A Traditional Chinese Formula Against Severe Influenza

[herbsandhelpers]

Using Complementary and Alternative Medicines to Target the Host Response during Severe Influenza

Lisa M. Alleva1, Charles Cai2 and Ian A. Clark1

© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Introduction
 
It is now generally accepted that the infectious agent in isolation does not cause the illness and fatal outcome seen in acute systemic infectious diseases. Instead, the pathogen induces host cells to generate excessive amounts of pro-inflammatory cytokines, the prototypic example being tumor necrosis factor (TNF), that alter organ function and host metabolism, thus generating the disease we observe (1,2). This general concept, originally proposed to describe the severe disease caused by malaria infection (3), then sepsis (4) and influenza (5), has taken root in the mainstream, and is now often referred to as the ‘cytokine storm’ (6).

Influenza researchers have embraced the cytokine storm mechanism as an explanation for the fatal human disease caused by avian H5N1 influenza (7–9). Likewise, the pandemic influenza outbreak of 1918 is likely to have induced an overwhelming and fatal cytokine response in humans, as mice and monkeys infected with a reconstructed 1918 influenza virus exhibited a dysregulated immune response and hypercytokinemia, which leads to death (10–12). The inevitable 3–6-month delay in vaccine availability in the event of a pandemic (13) means that treatments to prevent death (but not necessarily infection) are a necessity. Existing problems with antiviral drugs (stockpiles not big enough to treat populations, drugs need to be taken prophylactically or very soon after infection, resistant virus strains have emerged) further necessitate investigation into other treatments (14). 

Targeting the detrimental host response generated by particularly pathogenic strains of influenza virus would allow disease severity to be reduced to the point where people will be sick, but will not die as a result of infection. We see agents with an ability to damp inflammatory cytokine release [be they natural or pharmaceutical (15)] as ideal candidates for influenza disease treatments, particularly during the period while a new vaccine is being generated, and as useful adjunct treatments to antivirals. As has been suggested for statins (16), using agents that are in use in the human population for the treatment of other conditions means that the safety of such agents is already established, as is the optimal human dose range.

A Traditional Chinese Formula Could Also Protect Against Severe Influenza
 
Prescribed mixtures of Chinese herbs are given to patients with influenza. A common formula contains Jin Yin Hua (honeysuckle flower), Lian Qiao (forsythia fruit), Bo He (field mint), Jing Jie (schizonepeta), Jie Geng (root of balloon flower), Gan Cao (licorice root), Dang Gui (A. sinensis root), Dang Shen (Codonopsis root), Chai Hu (thorowax), Qianghuo (Notopterygium root) and Sheng Jiang (fresh ginger rhizome). Intriguingly, nine of these 11 herbs have been shown to possess anti-inflammatory properties. A. sinensis is dose-dependently protective during lethal experimental sepsis and endotoxemia (37) via its ability to limit release of HMGB1, as has already been discussed. There are many examples of Jie Geng (root of balloon flower), reducing both production of pro-inflammatory cytokines and pro-inflammatory mediators (such as reactive oxygen species and nitric oxide), with these effects likely to be mediated through suppression of activation of NF-B [e.g. see ref. (67)]. Sheng Jiang (fresh ginger rhizome), Gan Cao (licorice root) and Lian Qiao (forsythia fruit) also reduce levels of inflammatory cytokines via suppression of NF-B induction (e.g. see refs (68–70). Thus it seems that a mixture of herbs, as traditionally prescribed, is likely to have profound effects on the inflammatory cytokine balance, warranting further investigation of the mixture itself in vitro and in vivo.

Conclusion
 
The example given here of an ancient Chinese medicine formula used to treat influenza containing nine (out of 11) herbs with anti-inflammatory properties provides compelling evidence that the way forward for the treatment of influenza in a pandemic should be immunomodulation. The host response is targeted, rather than the virus itself. Our observation that treatment of influenza virus-infected mice with a pharmaceutical used in humans, the lipid-lowering and immunomodulatory PPAR alpha agonist gemfibrozil, resulted in significantly decreased influenza-induced mortality, further shows that targeting the host response is a valid possibility. The natural immunomodulatory agent biochanin A from Red Clover, which is both a PPAR alpha and PPAR gamma agonist, could have similar effects to gemfibrozil on the course of influenza disease in vivo. Chinese herbs such as A. sinensis and S. miltiorrhiza which independently reduce secretion of the novel inflammatory cytokine HMGB1, and glycyrrhizin from liquorice root, which binds to HMGB1 and inactivates its activity, provide another avenue for investigation, as does the establishment of the role of HMGB1 in severe influenza. The wide availability and low economic price of these agents could make such agents an inexpensive alternative treatment, particularly in countries with large populations who will have no access to pandemic vaccines or antivirals.

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