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J Infect Dis. 2016 Apr 1;213(7):1180-8. doi: 10.1093/infdis/jiv550. Epub 2015 Nov 23.

Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza.

Author information

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

Abstract

BACKGROUND:

Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive 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 influenza A(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, cases of influenza A(H1N1) infection 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 influenza A(H1N1) 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 individuals with influenza A(H1N1) infection.

KEYWORDS:

H1N1 influenza; LYST; cytolytic pathway; hemophagocytosis; macrophage activation syndrome; perforin

PMID:
26597256
PMCID:
PMC4779301
DOI:
10.1093/infdis/jiv550
[Indexed for MEDLINE]
Free PMC Article

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