2020; 8:68-70. [PMID: 32300447 PMCID: PMC7153684 DOI: 10.14740/jh495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/06/2019] [Indexed: 01/19/2023] Open
Abstract
Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are two overlapping, potentially fatal syndromes classified by disorganization and malfunction of the immune system that results in wide spread inflammation and end-organ damage. We present the case of a 22-year-old female with both underlying adult-onset still’s disease and active Epstein-Barr virus (EVB) viremia who presented with criteria for MAS/HLH. She ultimately improved on an immunosuppressive regimen, and during follow-up was also found to be heterozygote carrier for a known genetic mutation that has been associated with “primary” HLH. This case thus highlights the clinical spectrum of HLH/MAS, the different treatment approaches, and the new investigations into the relationship between primary and secondary HLH.
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Affiliation(s)
- Roberta Gomez
- Department of Medicine/Pediatrics, The Ohio State University, Columbus, OH 43210, USA
| | - Joseph Maakaron
- Division of Hematology/Oncology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Robert Baiocchi
- Division of Hematology/Oncology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA
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46
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Tan CL, Yahaya MH, Ahmad NS, Lim CH. Macrophage activation syndrome as an initial presentation of systemic lupus erythematosus with sensorineural hearing loss in a young male patient. BMJ Case Rep 2020; 13:13/3/e233330. [PMID: 32169986 DOI: 10.1136/bcr-2019-233330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
An 18-year-old male adolescent presented with prolonged high spiking temperature, photosensitive rash, oral ulcers and reduced hearing bilaterally of recent onset. Examination revealed malar rash, vasculitis rash over bilateral palms and soles, oral and buccal ulcers, palpable posterior auricular and inguinal lymph nodes, and reduced hearing bilaterally. His further investigations noted pancytopaenia, elevated transaminases, hyperferritinaemia, low C3 and C4 levels, positive antinuclear antibody, double-stranded DNA and direct Coombs test, while bone marrow aspiration revealed active phagocytic activity suggestive of hemophagocytic syndrome. We made a diagnosis of systemic lupus erythematosus with macrophage activation syndrome. We treated him with pulse intravenous methylprednisolone and his condition improved drastically. Temperature resolved on the next day after intravenous methylprednisolone; bilateral sensorineural hearing loss improved to near-normal hearing after treatment. He remained well during follow-up with a tapering dose of prednisolone.
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Affiliation(s)
- Chou Luan Tan
- Rheumatology Unit, Department of Internal Medicine, Hospital Sultanah Bahiyah, Alor Setar, Malaysia
| | | | - Noor Shahrazat Ahmad
- Department of Internal Medicine, Hospital Sultanah Bahiyah, Alor Setar, Malaysia
| | - Chong Hong Lim
- Rheumatology Unit, Department of Internal Medicine, Hospital Sultanah Bahiyah, Alor Setar, Malaysia
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47
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Viñas-Giménez L, Padilla N, Batlle-Masó L, Casals F, Rivière JG, Martínez-Gallo M, de la Cruz X, Colobran R. FHLdb: A Comprehensive Database on the Molecular Basis of Familial Hemophagocytic Lymphohistiocytosis. Front Immunol 2020; 11:107. [PMID: 32076423 PMCID: PMC7006814 DOI: 10.3389/fimmu.2020.00107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 01/15/2020] [Indexed: 12/26/2022] Open
Abstract
Background: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders. The lack of comprehensive disease-specific mutation databases may hinder or delay classification of the genetic variants found in samples from these patients. This is especially true for familial hemophagocytic lymphohistiocytosis (FHL), a life-threatening PID classically considered an autosomal recessive condition, but with increasingly demonstrated genetic heterogeneity. Objective: The aim of this study was to build an open-access repository to collect detailed information on the known genetic variants reported in FHL. Methods: We manually reviewed more than 120 articles to identify all reported variants related to FHL. We retrieved relevant information about the allelic status, the number of patients with the same variant, and whether functional assays were done. We stored all the data retrieved in a PostgreSQL database and then built a website on top of it, using the Django framework. Results: The database designed (FHLdb) (https://www.biotoclin.org/FHLdb) contains comprehensive information on reported variants in the 4 genes related to FHL (PRF1, UNC13D, STXBP2, STX11). It comprises 240 missense, 69 frameshift, 51 nonsense, 51 splicing, 10 in-frame indel, 7 deep intronic, and 5 large rearrangement variants together with their allelic status, carrier(s) information, and functional evidence. All genetic variants have been classified as pathogenic, likely pathogenic, uncertain significance, likely benign or benign, according to the American College of Medical Genetics guidelines. Additionally, it integrates information from other relevant databases: clinical evidence from ClinVar and UniProt, population allele frequency from ExAC and gnomAD, and pathogenicity predictions from well-recognized tools (e.g., PolyPhen-2, SIFT). Finally, a diagram depicts the location of the variant relative to the gene exon and protein domain structures. Conclusion: FHLdb includes a broad range of data on the reported genetic variants in familial HLH genes. It is a free-access and easy-to-use resource that will facilitate the interpretation of molecular results of FHL patients, and it illustrates the potential value of disease-specific databases for other PIDs.
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Affiliation(s)
- Laura Viñas-Giménez
- Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain.,Jeffrey Model Foundation Excellence Center, Barcelona, Spain
| | - Natàlia Padilla
- Research Unit in Clinical and Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Laura Batlle-Masó
- Servei de Genòmica, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.,Departament de Ciències Experimentals i de la Salut, Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
| | - Ferran Casals
- Servei de Genòmica, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
| | - Jacques G Rivière
- Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP), Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.,Jeffrey Model Foundation Excellence Center, Barcelona, Spain
| | - Mónica Martínez-Gallo
- Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain.,Jeffrey Model Foundation Excellence Center, Barcelona, Spain
| | - Xavier de la Cruz
- Research Unit in Clinical and Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.,Institut Catala per la Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Roger Colobran
- Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain.,Jeffrey Model Foundation Excellence Center, Barcelona, Spain.,Genetics Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain
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48
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Disturbances in NK Cells in Various Types of Hemophagocytic Lymphohistiocytosis in a Population of Polish Children. J Pediatr Hematol Oncol 2019; 41:e277-e283. [PMID: 31107368 DOI: 10.1097/mph.0000000000001514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease associated with immune system hyperactivation and the appearance of serious systemic disturbances. The purpose of this study was an assessment of natural killer (NK) cell disturbances in a group of children with clinical signs of HLH. A total of 43 children with HLH and 17 healthy children were enrolled in the study. NK phenotyping, intracellular perforin staining, and cytotoxicity tests were performed by using the flow cytometry method. HLH patients were divided into 6 HLH types: 9% infection-related HLH; 7% malignancy-related HLH; 21% macrophage activating syndrome; 12% familial hemophagocytic lymphohistiocytosis; 2% X-linked lymphoproliferative syndrome; and 49% as HLH of unknown background. A positive correlation was observed between cytotoxicity and NK cells in children with HLH (P=0.01). In all HLH groups, the percentage of NK cells was significantly lower than in the control population. The spontaneous cytotoxicity was significantly lower in HLH patients. The results presented in this study indicate the importance of impaired function and the number of NK cells in the pathogenesis of HLH. Nonetheless, the background of disturbances seems to be different in various cases.
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49
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The inhibitory receptors on NK cells and CTLs are upregulated in adult and adolescent patients with secondary hemophagocytic lymphohistiocytosis. Clin Immunol 2019; 202:18-28. [PMID: 30914280 DOI: 10.1016/j.clim.2019.03.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 02/15/2019] [Accepted: 03/22/2019] [Indexed: 01/18/2023]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) includes primary HLH (pHLH) and secondary HLH (sHLH). Mutations that cause abnormal functions in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are frequently identified in pHLH. However, why NK cells and CTLs exhibit abnormal functions in sHLH remains unclear. Here, we demonstrated that NK cells in sHLH exhibited a high expression of inhibitory receptor NKG2A and a low expression of activating receptor NKG2D. Besides, the expression of HLA-E on lymphocyte, the adaptor of NKG2A on NK cells, was elevated in sHLH. Moreover, CTLs in sHLH patients expressed a higher level of functional exhaustion markers PD-1, TIM-3 and LAG-3 as well as a lower secretion of IFN-γ and CD107a upon stimulation. In addition, the expression of MHC-I on lymphocytes was decreased. Taken together, our study indicates a potentially pathological mechanism of sHLH and may open up new avenues for the development of immunotherapies against sHLH.
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50
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Al-Samkari H, Snyder GD, Nikiforow S, Tolaney SM, Freedman RA, Losman JA. Haemophagocytic lymphohistiocytosis complicating pembrolizumab treatment for metastatic breast cancer in a patient with the PRF1A91V gene polymorphism. J Med Genet 2018; 56:39-42. [PMID: 30287596 DOI: 10.1136/jmedgenet-2018-105485] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/12/2018] [Accepted: 09/18/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Immune checkpoint inhibitor therapy is a modern breakthrough in medical oncology, but it can precipitate inflammatory and autoimmune adverse effects. Among the most serious of these toxicities is haemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of unbridled immune activation that results in injury to multiple organ systems. OBJECTIVE Description of a case of pembrolizumab-associated HLH in a patient with a proposed underlying genetic risk factor for its occurrence. METHODS AND RESULTS We describe a patient with aggressive metastatic breast cancer who developed HLH while undergoing experimental treatment with pembrolizumab, resulting in critical illness and multiorgan system failure. Pembrolizumab discontinuation and high-dose corticosteroids were effective in managing HLH. Subsequent next-generation sequencing of 15 genes associated with HLH revealed a germline polymorphism in perforin-1 (PRF1), PRFA91V, that may have predisposed the patient to develop HLH. The patient has had no evidence of malignancy for 2 years following recovery despite receiving no further cancer-directed treatment. CONCLUSIONS HLH is a rare but serious complication of immune checkpoint blockade. Patients with underlying hypomorphic alleles in PRF1 may be predisposed to develop this toxicity. Further studies are necessary to confirm a possible link between perforin gene mutations and immune checkpoint blockade-associated HLH.
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Affiliation(s)
- Hanny Al-Samkari
- Center for Hematology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Gregory D Snyder
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sarah Nikiforow
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Rachel A Freedman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Julie-Aurore Losman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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