Wednesday, July 20, 2016

CMI: An Influenza Gut Check

Credit NIAID


Although influenza is primarily a gastrointestinal infection in birds, in humans it is generally perceived almost exclusively as an illness of the upper and lower respiratory tract. 

But over the years we've looked at atypical influenza presentations that raise some interesting questions about the tropism of influenza viruses. 

Perhaps the most commonly reported non-respiratory influenza presentation is conjunctivitis (see I Only Have Eyes For Flu). While not normally a presentation of seasonal flu, it was widely reported with the 2009 H1N1 virus, and is regularly reported with mild human infection with LPAI H7 viruses. 

Unlike a lot of other viruses, influenza is not generally regarded as a bloodborne pathogen, but a handful of studies have found viremia in both symptomatic and asymptomatic patients (see 2007's Influenza viremia and the potential for blood-borne transmission).

In the wake of the 2009 pandemic, additional evidence surfaced (see PLoS One: Viremia In The 2009 H1N1 Pandemic Influenza), which associated viremia with severe infection and  was strongly associated with the D222G/N mutation (see EuroSurveillance: Revisiting The D222G Mutation In A/H1N1pdm09).

Also rare, but not unheard of, is that influenza can be neuroinvasive

In January of 2010, the CDC’s EID Journal carried a report called Neurologic Manifestations of Pandemic (H1N1) 2009 Virus Infection and in September 2010 , the Annals of Neurology carried a study called Heightened Neurologic Complications in Children with Pandemic H1N1 Influenza.

H5N1 in particular has been cited as capable of directly infecting the brain (see PNAS study Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration).

And last, but not least, we've seen reports over the years linking influenza (not to be confused with the misnamed `stomach flu') with gastrointestinal infections. 

This became of some concern during the middle of the last decade when we saw a number of H5N1 infections supposedly linked to the consumption of contaminated poultry or poultry products in Southeast Asia.

This idea gained further momentum in  2010, when the Journal of Infectious Diseases published a study ( here) that demonstrated that the H5N1 avian flu virus can replicate ex vivo in the human gut.

And pdmH1N1 (and perhaps Influenza B) have also been looked at for exhibiting unusual gastrointestinal symptoms. In 2010, in Influenza’s Gastrointestinal Connection, I wrote about a study that appeared in BMC Infectious Diseases.

Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness
The detection of influenza viral RNA and viable influenza virus from stool suggests that influenza virus may be localized in the gastrointestinal tract of children, may be associated with pediatric diarrhea and may serve as a potential mode of transmission during seasonal and epidemic influenza outbreaks.

All of which brings us to a new study, published in Clinical Microbiology & Infection, that finds influenza A & B RNA present in fecal samples of more than 1/3rd of the patients they tested.

In two cases, viral RNA was detectable in their stool 2 weeks after it was no longer detectable in their sputum. 

For one patient who developed hemorrhagic colitis, a biopsy of the mucosal epithelium of the sigmoid colon yielded both viral mRNA and antigens, suggesting direct infection of the intestines.

Long term detection of seasonal influenza RNA in faeces and intestine
Ryohei Hirose, Tomo Daidoji correspondenceemail, Yuji Naito, Yohei Watanabe, Yasuha Arai, Tadashi Oda, Hideyuki Konishi, Masanaga Yamawaki, Yoshito Itoh, Takaaki Nakaya



Some cases of seasonal influenza virus (IAV/IBV) are associated with abdominal symptoms. Although viral RNA has been detected in faeces, intestinal infection has not been clearly demonstrated. We aimed to provide evidence that IAV/IBV infects the human intestine.


This prospective observational study measured viral RNA in faecal and sputum samples from 22 patients infected with IAV/IBV (19 IAV-positive and three IBV-positive). Nineteen patients were included in the analysis and assigned to “faecal IAV-positive” and “-negative” groups. Viral kinetics were examined in faecal samples from an IAV-infected patient (Case 1) and an IBV-infected patient (Case 2). Finally, intestinal tissue from an IAV-diagnosed patient, who developed haemorrhagic colitis and underwent colonoscopy, was examined for the presence of replicating IAV (Case 3).


Viral RNA was detected in faecal samples from 8/22 IAV/IBV-infected patients (36.4%). Diarrhoea occurred significantly more often in the faecal IAV-positive group (P = 0.002). In Cases 1 and 2, viral RNA became undetectable in sputum on Days 7 and 10 post-infection, respectively, but was detected in faeces for a further 2 weeks. Viral mRNA and antigens were detected in intestinal tissues (mucosal epithelium of the sigmoid colon) from Case 3.


These findings suggest that IAV/IBV infects within the intestinal tract; thus, the human intestine may be an additional target organ for IAV/IBV infection.

Proving once again, you never know what you might find, until you look for it.

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