Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.
Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.
From Study Center of Primary Immunodeficiencies, Assistance Publique Hôpitaux de Paris (CP); Necker Hospital, Paris, France. Laboratory of Human Genetics of Infectious Diseases (CP, HvB, PG, MC, CLK, L. Abel, AP, JLC), Necker Branch, INSERM U980, Paris, France. Paris Descartes University (CP, HvB, PG, MC, CLK, L. Abel, AP, JLC), Paris, France. Department of Pediatric Pneumology and Immunology (HvB), Charité Hospital-Humboldt University, Berlin, Germany. Prince Naif Center for Immunology Research (PG, SAM, SAH, AAG, JLC), College of Medicine, King Saud University, Riyadh, Saudi Arabia. Division of Infectious Diseases (OL); and Division of Immunology (DM, RSG), Children's Hospital Boston (OL), Boston, Massachusetts. Harvard Medical School (OL, DM, RSG), Boston, Massachusetts. University of Manchester (PDA), Royal Manchester Children's Hospital, Manchester, United Kingdom. Department of Pediatrics (HT, TH), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Department of Pediatrics (JCK, CBC), Division of Pediatric Infectious Diseases, Vanderbilt University, Nashville, Tennessee. Centre of Chronic Immunodeficiency (SE), University of Freiburg, Freiburg, Germany. Department of Infectious and Pediatric Immunology (LM), Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. Department of Pediatrics (SAM, SAH, AAG), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Department of Pediatrics (NKDG), Division of Allergy and Immunology, University of South Florida and All Children's Hospital, St. Petersburg, Florida. Laboratory of Clinical Infectious Diseases (SMH, JIG), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. University of Oxford and Oxford Radcliffe Hospital (HC), Oxford, United Kingdom. Division of Infectious and Immunological Diseases (DPS), Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. Department of Immunology (CRG), Dr Negrin University Hospital of Gran Canaria, Las Palmas de Gran Canaria, Spain. Department of Pediatrics (EC), Unit of Infectious Diseases, Insular-Materno-Infantil University Hospital, Las Palmas de Gran Canaria, Spain. Schneider Children's Medical Center (BZG), Petah Tiqva, Israel. Division of Immunology and Allergy (C. Roifman), Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Department of Neurology (HY), Miyagi Children's Hospital, Sendai, Japan. Department of Pediatrics (SN), National Defense Medical College, Saitama, Japan. Pediatrics, Microbiology and Immunology (JD), SUNY Upstate Medical University, Syracuse, New York. Dalhousie University (ACI), Halifax, Nova Scotia, Canada. Royal Children's Hospital (MT, JS), Parkville, Victoria, Australia. University Children Hospital Ljubljana (SEZ), Ljubljana, Slovenia. Unité transversale d'Allergologie, Néphrologie et Immunologie Clinique (CH), Centre hospitalier universitaire de Tours, Tours, France. Department of Clinical Biochemistry and Immunology (DSK, RD), Addenbrookes Hospital, Cambridge, United Kingdom. Paediatric Immunology and Molecular Immunology Unit (AJT), Institute of Child Health, London, United Kingdom. Department of Clinical Immunology (EGD), Great Ormond St Hospital, London, United Kingdom. Immunology Department (CB), Derriford Hospital,Plymouth, United Kingdom. University Hospital Archet 2 (NS), Nice, France. Lenval Foundation (DDR), Children's Hospital, Nice, France. Cerrahpasa Medical School (YC), Istanbul University, Istanbul, Turkey. Clinical Pathology and Pediatric Department (JV, MG), General Hospital of Santo António, Porto, Portugal. Pediatric Department (ABV), Hospital S. João, Porto, Portugal. Pediatric Department (C. Rodrigo, FA, MM), Germans Trias i Pujol Hospital,Barcelona Autonomous University, Barcelona, Spain. Immunology Department-CDB (JIA), Hospital Clínic-IDIBAPS, Barcelona University, Barcelona, Spain. Pediatric Department (L. Alsina, CF), Hospital Sant Joan de Deu, Barcelona University, Barcelona, Spain. Immunology Department (JR), Universitäts-Kinderspital Zürich, Zürich, Switzerland. Pediatrics and Microbiology and Molecular Genetics (JMV), Medical College of Wisconsin, Milwaukee, Wisconsin. Experimental Laboratory Medicine (XB), Department of Medical Diagnostic Sciences, Biomedical Science Group, Catholic University Leuven, Leuven, Belgium. St. Giles Laboratory of Human Genetics of Infectious Diseases (JLC), Rockefeller Branch, The Rockefeller University, New York, New York. Pediatric Hematology-Immunology Unit (JLC), Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
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Horst
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Pegah
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Ghandil
Maya
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Chrabieh
Ofer
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Levy
Peter D
PD
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Douglas
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McDonald
Raif S
RS
Geha
Hidetoshi
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Jens C
JC
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CB
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CL
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Stephan
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László
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Maródi
Saleh
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Al-Muhsen
Sami
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Al-Hajjar
Abdulaziz
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Noorbibi K
NK
Day-Good
Steven M
SM
Holland
John I
JI
Gallin
Helen
H
Chapel
David P
DP
Speert
Carlos
C
Rodriguez-Gallego
Elena
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Ben-Zion
BZ
Garty
Chaim
C
Roifman
Toshiro
T
Hara
Hideto
H
Yoshikawa
Shigeaki
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Nonoyama
Joseph
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Domachowske
Andrew C
AC
Issekutz
Mimi
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Tang
Joanne
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Simona Eva
SE
Zitnik
Cyrille
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Dinakantha S
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Kumararatne
Adrian J
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Thrasher
E Graham
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Davies
Claire
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Nicolas
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Dominique
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Yildiz
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Júlia
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Vasconcelos
Margarida
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Guedes
Artur Bonito
AB
Vitor
Carlos
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Rodrigo
Francisco
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Almazán
Maria
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Juan Ignacio
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Laia
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Alsina
Claudia
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Janine
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James W
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Xavier
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Rainer
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Anne
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D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001424:Bacterial Infections / Q000453:epidemiology / Q000517:prevention & control; D002648:Child; D002675:Child, Preschool; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D007109:Immunity; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency* / Q000235:genetics; D008297:Male; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
D000900:Anti-Bacterial Agents; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases