J.Infect.Dis. Whole exome sequencing reveals mutations in hemophagocytic lymphohistiocytosis and macrophage activation syndrome linked genes in fatal

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1. J Infect Dis. (2015) doi: 10.1093/infdis/jiv550 First published online: November 23, 2015

[h=1]Whole exome sequencing reveals mutations in hemophagocytic lymphohistiocytosis and macrophage activation syndrome linked genes in fatal cases of H1N1 influenza[/h]

• Grant S. Schulert1,
• Mingce Zhang2,
• Ndate Fall1,
• Ammar Husami3,
• Diane Kissell3,
• Andrew Hanosh4,
• Kejian Zhang3,
• Kristina Davis4,
• Jeffrey M. Jentzen4,
• Lena Napolitano5,
• Javed Siddiqui4,7,
• Lauren B. Smith4,
• Paul W. Harms4,6,7,
• Alexei A. Grom1 and
• Randy Q. Cron2

+ Author Affiliations

• [SUP]1[/SUP]Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
• [SUP]2[/SUP]Division of Pediatric Rheumatology, Children's Hospital of Alabama/University of Alabama at Birmingham, Birmingham, AL
• [SUP]3[/SUP]Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
• [SUP]4[/SUP]Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
• [SUP]5[/SUP]Department of Surgery, University of Michigan Medical School, Ann Arbor, MI
• [SUP]6[/SUP]Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI
• [SUP]7[/SUP]Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI

• Address for Correspondence: Randy Q. Cron MD, PhD, Division of Pediatric Rheumatology, Children's Hospital of Alabama/University of Alabama at Birmingham, Children's Park Place, Ste. 210, 1601 4[SUP]th[/SUP] Avenue South, Birmingham, AL 35233, P: (205) 996-9191, F: (205) 996-9545, rcron@peds.uab.edu Or Alexei A. Grom MD, Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4010, Cincinnati, OH 45229, P: (513) 636-3339, F: (513) 636-5568, alexi.grom@cchmc.org

[h=2]Abstract[/h] Background.  Severe H1N1 influenza can be lethal in otherwise healthy individuals, and have features of secondary hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza.
Methods. Sixteen cases of fatal H1N1 infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells.
Results. Despite several lacking variables, H1N1 cases met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS.
Conclusions.  This cohort of fatal H1N1 influenza infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among H1N1 influenza infection.

http://jid.oxfordjournals.org/content/early/2015/11/23/infdis.jiv550