Drug Discovery Opinion

The pandemic swine flu (H1N1) virus has proved to be less lethal than originally feared but, although most infected individuals experience relatively mild and self-limiting symptoms, some patients with no previous underlying medical condition have died. An international team of researchers has now found a possible explanation of why some people develop severe pneumonia when infected with the H1N1 virus. The team profiled immune mediators in 20 patients with severe symptoms, 15 patients with mild symptoms and 15 healthy controls. A typical innate antiviral response with increased levels of chemokines IP-10, MCP-1 and MIP-1β and an absence of anti-H1N1 antibodies characterised the early response in all infected individuals, but elevated levels of IFN-γ and mediators that stimulate Th17 and Th1 responses were found only in hospitalised patients. Both critical and non-critical hospitalised patients had increased levels of IFN-γ, Th17 mediators (IL-8, IL-9, IL17 and IL6) and Th1 mediators (TNF-α, IL-15 and IL-12p70) compared to outpatients. All hospitalised patients showed higher levels of IL-17 and TNF-α than controls but only the non-critical patients showed significant higher levels of IL-17 and TNF-α than those with mild symptoms. Levels of IL-15, IL-12p70 increased exclusively in critical patients who also showed the highest levels of IL-6.

Around half of hospitalised patients and nearly all outpatients tested positive for virus, with all those who tested positive having similar viral loads. Significantly higher levels of IL-13 and IL-17 were found in hospitalised patients with undetectable virus. IL6 was found to show a significant inverse association with arterial blood oxygen pressure in hospitalised patients and a similar inverse relationship was found for IL-8 in the critically ill patients.

Th1 and Th17 cells form an important part of host defence against pathogens but TH17 cells have also been linked to the pathogenesis of autoimmune and inflammatory diseases. It is presently unclear whether the increase in Th1 and Th17 responses reflects a vigorous antiviral defence necessary to clear lower respiratory infection or whether the inflammatory response contributes to disease severity. Although the ability of influenza viruses to evoke an inflammatory response is well known, this is the first study to link a Th17 response to severe influenza disease in humans. The authors suggest that immunomodulatory drugs which down-modulate Th1 and Th17 responses could be used to clarify the role of these pathways in the pathogenesis of the acute respiratory symptoms shown by patients with severe H1N1 disease. “Hypercytokinemia” of specific chemokines and cytokines has previously been shown to be associated with severe and often fatal cases of human H5N1 infections.

The study is published in the journal Critical Care.

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