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CSU 26/2008: PREPARATIONS FOR INFLUENZA PANDEMIC IN DEVELOPING COUNTRIES

Friday, 13th of June 2008

CSU 26/2008: PREPARATIONS FOR INFLUENZA PANDEMIC IN DEVELOPING COUNTRIES
 
 The spectre of a future influenza pandemic, like that of 1918, is very much
 potential, in contrast to the immediate problems of HIV, malaria and
 malnutrition which are at the top of the agenda in most developing
 countries.
 
 In this article from Emerging Infectious Diseases, Oshitani and colleagues
 review the state of preparations for pandemic influenza in the developing
 world. Full text with tables is at www.cdc.gov/eid. They
 conclude that mitigation strategies should take priority in resource scarce
 settings.
 
 Good reading.
 
 BD
 
 
 
 EID Journal Home Volume 14, Number 6–June 2008
 
 Volume 14, Number 6–June 2008
 
 Perspective
 
 Major Issues and Challenges of Influenza Pandemic Preparedness in
 Developing Countries
 
 Hitoshi Oshitani,* Taro Kamigaki,* and Akira Suzuki*
 *Tohoku University Graduate School of Medicine, Sendai, Japan
 
 Suggested citation for this article
 
 Abstract
 

Better preparedness for an influenza pandemic mitigates its impact. Many
 countries have started developing and implementing national influenza
 pandemic preparedness plans. However, the level of preparedness varies
 among countries. Developing countries encounter unique and difficult issues
 and challenges in preparing for a pandemic. Deaths attributable to an
 influenza pandemic could be substantially higher in developing countries
 than in industrialized countries. Pharmaceutical interventions such as
 vaccines and antiviral agents are less likely to be available in developing
 countries. The public health and clinical infrastructure of developing
 countries are often inadequate to deal with a widespread health crisis such
 as an influenza pandemic. Such an event will inevitably have a global
 effect. Therefore, improving pandemic preparedness in every country,
 particularly developing ones, is urgently needed.
 
 Avian influenza, caused by influenza A virus (H5N1), continues to cause
 outbreaks among poultry and wild birds worldwide. It has spread from Asia
 to other regions, including Europe, the Middle East, and Africa. The number
 of cases of human subtype H5N1 infection also continues to rise. These
 historically unprecedented outbreaks have raised serious global concerns
 about the imminent arrival of an influenza pandemic. The World Health
 Organization (WHO) urges countries to develop and implement national
 pandemic preparedness plans to mitigate the health and social effects of a
 pandemic (1). However, the level of preparedness varies among countries. In
 general, developing countries have limited financial and technical
 resources to strengthen pandemic preparedness. They also face some unique
 and difficult issues, which make preparing for a pandemic more challenging.
 These have not been addressed adequately during planning. Effective and
 feasible strategies are needed to mitigate the impact of the next influenza
 pandemic in developing countries.
 
 Major Issues
 
 Potential Impact of Next Influenza Pandemic in Developing Countries
 
 When an influenza pandemic emerges, all countries worldwide will inevitably
 be affected. However, the impact may vary both between and within
 countries. The estimated deaths for various countries during the Spanish
 flu pandemic from 1918 to 1920 shows that mortality rates in Europe and
 North America were significantly lower than those in Asia, Sub-Saharan
 Africa, and Latin America (2,3). A recent study that estimated the global
 impact of the Spanish flu pandemic indicated that a considerable difference
 in mortality rates was observed between high- and low-income countries (4).
 Why the pandemic caused such high mortality rates in developing countries
 is not entirely clear. Several factors may have been involved, including
 lack of access to adequate medical care, weak public health
 infrastructures, social factors such as housing conditions and population
 density, and host factors such as nutritional status and co-existing
 medical conditions. Another potential factor likely to influence mortality
 in a future pandemic is the high HIV/AIDS prevalence in some developing
 countries. Excess deaths attributed to pneumonia or influenza are
 significantly higher in HIV-positive persons during influenza seasons (5).
 HIV co-infection with a pandemic virus can be associated with more severe
 infections, which may further raise death rates in countries with high
 HIV/AIDS prevalence.
 
 For these reasons, deaths associated with a future pandemic may be greater
 in developing countries than in industrialized countries. One study
 concluded that 96% of the estimated 62 million deaths in a future pandemic
 would occur in developing countries (4). The impact of such high mortality
 rates obviously needs to be taken into account when creating pandemic
 preparedness plans for developing countries. However, no appropriate model
 that can estimate the impact of an influenza pandemic in developing
 countries exists. Models are based on data from industrialized countries
 (6), which may underestimate the actual impact of a pandemic in developing
 countries.
 
 Availability of Vaccines and Antiviral Agents in Developing Countries
 
 Several possible interventions can be implemented to control or mitigate
 the effects of an influenza pandemic, which include pharmaceutical
 interventions such as vaccines and antiviral agents, and nonpharmaceutical
 interventions such as quarantine, isolation, social distancing, and
 personal hygiene (7). Pharmaceutical interventions are needed for
 mitigating the impact of an influenza pandemic (8). Vaccines for subtype
 H5N1 viruses are currently being developed, and clinical trials are under
 way (9,10). However, worldwide vaccine production capacity is limited and
 is primarily in industrialized countries, where most seasonal influenza
 vaccine is produced (11). A recent WHO report estimated that the worldwide
 vaccine production capacity for current influenza vaccines is 350 million
 doses per year (12). That level of production is clearly insufficient to
 supply vaccines to all countries. Only a limited number of vaccine doses
 would be available, particularly in the early stages of the pandemic, and
 most of them would likely be supplied to industrialized countries. Many
 countries, especially developing countries, will be forced to confront the
 next pandemic with few or no available vaccines.
 
 Antiviral agents are also considered effective for an influenza pandemic.
 They are particularly useful in the early stages of a pandemic when there
 is a shortage of vaccines (13). Two groups of antiviral agents for
 influenza are currently available, including M2 ion-channel inhibitors
 (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and
 zanamivir). Neuraminidase inhibitors are preferred because some influenza
 viruses show high frequencies of resistance to M2 ion-channel inhibitors
 (14). Stockpiling of neuraminidase inhibitors is under way in many
 industrialized countries as part of national influenza pandemic
 preparedness (15). However, the stockpiles of antiviral agents available in
 developing countries are small and limited. WHO has global and regional
 stockpiles of antiviral agents, which are limited and are specifically used
 for early response and containment. The stockpile of antiviral agents is
 insufficient for a global pandemic.
 
 The most critical limiting factor for stockpiling of neuraminidase
 inhibitors in developing countries is their high cost. One treatment course
 of oseltamivir (i.e., 10 tablets) costs US $15, even at a discount rate
 (16), which is far too expensive for developing countries. Some
 industrialized countries have set a target to stockpile oseltamivir to
 treat 25% of the general population. To purchase adequate oseltamivir for
 25% of the total population, only 0.11% of the total annual health
 expenditure is required in high-income countries. In low-income countries,
 however, the expense would be 12.9% of the annual expenditure (Table 1).
 Therefore, it is not feasible for low-income countries to allocate scarce
 resources to stockpile sufficient quantities of oseltamivir for an
 unpredictable influenza pandemic.
 
 Limitations of Pharmaceutical Interventions
 
 The recent efforts to increase global availability of vaccines and
 antiviral agents can contribute to increasing the global availability of
 these pharmaceutical interventions. However, increased availability alone
 will not solve all the problems in many countries. Several other issues
 need to be addressed to implement pharmaceutical interventions. These
 pharmaceutical commodities, including syringes and needles for vaccines,
 should be delivered to healthcare facilities throughout the country. That
 is a difficult logistic challenge for many developing countries. Human
 resources are also required to implement these interventions. Yet, there
 are some uncertainties about the effectiveness of these pharmaceutical
 interventions. Even neuraminidase inhibitors may not be fully effective for
 a pandemic virus, whose pathogenesis in human hosts differs from that of
 seasonal influenza viruses. Another potential problem with the antiviral
 drugs is the risk that resistant strains will emerge. Vaccines may not be
 effective because of antigenic differences between a vaccine strain and a
 pandemic virus, or for other reasons. Full-scale implementation of
 pharmaceutical interventions that requires enormous financial and human
 resources may not be the best use of limited resources in developing
 countries. The governments, international organizations such as WHO, and
 donors should consider various factors when providing support for
 pharmaceutical interventions in developing countries. Maintaining a balance
 between pharmaceutical and nonpharmaceutical interventions is necessary to
 achieve the best use of limited resources.
 
 Lack of Medical and Public Health Infrastructure to Cope with an Influenza
 Pandemic
 
 During an influenza pandemic, morbidity and mortality may be extremely
 high. Healthcare facilities would be quickly overwhelmed with increased
 numbers of patients. In the United States alone, an estimated 18–42 million
 outpatient visits and 314,000–734,000 hospitalizations could occur (6). The
 surge capacity in healthcare systems will likely be insufficient to cope
 with this rise in patient numbers, even in industrialized countries
 (17,18). Healthcare resources such as the number of physicians, nurses, and
 available hospital beds are limited in developing countries. In some
 countries, resources are insufficient to cope with patients even during
 normal circumstances. Hospitals and clinics in developing countries will be
 easily overwhelmed by the increasing number of patients during an influenza
 pandemic.
 
 Using the method described by Wilson et al. (19), we estimated the number
 of required hospital admissions for countries of varying economic status.
 The percentages of available hospital beds occupied by influenza patients
 at incidence rates of 15% and 35% were calculated by using FluSurge
 software, version 2.0 (20). Demographic data were obtained from the US
 Census Bureau website (www.census.gov/ipc/www/idb) and information related
 to the number of available beds was obtained from a WHO database (WHOSIS,
 www.who.int/whosis/en). Results are shown in Table 2. The percentage of
 hospital beds required for patients with pandemic influenza is much higher
 in low-income countries than in high-income countries. With an incidence
 rate of 35%, up to 79.1% of hospital beds are required for patients with
 pandemic influenza in low-income countries. In countries like Bangladesh
 and Nepal,100% of beds would be required for patients with pandemic
 influenza, even at the incidence rate of 15% (data not shown). This model
 is based on data from the United States, and the difference in disease
 severity among the countries was not considered. This model may
 underestimate the hospital bed requirements in developing countries, where
 a pandemic virus may cause more severe infections. Some hospitalized
 patients will require mechanical ventilation (17), but few mechanical
 ventilators, if any, are available in many hospitals in developing
 countries.
 
 During an influenza pandemic, additional essential medical supplies such as
 gloves, masks, syringes, antipyretics, and antimicrobial agents will also
 be required. These supplies are insufficient in healthcare facilities in
 developing countries, even in nonemergency situations. Lack of these
 supplies may hamper provision of adequate medical care for patients with
 pandemic influenza. Basic personal protective equipment such as disposable
 gloves and surgical masks are needed for protecting healthcare workers.
 Antimicrobial agents are expected to be effective for secondary bacterial
 pneumonia, which can be a major cause of death for patients with pandemic
 influenza (21). Therefore, proper treatment with antimicrobial agents can
 be crucial for preventing deaths. However, in some developing countries,
 sufficient stocks of essential drugs, including antimicrobial agents, are
 often unavailable.
 
 In countries with limited healthcare resources, providing routine medical
 care for other conditions may become difficult during a pandemic. For
 example, the treatment for tuberculosis or the antiretroviral treatment for
 AIDS patients may not be provided because of disruption in healthcare
 systems. Maintaining other public health programs, such as vaccination, may
 also be difficult when most of public health resources are spent for the
 response to a pandemic.
 
 Future Directions
 
 Improving Planning Process
 
 To minimize the impact of an influenza pandemic, good preparedness plans
 need to be developed. With the increasing risk for a pandemic caused by the
 spread of influenza A virus (H5N1), most countries have started such
 planning. These national plans were recently reviewed from different
 perspectives (15,22–24). The level of planning in many developing countries
 is still inadequate to deal with such a major public health crisis. Some
 plans are based on the available plans of industrialized countries, or
 follow similar approaches to those of industrialized countries. As
 described above, the approaches used by industrialized countries may not be
 feasible or appropriate for developing countries. In addition, each country
 has specific issues, and therefore it should develop a plan based on its
 own requirements. This task can be difficult for most developing countries
 because they have little or no expertise with influenza and pandemic
 preparedness. For the few infectious disease experts working on infectious
 diseases in each country, numerous competing priorities exist, such as
 HIV/AIDS, malaria, tuberculosis, and vaccine-preventable diseases.
 Feasible, user-friendly tools are needed to assist these countries. WHO has
 developed several such tools, including a checklist for national
 preparedness (25). However, these tools describe the general approaches to
 pandemic preparedness and are not specifically designed for countries with
 limited resources. For developing countries more practical tools are
 needed, among them models to estimate the impact of a pandemic in
 developing countries, a list of feasible interventions to mitigate the
 impact of pandemic without available pharmaceutical interventions, and
 planning guidelines for hospitals with limited resources.
 
 Increasing Availability of Antiviral Agents and Vaccines
 
 If the next pandemic occurs in a few years, vaccines and antiviral agents,
 particularly neuraminidase inhibitors, may not be available as a main
 intervention in developing countries. Availability needs to be increased to
 fill the gaps between developed and industrialized countries. WHO
 recommends an increase in worldwide vaccine production to meet the demand
 during a pandemic (12). Several countries have initiated projects to
 improve influenza vaccine production with technical and financial support
 from WHO and donors. However, improved vaccine production capacity is not
 sustainable if only used for pandemic influenza vaccines. The use of
 seasonal influenza vaccines would also need to increase in these countries.
 However, the cost of the vaccines (US $3–$7 per dose) is a barrier in
 increasing their use (12). There is also little available evidence on the
 effectiveness and cost benefits of seasonal influenza vaccines in tropical
 developing countries. Further efforts should be made to reduce the cost and
 to collect additional scientific data to increase the use of seasonal
 influenza vaccines.
 
 Some approaches have been proposed and tested to reduce the amount of
 antigens per vaccine dose for pandemic vaccine so that more vaccines,
 including adjuvant and whole virion vaccines, can be supplied (10). The
 world is expected to have an increased capacity to produce vaccines for
 pandemic influenza viruses by 2010 (12). In some countries, the vaccines
 for the subtype with a pandemic potential are being produced and stockpiled
 as a prepandemic vaccine, which can be a useful tool to mitigate the impact
 of a pandemic (26). However, both pandemic and prepandemic vaccines would
 not be available in developing countries unless an international mechanism
 exists to share such vaccines with them at a low cost.
 
 Some actions have also been taken to reduce the cost of neuraminidase
 inhibitors such as oseltamivir. It is being produced in sublicensing
 companies in developing countries to increase its supply at a lower cost.
 However, oseltamivir may still not be affordable for many developing
 countries. In industrialized countries, M2 ion-channel inhibitors are not
 considered a first choice of treatment because of the high rate of
 resistance to these inhibitors. However, amantadine is much cheaper than
 neuraminidase inhibitors and is more widely available. Most subtype H5N1
 isolates that belong to clade 1 are resistant to amantadine, but many clade
 2 viruses are still susceptible to amantadine (27). M2 ion-channel
 inhibitors can be a valid option for a pandemic, especially in developing
 countries (28). The value of M2 ion-channel inhibitors as a treatment
 option for an influenza pandemic should be evaluated further.
 
 Providing Better Medical Care
 
 The health consequences of a pandemic, including deaths, can be
 substantially reduced by providing better medical care. Several issues need
 to be addressed to provide adequate medical care during a pandemic. First,
 essential medical supplies such as masks, gloves, and antimicrobial agents
 should be available in hospitals and clinics. The stockpiles of these basic
 supplies can be more cost-effective in developing countries than the
 stockpiles of more expensive antiviral agents. Guidelines on the types and
 quantity of essential items that are required in hospitals and clinics
 should be developed. Second, healthcare personnel should be trained for
 infection control measures. Even surgical masks are not commonly used in
 many developing countries, and hand hygiene practices are not always
 followed. Basic training on infection control should be provided to improve
 pandemic preparedness in healthcare settings. Third, healthcare and public
 health systems need to be maintained to minimize the impact of a pandemic.
 These systems should be maintained to deal not only with a pandemic but
 also with other health problems such as malaria, tuberculosis, and HIV.
 
 Developing Feasible Mitigation Strategies
 
 More feasible and effective strategies should be developed as soon as
 possible to mitigate the negative impact of an influenza pandemic in
 developing countries. Since the availability of pharmaceutical
 interventions in developing countries is less likely, nonpharmaceutical
 interventions such as social distancing and personal hygiene may be the
 only available interventions. Public health measures such as school closure
 and household quarantine have been evaluated by using mathematical models
 for their effectiveness in mitigating the impact of a pandemic (29,30) and
 may have potential beneficial effects. However, the models suggest that
 substantial benefits of these measures require implementation with
 antiviral prophylaxis or vaccines (29,30). The evidence for effectiveness
 of public health measures is limited and is based primarily on experience
 in industrialized countries (31,32). For example, handwashing and hand
 hygiene have been highly publicized as a core management strategy for avian
 and pandemic influenza in developing countries (33). Although handwashing
 is effective in reducing the incidence of common diseases such as acute
 respiratory infections (34), data on its effectiveness specifically for
 community-acquired influenza infections are limited (31). Recommendations
 on nonpharmaceutical interventions have been based on available evidence
 (35). Accumulation of further scientific evidence for these measures, which
 can be implemented at a low cost, is urgently required.
 
 Strengthening Core Capacities
 
 Many health programs in developing countries depend on financial support
 from donors. Influenza had little donor interest before the current avian
 influenza outbreaks. More donor funds are available for avian and pandemic
 influenza. These funds are often earmarked for specific activities.
 However, a more general approach is required to improve pandemic
 preparedness in developing countries. Improving pandemic preparedness
 without establishing a proper national program for seasonal influenza is
 unrealistic. For example, increasing the availability of pandemic vaccines
 without increasing the use of vaccines for seasonal influenza is difficult.
 It is also difficult to implement infection control measures in hospitals
 and personal hygiene during a pandemic if they are not routinely
 implemented for seasonal influenza and other infections.
 
 Lack of adequate infrastructure and technical expertise is a fundamental
 issue for developing countries, not only for influenza pandemic
 preparedness but also for any other infectious disease threats. Revised
 International Health Regulations (2005) were adopted at the World Health
 Assembly in 2005, under which each country is required to have core
 capacities for disease surveillance and response (36). Strengthening the
 core capacity in each country should be an essential step to improve
 preparedness for any public health emergency, including an influenza
 pandemic. Although some actions should be taken immediately to address
 urgent issues regarding a pandemic threat posed by influenza A (H5N1), a
 long-term vision is required to establish such core capacity in every
 country.
 
 Strengthening International Collaboration
 
 An influenza pandemic will spread to every corner of the world; hence,
 every country must be prepared for such a global event. All human cases of
 infection with influenza A virus (H5N1) have so far occurred in less
 industrialized countries, and thus the pandemic virus is likely to emerge
 from these countries. Epidemiologic models have indicated the possibility
 of rapid containment of the virus with a pandemic potential (37,38). WHO
 has stockpiles of oseltamivir specifically for the early containment of a
 potential pandemic. However, the window of opportunity is narrow, and early
 containment operations should be initiated as soon as the initial sign of a
 potential pandemic is detected. Timely sharing of the virus strains and
 relevant information is essential for such containment to be successful.
 
 Sharing of the virus stains is also critical to develop pandemic vaccines.
 However, some countries do not share the virus strains with WHO reference
 laboratories. These countries argue that the virus strains from their
 countries would be used to develop pandemic vaccines that would only be
 available for rich countries (39). Developing countries have no incentives
 to share the virus strains if they do not benefit from the vaccines
 developed from these strains. The gaps in resources, including vaccine
 production capacity between the developing and industrialized countries,
 hinder the global effort to respond to a pandemic. Unequal distribution of
 resources, including antiviral stockpiles, could also be a major
 international issue when an influenza pandemic occurs. Countries with
 limited or no antiviral stockpiles and other resources may not be able to
 cope with the pandemic. A pandemic poses a serious threat to global health
 security if large gaps in capacity and available resources continue to
 persist. Large numbers of people may attempt to cross international borders
 to obtain better medical care, including antiviral treatment, or to escape
 a chaotic situation. Preparing for a pandemic by simply strengthening
 preparedness within a single country is not possible. A pandemic is a
 global issue, and pandemic preparedness should be considered from a global
 perspective.
 
 Acknowledgments
 
 Dr Oshitani is a professor in the Department of Virology, Tohoku University
 Graduate School of Medicine. His research interests include epidemiology
 and control of viral infections, including influenza, particularly in
 developing countries.
 
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