Study Finds Genetic Risk Factor Can Lead to Hyperinflammatory Disorder, Death After Viral Infection

Researchers at Cincinnati Children’s Hospital Medical Center, the University of Alabama Birmingham and Children’s of Alabama led the study, published online Nov. 23. They suggest people with other types of infections and identical gene mutations also may be prone to the disorder, known as reactive HLH (rHLH), or hemophagocytic lymphohistiocytosis.

HLH causes the immune system to essentially overwhelm the body with inflammation that attacks vital organs, often leading to death. Study authors raise the possibility of screening children for HLH genes to identify those who may be at risk during a viral infection.

“Viruses that cause robust immune responses may be more likely to trigger rHLH in genetically susceptible people,” said Randy Cron, M.D., Ph.D., a senior investigator on the study and physician in pediatric rheumatology at UAB and Children’s of Alabama. “Prenatal screening for mutations in common HLH-associated genes may find as much as 10 percent of the general population who are at risk for HLH when an inflammation threshold is reached from H1N1 or other infection triggers.”This study is the first to identify mutations of HLH-associated genes in H1N1 cases where patients had clinical symptoms of rHLH and a related condition called macrophage activation syndrome, or MAS. An outbreak of H1N1 in 2009 turned into a global pandemic. H1N1 has since become part of the viral mix for the annual flu season and preventive vaccine, the authors note.

Collaborating on the study were co-senior investigator Alexei Grom, M.D., and first author Grant Schulert, M.D., Ph.D., both physicians in the Division of Rheumatology at Cincinnati Children’s.

Cron and Grom have published articles linking clinical signs of rHLH to patients with hemorrhagic fever and systemic juvenile idiopathic arthritis, an inflammatory condition in which the body thinks it has an infection and attacks vital organs and joints. The precise reasons these patients have clinical signs of rHLH have not been clear, although some juvenile arthritis patients who develop MAS also have HLH-linked gene mutations, according to the authors.

There are two types of HLH, hereditary and the reactive form focused on in the current study. Both share common physical traits that involve the body’s immune system’s overheating, excessive proliferation of immune cells called macrophages and severe inflammation. The only curative treatment at present is a bone marrow transplant, a risky procedure that is not always successful.

“There are no widely accepted and validated diagnostic criteria for reactive HLH, and criteria for familial HLH are not considered effective for rHLH or MAS,” said Schulert. “Regardless, it seems clear that a sizeable number of patients with fatal H1N1 infection develop rHLH. Our data suggest some people may have a genetic predisposition to develop severe H1N1 influenza, and critically ill H1N1 patients should be carefully evaluated for rHLH and MAS. The question is whether immunosuppressive therapy may benefit some patients with life-threatening influenza infection.”

The current study examined the medical records of 16 adult patients ages 23 and 61 who died between 2009 and 2014 while infected with H1N1. The patients and their HLH-like symptoms initially were identified through the Michigan Hospital Department of Pathology Database by study collaborator Paul Harms, M.D., and his team at Michigan Center for Translational Pathology, University of Michigan Medical School.

Processed tissue samples from the patients were examined using whole exome genetic sequencing, which reads an individual’s entire genetic code of every gene.

Forty-four percent of the H1N1 cases met the clinical criteria for HLH and 81 percent for the related condition MAS. Five patients carried one of three different gene mutations in the commonly identified HLH gene LYST. Two of those same five patients also had a specific mutation in the gene PRF1, which decreases the function of immune system natural killer cells and aids the overproliferation of macrophage cells. Several patients in the study also carried variants of other genes linked to observed cases of MAS.

The current study involved a small patient population in a single state and was retrospective in design, looking at records from past cases. The authors recommend conducting a larger prospective study to determine whether genomic testing can predict the course of disease progression during influenza and other types of infections. Researchers also want to conduct further genomic and biological testing of children with juvenile arthritis to solidify potential links between gene mutations and secondary autoimmune disease.

Funding support for the study came in part from the National Institutes of Health (R01-AR059049, K12-HL119986), the Kaul Pediatric Research Institute and a Scientist Development Award from the American College of Rheumatology’s Rheumatology Research Foundation.

About Cincinnati Children’sCincinnati Children’s Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report’s 2015 Best Children’s Hospitals. It is also ranked in the top 10 for all 10 pediatric specialties, including a #1 ranking in pulmonology and #2 in cancer and in nephrology. Cincinnati Children’s, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati’s College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at www.cincinnatichildrens.org. Connect on the Cincinnati Children’s blog, via Facebook and on Twitter.

About UABKnown for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is an internationally renowned research university and academic medical center, as well as Alabama’s largest employer, with some 23,000 employees, and has an annual economic impact exceeding $5 billion on the state. The five pillars of UAB’s mission include education, research, patient care, community service and economic development. UAB is a two-time recipient of the prestigious Center for Translational Science Award. Learn more at www.uab.edu. UAB: Knowledge that will change your world.About Children’s of Alabama Since 1911, Children’s of Alabama has provided specialized medical care for ill and injured children, offering inpatient and outpatient services throughout central Alabama. Ranked among the best pediatric medical centers in the nation by U.S. News & World Report, Children’s provided care for youth from every county in Alabama, 42 other states and 10 foreign countries last year, representing more than 653,000 outpatient visits and nearly 14,000 inpatient admissions. With more than 2 million square feet, Children’s is the third-largest pediatric medical facility in the U.S. More information is available at www.childrensal.org.

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