Severe
influenza is characterized by
cytokine storm and multiorgan failure.
Influenza patients with underlying diseases show a rapid progression in disease severity. The major mechanism that underlies multiorgan failure during the progressive stage of
infection, particularly in patients with underlying risk factors, is mitochondrial energy crisis. The relationship between the factors that determine
infection severity, such as influenza virus,
cytokines, cellular
trypsin as a
hemagglutinin processing
protease for viral multiplication, accumulation of metabolic intermediates and
ATP crisis in mitochondria, is termed the "influenza virus-
cytokine-
trypsin" cycle. This occurs during the initial stages of
infection, and is interconnected with the "metabolic disorders-
cytokine" cycle in the middle to late phase of
infection. Experiments using animal models have highlighted the complex relationship between these two cycles. New treatment options have been proposed that target the
ATP crisis and multiorgan failure during the late phase of
infection, rather than
antiviral treatments with
neuraminidase inhibitors that work during the initial phase. These options are (i) restoration of
glucose oxidation in mitochondria by
diisopropylamine dichloroacetate, which inhibits
infection-induced
pyruvate dehydrogenase kinase 4 activity, and (ii) restoration of long-chain
fatty acid oxidation in mitochondria by
l-carnitine and
bezafibrate, an agonist of peroxisome proliferation-activated receptors-β/δ, which transcriptionally upregulates
carnitine palmitoyltransferase II. The latter is particularly effective in patients with
influenza-associated
encephalopathy who have thermolabile and short half-life compound variants of
carnitine palmitoyltransferase II.