Study finds influenza B may be more severe than thought

Feb 1, 2012 (CIDRAP News) – An autopsy study involving influenza B infections revealed how histologically similar the disease is to fatal influenza A and how quickly it can kill, challenging the notion that it is milder than influenza A.

The investigators, from the US Centers for Disease Control and Prevention (CDC), also found a high level of cardiac injury with fatal influenza B infections, especially in younger patients.

The research group said that comprehensive studies of influenza B deaths involving large series of patients and comparing those with and without bacterial pneumonia are lacking. Their findings appeared yesterday in the Journal of Infectious Diseases.

Scientists know more about influenza A, because they keep close watch for unpredictable antigenic changes and the virus is found in a wide range of birds and mammals.

In contrast, only two influenza B lineages circulate in humans. Though influenza B doesn't often dominate during flu seasons, mortality in epidemics involving the strain are typically somewhere in the middle for seasonal strains—more than for H1N1, but less than for H3N2.

Influenza B is more fatal in children, though the disease can cause a substantial number of seasonal flu infections in adults, including some deaths, according to the researchers.

The researchers obtained autopsy tissue samples submitted to the CDC from May 2000 until February 2010. They noted that supplemental clinical data were better for samples collected after 2003, when fatal pediatric flu infections became a nationally notifiable condition.

Histopathological examinations assessed airway, lung, cardiac, and lymph node tissue for evidence of influenza B. For lung tissue samples that had intraalveolar inflammatory cell infiltrates, researchers looked for evidence of bacterial coinfection. They examined cardiac tissue samples for signs of acute monocyte injury.

RNA extracted from tissue samples was evaluated with reverse-transcriptase polymerase chain reaction (rRT-PCR) tests to detect influenza B hemagglutinin gene segments, and lineage-specific probes were used to identify Victoria-like and Yamagata-like viruses.

Of the 45 case-patients, 29 were female and 16 male. The median age at death was 11 years, and 34 (76%) were younger than 18. For patients with available data, illnesses occurred between December and April, and preexisting medical conditions were present in 13 (43%). Of 35 patients with available information, 24 (69%) died within 4 days of illness onset.

Seventeen (38%) had evidence of bacterial pneumonia, which was more common in patients older than 18.

The most common pathologic finding, found in nearly all cases, was tracheal and bronchial inflammation. In 17 patients who had bacterial pneumonia, Staphylococcus aureus was found in 13 (76%), of whom 7 had genetic markers for methicillin resistance and 11 showed evidence of increased virulence.

Myocardial injury was seen in 20 (69%) of 29 case-patients for whom samples were available. Investigators found that 17 patients had evidence of myocyte damage, including 10 with myocarditis. They didn't find viral antigens in any of the myocardial samples, though rRT-PCR testing found evidence of influenza B from one patient's myocardial tissue.

Researchers said the study showed several key features of fatal influenza B infection, including how quickly the disease can kill and how histologically similar it is to fatal influenza A. They noted how infrequent bacterial coinfections were in young patients and how often cardiac injury was present.

The findings challenge the notion that influenza B infections are milder than influenza A infections, the group reported. CDC data from 2004 to 2008 suggest 34% of 309 pediatric flu deaths were linked to influenza B, they noted, adding that many of the case-patients had no underlying risk factors for flu complications, other than that they were young.

The group said the rapid progression from illness onset to death was a notable finding, with durations that were shorter than several other flu viruses, including the 1918 pandemic H1N1, 2009 H1N1, and seasonal H3N2. They added that reasons for the variations, which could relate to the disease itself or various biases, still need to be determined.

They also said the findings reinforce that the disease can be fatal in kids who don't have bacterial pneumonia coinfections.

Regarding the cardiac findings, the authors said they were surprised about how frequent evidence of cardiac damage was found, even when tests didn't reveal myocarditis.

To explore whether the finding was a testing artifact or related to an infectious disease process, they compared the cardiac tissue samples with cohorts who died suddenly from noninfectious causes and those who died from other types of infections. Myocardial injury in those without a myocarditis diagnosis still stood out in patients with influenza B, which suggests that cardiac injury might directly or indirectly play a role in some of the deaths, they suggested.

Previous reports have described skeletal myopathy in children infected with influenza B, and their histological descriptions are similar to those in the current case series, they wrote. The findings lend support to speculation that since influenza B can replicate in regenerating human muscle cell cultures, muscle growth in children may leave them more susceptible than older patients to flu-related myopathy.

The authors concluded that the burden of influenza B infection should not be overshadowed by the magnitude of influenza A viruses, and that increased awareness about fatal outcomes could help guide prevention and control strategies.

In an editorial in the same issue, Jonathan McCullers, MD, an infectious disease specialist at St. Jude Children's Research Hospital in Memphis, and Frederick Hayden, MD, a virologist at the University of Virginia School of Medicine in Charlottesville and Wellcome Trust in London, wrote that two features of the autopsy series are striking: that two-thirds had evidence of cardiac injury and that that those over 18 were more likely to have bacterial pneumonia coinfections and less likely to have cardiac injury.

They noted that the findings are consistent with the view that influenza rarely kills without a secondary cause.

However, they said the frequency of cardiac injury seen in the cases is unexpected, and that it's unclear if the findings are unique to the time span and patient population or if other contributing factors may have played a role in the children's deaths. The sparse clinical data that accompanied the autopsy samples makes speculation difficult, and more study, including cardiac disease in children, is needed, McCullers and Hayden added.

They noted that influenza B and seasonal flu are understudied, having been overshadowed by concerns over pandemics. Focusing more research efforts on seasonal flu, with its large burden, may benefit the response to novel strains, they said.

"The time may be ripe to rebalance research priorities," they wrote. "Increased funding is urgently needed for basic research and enhanced clinical study of risk factors and complications of seasonal influenza caused by both type A and B viruses."

The 2009 H1N1 pandemic showed how unprepared the scientific community is to rapidly conduct high-quality prospective research on flu, according to McCullers and Hayden, who suggested that establishing clinical networks dedicated to flu could improve seasonal flu research and pave the way for more rigorous study of emerging pandemic strains and other novel respiratory threats.

Paddock CD, Liu L, Denison AM, et al. Myocardial injury and bacterial pneumonia contribute to the pathogenesis of fatal influenza B virus infection. J Infect Dis 2012 Jan 30 [Abstract]

McCullers JA, Hayden FG. Fatal influenza B infections: time to reexamine influenza research priorities. (Editorial) J Infect Dis 2012 Jan 30 [Extract]

See also:

Mar 29, 2011, CIDRAP News story "Influenza B viruses with lower antiviral sensitivity reported"

Mar 12, 2010, CIDRAP News story "WHO: Influenza B gaining foothold in more countries"

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