title: The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.
abstract: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Sebastian Fn
authors.initials: SF
authors.lastname: Bode
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany Faculty of Biology, University of Freiburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ammann
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: Discipline of Pediatrics III, Victor Babes University of Medicine and Pharmacy Timisoara, Romania.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Bataneant
authors.affiliation: Pediatric Allergy, Immunology and Blood and Marrow Transplant Division, UCSF, Benioff Children's Hospital, San Francisco, California, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Dvorak
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Mainz, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gehring
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.affiliation: Camelia Botnar Laboratories, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.affiliation: Immunodeficiencies Unit, Hematology & Oncology Unit, Pediatrics, Hospital 12 Octubre, Madrid, Spain.
authors.forename: Luis I
authors.initials: LI
authors.lastname: Gonzalez-Granado
authors.affiliation: Pediatric Hematology, Oncology and Immunology, Olga Hospital, Stuttgart, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Groß-Wieltsch
authors.affiliation: Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ifversen
authors.affiliation: Department of Pediatrics, Halland Hospital, Halmstad, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lingman-Framme
authors.affiliation: St Anna Children's Hospital, Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Matthes-Martin
authors.affiliation: Department of Medicine/Hematology and Oncology, University Hospital Muenster, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Mesters
authors.affiliation: Department of Pediatrics, Department of Micriobiology and Immunology, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meyts
authors.affiliation: Department of Pediatric Immunology, Wilhelmina Children's, Hospital/University Medical Centre Utrecht, The Netherlands.
authors.forename: Joris M
authors.initials: JM
authors.lastname: van Montfrans
authors.affiliation: Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies, University Children's Hospital Zurich, Switzerland.
authors.forename: Jana
authors.initials: J
authors.lastname: Pachlopnik Schmid
authors.affiliation: Division of Hematology-Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Sung-Yun
authors.initials: SY
authors.lastname: Pai
authors.affiliation: Pediatric Infectious Diseases and Immunodeficiencies Unit. Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Soler-Palacin
authors.affiliation: Children's Hospital of Datteln, University of Witten-Herdecke, Datteln, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Schuermann
authors.affiliation: Hospital for Children and Adolescents, University of Leipzig, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Schuster
authors.affiliation: Pediatric Hematology-Oncology, Medical University of Graz, Austria.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Seidel
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Pediatric Hematology-Oncology, Medical School Hannover, Germany.
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vraetz
authors.affiliation: Sheffield Children's Hospital, NHS Foundation Trust, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Waruiru
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.affiliation: Unit for Pediatric Immunology, Hematology and Rheumatology (UIHR), Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: Department of Hematology and Oncology, Children's Hospital, University of Hamburg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Lehmberg
authors.affiliation: Division of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical School, Ohio, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jordan
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany stephan.ehl@uniklinik-freiburg.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
mesh_terms: D000293:Adolescent; D000328:Adult; D001424:Bacterial Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005060:Europe; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology; D007155:Immunologic Factors / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007896:Leishmaniasis / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology; D008297:Male; D009181:Mycoses / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D009894:Opportunistic Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D012042:Registries; D013256:Steroids / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009626:Terminology as Topic; D014777:Virus Diseases / Q000150:complications / Q000188:drug therapy / Q000276:immunology
chemical_list: D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D013256:Steroids