Emerg Infect Dis. Meeting the challenge of influenza pandemic preparedness in developing countries.

[Giuseppe]

Meeting the challenge of influenza pandemic preparedness in developing countries (CDC EID)

DOI: 10.3201/eid1503.080857
Suggested citation for this article: Fedson DS. Meeting the challenge of influenza pandemic preparedness in developing countries. Emerg Infect Dis. 2009 Mar; [Epub ahead of print]
Meeting the Challenge of Influenza Pandemic Preparedness in Developing Countries
David S. Fedson

Author affiliation: University of Virginia, Charlottesville, Virginia, USA (retired)

[Original full free PDF document at LINK. EDITED.]

Developing countries face unique difficulties in preparing for an influenza pandemic. Our current top-down approach will not provide these countries with adequate supplies of vaccines and antiviral agents. Consequently, they will have to use a bottom-up approach based on inexpensive generic agents that either modify the host response to influenza virus or act as antiviral agents. Several of these agents have shown promise and many are currently produced in developing countries. Investigators must primarily identify agents for managing infection in populations, and not simply seek explanations for how they work. They must determine in which countries these agents are produced and define patterns of distribution and costs. Because prepandemic research cannot establish whether these agents will be effective in a pandemic, randomized controlled trials must begin immediately after a new pandemic virus has emerged. Without this research, industrialized and developing countries could face an unprecedented health crisis.
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[Giuseppe]

Re: Emerg Infect Dis. Meeting the challenge of influenza pandemic preparedness in developing countries.

Some excerpts:

Many influenza scientists doubt this approach will work (14?16). Nonetheless, as reviewed elsewhere (13,14), several retrospective studies suggest that outpatient statins (drugs taken to lower cholesterol levels and prevent cardiovascular diseases) reduce 30-day pneumonia mortality rates by ≈50% (Table 2) (17?22). Most investigators agree that these observational studies must be interpreted with caution and that promising results should be followed by prospective clinical trials. One such trial is already under way, and a preliminary report has shown that in 67 pneumonia patients in intensive care units, treatment with statins reduced hospital mortality rates by 51% (p = 0.026) (23). Pulmonary investigators also believe that peroxisome proliferator?activated receptor (PPAR) α and PPARγ agonists (fibrates and glitazones, respectively) could be used to treat acute lung injury (14). An important experimental study has shown that the fibrate gemfibrozil, a PPARα agonist used to prevent heart disease, reduced mortality rates for mice infected with influenza virus (H2N2) by 54% (24). Statins and PPAR agonists have antiinflammatory and immunomodulatory activities, and there is considerable molecular cross-talk between these agents (14). Moreover, combination treatment is safe, and in patients with cardiovascular diseases, clinical benefits are additive. Used either alone or together, this treatment might similarly benefit patients during an influenza pandemic.

Other generic agents, some with direct activity against influenza virus, should also be considered (14). Chloroquine, long used as an antimalarial drug, increases endosomal pH and acts as an antiviral agent by impairing virus release into the cytosol. Resveratrol, a polyphenol found in red wine, reduces influenza mortality rates in experimentally infected mice (25). Catechins (found in green tea) (26) and curcumin (turmeric; found in curry powder) (27) have numerous cell-signaling effects, suggesting that they too might be beneficial. A combination of agents that act on both the host response and the virus might be required.
It is becoming increasingly difficult for investigators to ignore arguments for treating the host response to influenza. Recently, investigators showed that giving a neuraminidase inhibitor to mice infected with influenza virus A (H5N1) was not nearly as effective as treating the mice with an antiviral agent and 2 immunomodulatory agents, mesalazine, a PPARγ agonist, and celecoxib, a cyclooxygenase (COX)?2 inhibitor (28,29). In this model, targeting the host response to infection was essential for improving survival rates and times. More important, 2 studies of mice showed that intratracheal administration of either a fragment of the PB1-F2 protein of the 1918 influenza virus (30) or an inactivated influenza virus A (H5N1) (31) caused severe acute lung injury similar to that seen in fatal human cases of influenza (either from the 1918?1920 pandemic or from the current H5N1 subtype). In these experimental models, there was no virus replication. Thus, antiviral agents would have had no effect. Although we still lack direct evidence that one or more antiinflammatory and immunomodulatory agents alone would effectively treat human influenza virus A (H5N1) infections, these results and those from the study of influenza virus (H2N2)?infected mice treated with gemfibrozil (24) suggest these agents might be effective.
What makes these agents so important is that many of them are currently being produced as generic drugs in developing countries (13,14). These drugs are inexpensive, could be produced in abundance, and could even be stockpiled and made available for use on the first day of a pandemic. No matter what is accomplished in the years ahead, adequate supplies of vaccines and specific antiviral agents will never be available to persons in developing countries on the first pandemic day.

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[Giuseppe]

Re: Emerg Infect Dis. Meeting the challenge of influenza pandemic preparedness in developing countries.

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Conclusions
Oshitani et al. correctly emphasize that preparing for the next pandemic requires a global perspective, but this does not necessarily mean that the measures used to confront the pandemic in developing countries must be supplied through an internationally organized top-down process. An international process will surely be required for distributing vaccines and antiviral agents, but experience indicates that the process will be slow and cumbersome and supplies of these agents will remain scarce (2). Nonetheless, developing countries will need abundant supplies of effective agents, and abundance will be guaranteed only if these agents are generic, inexpensive, and produced in developing countries themselves.
It is too soon to know whether generic agents could be used to confront the next influenza pandemic, yet developing countries lack realistic alternatives. For this reason, their leaders must convince scientists and international organizations, including WHO, of the urgent need for research to determine whether these inexpensive agents could mitigate the effects of a pandemic. Otherwise, developing and industrialized countries alike could be faced with an unprecedented global health crisis.
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