Home Books Journals Flying Publisher Guides

Flying Publisher   

 

Download (free)
PDF, 225 pages, 2.8 MB
ISBN 3-924774-51-X
25 €

Publish this book under your own name

1. Influenza

2. Avian Influenza

3. Virology

4. Pathogenesis and Immunology

5. Pandemic Preparedness

6. Vaccines

7. Laboratory Findings

8. Clinical Presentation

9. Treatment and Prophylaxis

10. Drugs

Other Languages

Comments & Suggestions

We'll inform you

Privacy

About

Amedeo Influenza


  

 

Pandemic Preparedness

Gustavo Reyes-Terán and René Gottschalk

 

(Green links: Free full-text articles)

Introduction

Previous Influenza Pandemics

Three influenza pandemics (worldwide epidemics) are known to have occurred, all caused by influenza A viruses. When a significant change in at least one of the influenza A virus surface proteins haemagglutinin and neuraminidase occurs spontaneously, nobody has immunity to this entirely new virus. If the virus also achieves efficient human-to-human transmission and has the ability to replicate in humans causing serious illness, a pandemic can occur. This happened in 1918 (the "Spanish flu", caused by a H1N1 subtype), in 1957 (the "Asian flu" caused by a H2N2 subtype) and in 1968 (the "Hong Kong flu", caused by a H3N2 subtype). Conservative estimates suggested that the mortality from the 1918 pandemic was 20 to 40 million. However, recent studies from Africa and Asia suggest that the number of victims worldwide might have been closer to 50-100 million (Johnson 2002).

Influenza experts have estimated that in industrialised countries alone, the next influenza pandemic may result in up to 130 million outpatient visits, 2 million hospital admissions and 650,000 deaths over two years. The impact is likely to be even greater in developing countries ( WHO 2004). A 1918-type influenza pandemic today is projected to cause 180-360 million deaths globally (Osterholm 2005).

H5N1 Pandemic Threat

So far (January 2006), nine countries in the Far East have reported poultry outbreaks of a highly pathogenic H5N1 avian influenza virus: the Republic of Korea, Vietnam, Japan, Thailand, Cambodia, Laos, Indonesia, China, and Malaysia. The outbreaks in Japan, Malaysia, and the Republic of Korea were successfully controlled, but the virus seems to have become endemic in several of the affected countries. The Southeast Asian outbreaks resulted in the death or destruction of more than 150 million birds and had severe consequences for agriculture, most especially for the many rural farmers who depend on small backyard flocks for income and food.

The recent outbreaks of the same virus strain in birds in Russia, Kazakhstan, Turkey, Romania, and Croatia provide evidence that it has spread beyond the initial focus (WHO 2005a, WHO 2005b).

Human cases of avian influenza A (H5N1), most of which have been linked to direct contact with diseased or dead poultry in rural areas, have been confirmed in six countries: Vietnam, Thailand, Cambodia, Indonesia, China, and Turkey (see Table 1). The figures for confirmed human cases of avian influenza A (H5N1) infection reported to the WHO are regularly updated on the WHO webpage ( WHO 2005c).

Table 1. Cumulative Number of Confirmed Human Cases of Avian Influenza A / (H5N1) Reported to the WHO up until January 25, 2006 (WHO 2005c) *

 

Cases**

Deaths

Vietnam

Thailand

Cambodia

Indonesia

China

Turkey

93

22

4

19

10

4

42

14

4

14

7

2

Total

152

83

* WHO reports only laboratory-confirmed cases.
** Total number of cases includes number of deaths

Recent research suggests that the 1918 virus might not have been a reassortant virus (like those of the 1957 and 1968 pandemics), but more likely an entirely avian-type virus that adapted to humans (Taubenberger 2005). There is some evidence that the high pathogenicity of the 1918 virus was related to its emergence as a human-adapted avian influenza virus. The intriguing similarity in a number of changes in the polymerase proteins of both the 1918 strain and in the recently circulating, highly pathogenic strains of H5N1 avian viruses that have caused fatalities in humans (Taubenberger 2005), is reason for concern.

Considering that H5N1 is antigenically new, is highly pathogenic in humans and that it may acquire the ability to be efficiently transmitted from human to human, the World Health Organisation reiterated its 1997 call for all countries to prepare for the next pandemic, which it termed "inevitable and possibly imminent" (BWHO 2004), and updated its own pandemic preparedness plan in April 2005 (WHO 2005d).

 

Influenza Pandemic Preparedness

Planning is essential for reducing or slowing transmission of a pandemic influenza strain and for decreasing or at least spreading out the number of cases, hospitalisations and deaths over time. Preparedness will help to maintain essential services and to reduce the economic and social impact of a pandemic (WHO 2004).

Epidemiological models indicate that a pandemic would have the greatest impact on the poorest countries, as a result of limited surveillance and healthcare resources, as well as the general poor health and nutritional status of the population (WHO 2004).

Pandemic Phases

In order to define the sequence of actions during certain key events, the WHO Global Influenza Preparedness Plan (WHO 2005d) distinguishes different phases. Each phase is associated with international and national public health actions. The national actions to be taken during each phase are further subdivided according to the national epidemiological situation. The WHO strongly recommends that countries consider the national actions proposed in the WHO Global Influenza Preparedness Plan when developing or updating a national plan. A summary of these new phases is presented in Table 2. The world is presently (January 2006) in phase 3, as a new influenza virus subtype is causing disease in humans, but is not yet spreading efficiently and sustainably among humans.

 

Table 2. Phases according to the WHO Global Influenza Preparedness Plan of 2005 (based on WHO 2005d).

Period/ Phase

Event

Interpandemic Period

 

Phase 1

No new influenza virus subtypes have been detected in humans. An influenza virus subtype that has caused human infection may be present in animals. If present in animals, the riska of human infection or disease is considered to be low.

Phase 2

No new influenza virus subtypes have been detected in humans. However, a circulating animal influenza virus subtype poses a substantial riska of human disease.

Pandemic Alert Period

 

Phase 3

Human infection(s) with a new subtype, but no human-to-human spread, or at most rare instances of spread to a close contact.

Phase 4

Small cluster(s) with limited human-to-human transmission but spread is highly localised, suggesting that the virus is not well adapted to humansb.

Phase 5

Larger cluster(s) but human-to-human spread still localised, suggesting that the virus is becoming increasingly better adapted to humans, but may not yet be fully transmissible (substantial pandemic risk)b.

Pandemic period

 

Phase 6

Pandemic phase: increased and sustained transmission in the general populationb.

Postpandemic period

Return to interpandemic period.

a. The distinction between phase 1 and phase 2 is based on the risk of human infection or disease resulting from circulating strains in animals. The distinction would be based on various factors and their relative importance according to current scientific knowledge. Factors may include: pathogenicity in animals and humans; occurrence in domesticated animals and livestock or only in wildlife; whether the virus is enzootic or epizootic, geographically localised or widespread; other information from the viral genome; and/or other scientific information.

b. The distinction between phase 3, phase 4 and phase 5 is based on an assessment of the risk of a pandemic. Various factors and their relative importance according to current scientific knowledge may be considered. Factors may include: rate of transmission; geographical location and spread; severity of illness; presence of genes from human strains (if derived from an animal strain); other information from the viral genome; and/or other scientific information.

 

Inter-Pandemic Period and Pandemic Alert Period

Surveillance

Surveillance has been defined as "an ongoing systematic collection, analysis, and interpretation of outcome-specific data for use in the planning, implementation, and evaluation of public health practices", and not merely collection of data (Flahault 1998). Thus, a timely, representative and efficient surveillance system is the cornerstone of control of epidemic-prone communicable diseases (PPHSN 2004).

In order to be able to detect an unusual cluster or number of cases of illness that may be due to a new influenza virus, it is essential for every country to have an early warning system for human disease. By participating in the Global Influenza Surveillance Network, a country contributes to the detection of influenza viruses with pandemic potential. The type of surveillance will depend on whether a potential pandemic strain of influenza virus has first been recognised in domestic animals, in wild animals or in humans, and in which geographical area the new strain is known or expected to be circulating ( WHO 2005e).

Surveillance should lead to action. Before setting surveillance priorities, countries should define the objectives of surveillance. Speed of laboratory confirmation will affect the rapidity of implementation of control measures. The WHO strongly recommends separating the analysis of potential pandemic strains from normal routine influenza diagnosis.

National and international reporting systems should take into account the new International Health Regulations (IHR 2005).

During the interpandemic period and the pandemic alert period (phase 1-5), surveillance in all countries should target the rapid identification of the circulating strain and the early detection and reporting of the potential pandemic strain in animals and humans. Countries affected by a pandemic threat should also determine how widespread the outbreak is, as well as whether or how efficiently human-to-human transmission is occurring. Activities during these periods should include: laboratory surveillance; a clinical case reporting system including reporting from hospitals; an early warning system for investigating clusters of acute respiratory disease; a basic system for animal surveillance; and collaboration with a reference laboratory to identify non-typable influenza. Activities in countries affected by animal outbreaks should also include case investigation and contact tracing, cluster investigation and health monitoring of high-risk groups. Desirable surveillance activities during the pre-pandemic phase may include pneumonia surveillance and monitoring of antiviral drug resistance (WHO 2004).

Sentinel hospital-based surveillance is crucial for the timely triggering of public health measures and laboratory investigations. A national network of hospital sentinel surveillance should detect individuals with acute respiratory illness among hospitalised patients, unexplained deaths caused by acute respiratory illness, or clusters of severe acute respiratory illness in the community. Healthcare staff from sentinel hospitals should receive specific training for responding during influenza pandemics. Education and training needs for healthcare workers, laboratory personnel, volunteers, and others who may be working outside their area of competence and training, must be considered.

Implementation of Laboratory Diagnostic Services

As outlined by the WHO ( WHO 2005e), basic diagnostic capacity must be available for the rapid confirmation of suspected human infections with a new influenza virus strain. In countries with limited resources, a network of laboratories that have their own expertise (i.e. in influenza diagnostic tests) should be established. In the interpandemic phase, all countries should have access to at least one laboratory able to offer routine influenza diagnosis, typing and subtyping, but not necessarily strain identification. These laboratories should be made known to the WHO. The minimal laboratory capacity for these laboratories include immunofluorescence (IF) and reverse transcriptase polymerase chain reaction (RT-PCR). In the absence of laboratories able to offer routine influenza diagnosis, typing and subtyping, countries may use commercial rapid antigen detection kits. However, governments should designate resources or seek them in other countries in order to build the necessary laboratories for epidemiological surveillance.

Under optimal conditions, a national inventory of laboratories with biosafety security levels (BSL) 3 and 4 should be available. However, usually developing countries have no BSL-4 and have very few or no BSL-3 laboratories. Therefore, the available BSL-3 laboratories should be adapted to work locally (this way the diagnosis would be faster), or arrangements with BSL-3 and BSL-4 laboratories in other countries may be facilitated by the WHO. In the early stages of a pandemic, increased testing will be required when the diagnosis of pandemic strain influenza in patients with influenza-like illness cannot be assumed. Once the pandemic is established, testing of all cases will not be possible. Laboratories should provide regularly updated advice to healthcare workers. For countries whose pandemic preparedness plan includes the use of antiviral drugs, laboratory facilities will need to be in place for monitoring antiviral drug resistance. Daily reporting of cases to national authorities and the WHO, including information on the possible source of infection, must be performed ( WHO 2005e).

Vaccines

Antiviral therapy and vaccination are the only options for controlling an influenza virus infection (Yen 2005, Korsman 2006). Vaccination represents the best protection against influenza (van Dalen 2005), but an appropriate vaccine cannot be developed before a new virus strain emerges. Normally, it takes at least six months to develop a vaccine and manufacture it on a large scale (Flemming 2005). But even then, most countries without production facilities will have no access to vaccines during the first pandemic wave, as a result of limited global production capacity and concentration of these facilities in developed countries.

Countries with production facilities should support and ensure by all means that rapid and large-scale production can take place during a pandemic. In some developed nations, the government considers it to be its responsibility to provide the highest possible protection at the onset of a pandemic. For example, the Dutch government is currently negotiating with a manufacturer to ensure that a vaccine against any future pandemic influenza strain is available in the Netherlands as soon as possible following its development (van Dalen 2005). Meanwhile, countries without vaccine production facilities should prepare for a vaccination programme to be implemented as soon as vaccines against the pandemic become available ( WHO 2005e).

Plans for pandemic vaccine use should include: designation of mass immunisation clinics, strategies for staffing and staff training, strategies to limit distribution to persons in the priority groups, vaccine storage capacity of the cold chain, identification of current and potential contingency depots, vaccine security (theft prevention) during its transport, storage and use in clinics. Some examples of priority groups are animal or bird cullers, veterinarians and farmers in the case of animal or avian influenza; healthcare workers and workers in essential services when a pandemic is imminent or established (WHO 2005e).

Antiviral Drugs

Antiviral drugs include M2 inhibitors, which are ion channel blockers (amantadine and rimantadine), and the neuraminidase inhibitors (oseltamivir and zanamivir) (Hoffmann 2006b). The emergence of resistant variants is a concern with the use of any antiviral drugs. Treatment with M2 inhibitors can cause emergence of fully pathogenic and transmissible resistant variants in at least 30 % of individuals (Hayden 1997). Moreover, M2 inhibitors are ineffective against H5N1 in vitro (Lipatov 2004).

After treatment with neuraminidase inhibitors, resistant variants were initially found in approximately 4 % to 8 % of children and < 1 % of adults (McKimm-Breschkin 2003, Stilianakis 2002), and were identified later in 18 % of Japanese children during treatment with oseltamivir (Kiso 2004). The emergence of resistant influenza A (H5N1) variants during oseltamivir treatment was recently reported in two Vietnamese patients (de Jong 2005). Influenza A (H5N1) viruses with a H274Y substitution in the neuraminidase gene, which confers high-level resistance to oseltamivir (Gubareva 2001), were isolated from both patients. Even though oseltamivir was administered at the recommended dose and duration (75 mg twice daily for five days, with a weight-based reduction in the dose for children less than 13 years old) and treatment was started when the greatest clinical benefit could be expected (within 48 hours after the onset of symptoms), both patients died. These observations suggest that the development of drug resistance contributed to the failure of therapy in these patients. The authors conclude that strategies aimed at improving antiviral efficacy (e.g., the use of higher doses, longer durations of therapy, or combination therapy) deserve further evaluation.

New routes of administration of antivirals should also be explored, as altered pharmacokinetics in severely ill influenza patients, who may be affected by diarrhoea, have been reported (Hien 2004).

There are concerns that young children and patients with intellectual or co-ordination impairments are not able to inhale zanamivir properly (Imuta 2003). However, as resistance against oseltamivir can emerge during the currently recommended regimen, and as zanamivir might be less prone to the development of resistance mutations (Moscona 2005), zanamivir might be included in the treatment arsenal for influenza A (H5N1) virus infections.

Drug Stockpiling

Some governments have recently opted for stockpiling of oseltamivir. The number of courses of oseltamivir to be stockpiled by each country depends on existing resources and population size. The World Health Organisation has been urging countries to stockpile the drug in advance (Abbott 2005). For example, the Dutch government has stockpiled approximately 225,000 courses of oseltamivir (Groeneveld 2005). However, many developing countries may not be able to afford to stockpile antiviral drugs.

The cost benefit of stockpiling and the optimal strategy for antiviral use were recently investigated for the Israeli population by using data (numbers of illness episodes, physician visits, hospitalisations, and deaths) derived from previous influenza pandemics. Costs to the healthcare system and overall costs to the economy, the latter including the value of lost workdays but not the potential value of lost lives, were calculated (Balicer 2005). Three strategies for the use of oseltamivir during a pandemic were defined: therapeutic use, long-term pre-exposure prophylaxis, and short-term postexposure prophylaxis for close contacts of influenza patients (with index patients under treatment). The first two strategies could target either the entire population or only those at high risk of complications. The economic outcomes of each of the five strategies were compared with nonintervention. Stockpiling costs were estimated and cost-benefit ratios were calculated. The most favourable cost-benefit ratio was found when stockpiled antiviral drugs were administered either solely as a therapeutic measure or as a short-term prophylaxis for exposed contacts, a strategy termed "targeted prophylaxis" (Longini 2004). The objective of targeted strategies is to minimise drug usage while maximising effect. Therefore, in developing countries targeted prophylaxis is particularly important for saving resources.

While in most developing countries the use of antiviral agents is not expected, in developed nations the use of antiviral agents depends on whether the drugs are in short or large supply (see Table 3).

Table 3. Recommended use of antiviral agents by the Dutch Ministry of Health (adapted from Groeneveld 2005)

1. When the pandemic first reaches the Netherlands

 

Treat

Index patientsa

Provide prophylaxis to

Families, housemates and other contacts of index patients: post-exposure prophylaxis

2. In a manifest pandemic or in the event of large-scale virus introduction from abroad

If neuraminidase inhibitors are in short supply

Treat

Risk groupsb, professionalsc, and (when relevant) people in pandemic-specific risk groupa; otherwise healthy people: in the event of hospitalisation due to complications

 

If neuraminidase inhibitors are not in short supply

Treat

Patients displaying symptoms consistent with influenza

Provide prophylaxis to Individual patientsd and risk groups, professionals, and (where relevant) people in pandemic-specific risk groupe

a. As soon as possible following the appearance of the first symptoms; if treatment is not started within 48 hours, it may not be effective.
b. Patients with serious respiratory, pulmonary or cardiovascular abnormalities or dysfunction, who, if infected with the pandemic influenza virus, would be at serious risk of pulmonary or cardiovascular function decompensation, patients with an insulin-dependent form of diabetes.
c. All persons responsible for the diagnosis, treatment and care of influenza patients, or for logistic management of the necessary resources.
d. Where considered appropriate by the doctor in charge of the individual patient.
e. Following vaccination and while the virus is circulating.

Personal stockpiling of oseltamivir is strongly discouraged (Brett 2005, Moscona 2005) as this would likely lead to the use of insufficient doses or inadequate courses of therapy, and thus facilitate the emergence of oseltamivir-resistant variants. Moreover, personal stockpiling of oseltamivir further depletes the current supply that is already inadequate to meet the demand.

Antibiotics should be stockpiled for the treatment of Staphylococcus aureus and other secondary infections by each hospital.

General Measures

Non-medical interventions have been shown to be relevant for controlling emergent infectious diseases. In Thailand, community participation at different levels was considered in the national program against H5N1 avian influenza. Public health workers, veterinary health workers, village health volunteers, and others participated in an ongoing national surveillance campaign beginning in October 2004 with written guidance from national authorities (Barnett 2005). The fact that 17 patients were infected with H5N1 during 2004, while only 5 were infected during 2005 in Thailand, might be reflecting an initial success in this nation's national program against H5N1 avian influenza (WHO 2005c). Intersectoral co-ordination involving non-health sectors (especially agriculture, economic, social and internal affairs) is needed. Professional networks outside the health sector (i.e. law, education, tourism) should also be engaged in the planning process.

Effective pre-event risk communication can reduce event-phase risk communication barriers (USDHHS 2005). Pre-event risk communication to at-risk populations and to the general population is of outstanding importance for easing social tension. By means of mass communication media (TV, radio), the general population should obtain essential information about relevant measures of hygiene, preventive measures, non-recommended actions, risk practices and other relevant issues. Mass communication media should contribute to the general knowledge of the influenza pandemic threat to create social awareness.

Training activities for healthcare professionals directed specifically at pandemic preparedness are useful in increasing healthcare workers' compliance with personal protective equipment and infection control procedures.

Finally, pandemic simulation exercises are useful for learning what to do in case a pandemic occurs. Around 1,000 health workers and civilians took part in an emergency drill in the Vietnamese capital Hanoi to practise the official response to a bird flu pandemic there. The rehearsal, organised by the city's authorities, involved people from the local quarter, hospitals, security and army units from Hanoi's Long Bien district where the event took place (Thanhnien 2005).

Seasonal Influenza Vaccination

Routine influenza vaccine should be administered to risk groups to decrease the chances of dual infection with the seasonal circulating influenza strain and the potential pandemic strain, facilitating reassortment. Vaccination with inactivated influenza vaccine is recommended for the following persons who are at increased risk of complications from influenza (ACIP 2005):

  • persons aged > 65 years;
  • residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions;
  • adults and children who have chronic disorders of the pulmonary or cardiovascular system, including asthma (hypertension is not considered a high-risk condition);
  • adults and children who required regular medical follow-up or hospitalisation during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, haemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus [HIV]);
  • adults and children who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration;
  • children and adolescents (aged 6 months - 18 years) who are receiving long-term aspirin therapy and, therefore, might be at risk of developing Reye's syndrome after influenza infection;
  • women who will be pregnant during the influenza season; and
  • children aged 6-23 months.

 

Political Commitment

One of the most significant factors is political and social willingness to acknowledge and report disease dissemination. Without this key factor, no further national action to prevent pandemics can take place. High-level political support and commitment are necessary to develop a preparedness plan. Increased regional collaboration and networking may not only lead to the mutual support of people involved in the planning, but can also be used as an instrument for increasing international pressure and thus political commitment (WHO 2004). Records of past pandemics, especially that of 1918, show that a pandemic event may have disastrous consequences for any country due to its impact on the national socio-economic and political structures (PPHSN 2004).

Legal and Ethical Issues

Appropriate legislation must be in place before the pandemic event arrives. In a national disaster situation such as that of a pandemic, there are public health measures that need the support of the national legal system to be efficiently implemented. For example, a quarantine act usually authorises designated services and persons to take necessary measures to eradicate or control the spread of infectious disease (PPHSN 2004). Similar coercive measures might be needed if vaccination became necessary to contain the pandemic.

Funding

Resource-limited countries need to formulate a feasible national influenza pandemic preparedness plan based on existing resources and the size and structure of the population. High political support is paramount for allocation of funding designated for emergency situations such as an influenza pandemic. The planning process should include identification of possible resources to fund pandemic response.

Global Strategy for the Progressive Control of Highly Pathogenic Avian Influenza

The likely progressive spread of highly pathogenic avian influenza (HPAI) into new regions will require pro-active intervention by the countries at risk, especially those situated along wild bird migration routes. Increased surveillance, detection capabilities and emergency preparedness will be required. Public awareness, along with education and training of veterinary professionals and para-professionals, farmers, marketers, poultry transport contractors and egg collectors, will be required to ensure that the disease is either prevented or detected and controlled, in order to prevent its establishment and maintenance in newly colonised ecosystems (FAO 2005).

The FAO and OIE, in collaboration with the WHO, have taken the initiative to start the process of developing the Global Strategy of Progressive Control and Eradication of HPAI. The overall goal of the strategy is to eventually eliminate HPAI from the domestic poultry sector in Asia and Europe, and prevent further introduction of HPAI into noninfected countries, thereby minimising the global threat of a human pandemic, promoting viable poultry production, enhancing robust regional and international trade in poultry and poultry products, increasing safety of food and feeds, and improving the livelihoods of all poultry sector stakeholders, especially the rural poor (FAO, OIE, WHO 2005).

Multiple opportunities exist for controlling highly pathogenic avian influenza: 1) prevent contact between wild and domestic poultry by use of screened poultry houses and treated water; 2) prevent contact between domestic waterfowl and gallinaceous poultry by use of screened houses and treated water and by exclusion of waterfowl from "wet markets"; 3) eradicate H5/H7 influenza viruses from gallinaceous poultry by culling or by using vaccines to prevent disease and transmission; 4) prevent or minimise contact between poultry, pigs, and humans and make vaccines and antiviral drugs available (Webster 2006).

 

Pandemic Period

During a pandemic phase the primary objective should be containment. It has been said that success depends on early identification of the first cluster of cases caused by the pandemic strain (Ferguson 2004), and on detection of a high proportion of ongoing cases (Ferguson 2005). Therefore, optimal surveillance at this point is essential for successful containment.

Surveillance

Pandemic surveillance should include monitoring of the following events: hospital admissions of suspected or confirmed cases of pandemic strain influenza, deaths among suspected or confirmed cases of influenza due to the pandemic strain, workforce absenteeism in services designated as essential, vaccine usage for routine and pandemic strain influenza vaccines (if these are available), adverse vaccine events attributed to the pandemic strain vaccine (if available), data collection for later use in the calculation of effectiveness of the pandemic strain vaccine, monitoring pneumococcal vaccine use and adverse events associated with its use (if this vaccine is available and being used), and monitoring of antiviral use and adverse events that may be attributed to antiviral use, if applicable. Moreover, a mechanism for data aggregation, interpretation and transmission for decision making must be ensured. The daily reporting of cases to national authorities and to the WHO, including information on the possible source of infection, must be performed (WHO 2005e).

Treatment and Hospitalisation

While the numbers of affected persons are still small, patients with suspected or proven influenza A (H5N1) should be hospitalised in isolation for clinical monitoring, appropriate diagnostic testing, and antiviral therapy. Both the patients and their families require education in personal hygiene and infection-control measures. The management is based on supportive care with provision of supplementary oxygen and ventilatory support. Patients with suspected influenza A (H5N1) should promptly receive a neuraminidase inhibitor pending the results of diagnostic laboratory testing (WCWHO 2005). For more details, see Hoffmann 2006.

Human Resources: Healthcare Personnel

High-efficiency masks (NIOSH-certified N-95 or equivalent), long-sleeved cuffed gowns, face shield or eye goggles, and gloves are recommended for healthcare workers in contact with patients . When feasible, the number of healthcare workers with direct patient contact and the access to the environment of patients should be limited. Healthcare workers involved in high-risk procedures (e.g., aerosol-generating procedures) should be considered for pre-exposure prophylaxis (WCWHO 2005).

Geographically Targeted Prophylaxis and Social Distancing Measures

Models can be used to estimate influenza-associated morbidity and mortality. Even though current models used for developed countries are not useful for developing countries, some interesting principles may be considered for the latter.

By means of a simulation model of influenza transmission in Southeast Asia, it was recently suggested that the elimination of a nascent pandemic may be feasible using a combination of geographically targeted prophylaxis and social distancing measures, if the basic reproduction number of the new virus is below 1.8 (Ferguson 2005). The basic reproduction number R0 (Anderson 1992) quantifies the transmissibility of any pathogen, and is defined as the average number of secondary cases generated by a typical primary case in an entirely susceptible population. A disease can spread if R0 > 1, but if R< 1, chains of transmission will inevitably die out. Hence, the goal of control policies is to reduce R0 to levels below 1. However, from this simulation model, Ferguson concluded that a number of key criteria must be met for a high probability of success: (1) rapid identification of the original case cluster, (2) rapid, sensitive case detection and delivery of treatment to targeted groups, (3) effective delivery of treatment to a high proportion of the targeted population, (4) sufficient stockpiles of drug, (5) population co-operation with the containment strategy and, in particular, any social distance measures introduced, (6) international co-operation in policy development, epidemic surveillance and control strategy implementation. Successful containment is unlikely if R0 exceeds 1.8 for the new pandemic strain.

In a stochastic influenza simulation model using a similar approach (Longini 2005), it was suggested that combinations of targeted antiviral prophylaxis, pre-vaccination, and quarantine could contain strains with an R0 as high as 2.4. In fact, the World Health Organisation welcomed both the pandemic influenza response modelling papers aforementioned (WHO 2005g). However, there are critical arguments with respect to the simulation models. For example, it has been noticed that Longini's article assumed that oseltamivir would be useful in a pandemic, but oseltamivir may not be effective on all new avian flu viruses (Chung 2005). Moreover, oseltamivir was ineffective in 50 % of patients in Thailand (Fergusson 2005). Handling the ever-changing disease pattern of pandemic avian influenza requires a contingency plan to prepare for the worst scenario. Such a worst-case scenario model provides valuable information for resource planning, for example, the number of ventilators, the amount of intensive care, and even funeral facilities that will be required (Chung 2005).

Measures to increase the social distance have been used in past pandemics and remain important options for responding to future pandemics (WHO 2005f). These measures include travel or movement restrictions (leaving and entering areas where infection is established), closure of educational institutions, prohibition of mass gatherings, isolation of infected persons and those suspected of being infected, and quarantine of exposed individuals or travellers from areas where pandemic strain influenza infection is established (WHO 2005e). However, the effectiveness of some distancing measures that were successfully implemented for the contention of SARS remains to be demonstrated for influenza. The reason for this is that SARS patients are not infectious prior to the onset of illness, whereas influenza patients are infectious before they develop apparent symptoms (Ho 2004).

Tracing of Symptomatic Cases

Influenza is predicted to be very difficult to control using contact tracing because of the high level of presymptomatic transmission. In addition, contact tracing for influenza would probably be unfeasible because of the very short incubation (2 days) and infectious (3-4 days) periods of that disease (Fraser 2004).

Border Control

During the SARS outbreak, body temperature screening was commonly performed on air passengers. This way, individuals with fever were prohibited from boarding aeroplanes. A hospital near each airport was designated to house, diagnose, and treat any passengers found with fever at the airport (Ho 2004). However, with an infrared body temperature screening device, only patients with symptomatic influenza disease would be detected.

Hygiene and Disinfection

Recommendations for "respiratory hygiene" such as covering one's mouth when coughing and avoiding spitting, have been made more on the basis of plausible effectiveness than controlled studies (CDC 2003). The influenza virus can remain viable on environmental surfaces and is believed to be transmissible by hands or fomites (WHO 2006). Most, but not all, controlled studies show a protective effect of hand washing in reducing upper respiratory tract infections; most of the infections studied were likely viral, but only a small percentage were due to influenza (Fasley 1999). No studies appear to address influenza specifically (WHO 2006).

Risk Communication

A risk communication strategy, flexible enough to increase its intensity during different pandemic phases, should be established. The most appropriate and effective media that can be employed should be identified. It is advisable to identify an official spokesperson during the interpandemic phase who will continue to carry out that task during subsequent phases of the pandemic. Information sources should be credible and acceptable to the public, e.g. WHO, CDC, FAO. The spokesperson(s) would ideally be someone associated with authority. Generation of fear and panic should be avoided, while practical information should remain accessible to everyone (PPHSN 2004).

 

Conclusions

A major influenza pandemic will have devastating consequences, with uncalculable risks for human health, global economy and political and social stability in most countries. Robust financial resources and a good medical infrastructure may help alleviate some of these consequences; however, developing countries are likely to be faced with insufficient or non-existent stocks of antiviral drugs, and without an appropriate vaccine.

The pandemic risk in developing countries is closely related to human exposure. In some African, Latin American and Southeast Asian countries, people sleep in the same places as poultry. In Southeast Asia and beyond, markets with live poultry pose a risk of human transmission (Webster 2004). Reducing human exposure requires education about handling poultry and a fundamental change in cultural attitudes towards human-animal interactions in many parts of the world (World Report 2005). Simple precautionary measures for food preparation, poultry handling, and avoidance of contaminated water are essential until effective human vaccines for H5N1 viruses become available (Hayden 2005). Therefore, pandemic preparedness in developing countries should consider funds for public education to generate cultural changes and improvements in hygiene.

Five essential action strategies to reduce the risk of a pandemic outlined by the WHO are:

  • Reduction of human exposure
  • Intensifying capacity for rapid containment (stockpiling of enough cycles of antiviral drugs for targeted prophylaxis combined with social distance measures)
  • Strengthening early warning systems
  • Rapid investigation of cases and clusters
  • Building general capacity for healthcare.

If transmission of a new pandemic strain begins in human beings, the speed at which influenza spreads will depend on how early it is detected, and how fast the international community can mobilise and deliver assistance, including providing antiviral drugs for prophylactic use. Therefore, in addition to a national preparedness plan, governments should actively seek international collaborations with neighbouring countries (Ho 2004). "Without international co-operation, no nation can consider itself safe", warned WHO Director-General Lee Jong-Wook.

In a meeting convened by the WHO in Geneva in November 2005, representatives of several low-income countries expressed concerns about the lack of action to promote equitable distribution of drug stockpiles and vaccines in the event of a pandemic. Many countries are too poor to buy drug stockpiles and have no capacity for manufacturing vaccine or generic versions of drugs (World Report 2005). Western nations are stockpiling antiviral drugs and developing vaccines, leaving poor and middle-income countries to worry that they will not have access to these potential lifesavers. At this meeting, none of the proposals directly addressed the question of equitable access to medicines and vaccines should a pandemic occur (Enserink 2005).

Support of developing countries from Western nations should precede the pandemic. Once the pandemic starts, it will be too late. Pandemics do not have frontiers, so international co-operation and equitable distribution of resources should start as soon as possible.


 
 
 


References

  1. ACIP 2005. Recommendations of the Advisory Committee on Immunization Practices (ACIP). July 13, 2005 / 54 (Early Release); 1-40. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr54e713a1.htm
  2. Anderson RM, May RM. Infectious Diseases of Humans: Dynamics and Control. Oxford Univ. Press, Oxford, 1992.
  3. Axbbott A. Avian flu special:  What's in the medicine cabinet? Nature 435;407-409. Available from http://www.nature.com/nature/journal/v435/n7041/full/435407a.html
  4. Balicer RD, Huerta M, Davidovitch N, Grotto I. Cost-benefit of stockpiling drugs for influenza pandemic. Emerg Infect Dis 2005; 11: 1280-2. Full text at http://www.cdc.gov/ncidod/EID/vol11no08/04-1156.htm
  5. Barnett DJ, Balicer RD, Lucey DR, et al. A systematic analytic approach to pandemic influenza preparedness planning. PLoS Med 2005; 2: 1-7. Full text at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/jour nal.pmed.0020359
  6. Brett AS, Zuger A. The run on tamiflu - should physicians prescribe on demand? N Engl J Med 2005; 353: 2636-37. Full text at http://content.nejm.org/cgi/content/full/353/25/2636
  7. Brown H. Nations set out a global plan for influenza action. Lancet 2005; 366: 1684-5.
  8. BWHO 2004. World is ill-prepared for "inevitable" flu pandemic. Bull World Health Organ 2004; 82:317-318.
  9. CDC 2003. Centers for Disease Control and Prevention. Respiratory hygiene/cough etiquette in healthcare settings 2003 Dec 17 [cited 2005 Nov 18]. Available at: http://www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm
  10. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005; 11: 201-9. Full text at http://www.cdc.gov/ncidod/eid/vol11no02/04-1061.htm
  11. Chung PH. Preparing for the worst-case scenario. Science 2005; 310:1117-8.
  12. CP/BSB 2003. Clinical Pharmacology/Biopharmaceutics Summary Background 2003. http://www.fda.gov/cder/foi/esum/2004/21246slr010,21087slr016_Tamiflu_Pharm_Biopharm _BPCA.pdf
  13. de Jong MD, Thanh TT, Khank TH, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005; 353: 2667-72. Full text at http://content.nejm.org/cgi/content/full/353/25/2667
  14. Enserink M. Meeting seeks global consensus, highlights global disparities. Science 2005; 310: 1103.
  15. Fal Falsey AR, Criddle MM, Kolassa JE, McCann RM, Brower CA, Hall WJ. Evaluation of a handwashing intervention to reduce respiratory illness rates in senior day-care centers. Infect Control Hosp Epidemiol 1999; 20: 200-2. Abstract: http://amedeo.com/lit.php?id=10100548
  16. FAO 2005. FAO Avian influenza disease emergency. Update on the avian influenza situation (as of 12/11/2005) - Issue no. 36. Available at: http://www.fao.org/ag/againfo/subjects/documents/ai/AVIbull036.pdf
  17. FAO, OIE, WHO 2005. A Food and Agriculture Organisation (FAO), World Organisation for Animal Health (OIE) in collaboration with World Health Organisation (WHO) Global Strategy for the Progressive Control of Highly Pathogenic Avian Influenza (HPAI). November 2005. Available at: http://www.fao.org/ag/againfo/resources/documents/empres/AI_globalstrategy.pdf
  18. Ferguson NM, Cummings DA, Cauchemez S, et al. Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature 2005; 437: 209-14. Abstract: http://amedeo.com/lit.php?id=16079797
  19. Ferguson NM, Fraser C, Donnelly CA, Ghani AC, Anderson RM. Public health risk from the avian H5N1 influenza epidemic. Science 2004; 304: 968-69.
  20. Flahault A, Dias-Ferrao V, Chaberty P, Esteves K, Valleron AJ, Lavanchy D. Flu Net as a tool for global monitoring of influenza on the Web. JAMA 1998; 280: 1330-2. Full text at http://jama.ama-assn.org/cgi/content/full/280/15/1330
  21. Fleming D. Influenza pandemics and avian flu. BMJ 2005;331:1066-9.
  22. Fraser C, Riley S, Anderson RM, Ferguson NM. Factors that make an infectious disease outbreak controllable. PNAS 2004; 101: 6146-51. Full text at http://www.pnas.org/cgi/content/abstract/101/16/6146
  23. Groeneveld K, van der Noordaa J. Use of antiviral agents and other measures in an influenza pandemic. The Neth J Med 2005; 63: 339-43. Full text at http://www.zuidencomm.nl/njm/getpdf.php?id=437
  24. Gubareva LV, Kaiser L, Matrosovich MN, Soo-Hoo Y, Hayden FG. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis 2001; 183: 523-31. Full text at http://www.journals.uchicago.edu/JID/journal/issues/v183n4/000943/000943.html
  25. Hayden F, Croisier A. Transmission of Avian Influenza Viruses to and between Humans. The J Infec Dis 2005; 192: 1311-4.
  26. Hayden FG. Antivirals for pandemic influenza. J Infect Dis 1997; 176: Suppl 1: Abstract: http://amedeo.com/lit.php?id=9240696
  27. Hien TT, Nguyen TL, Nguyen TD, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004; 350: 1179-88. Full text at http://content.nejm.org/cgi/content/abstract/350/12/1179
  28. Ho MS, Su IJ. Preparing to prevent severe acute respiratory syndrome and other respiratory infections. Lancet Infect Dis 2004; 4: 684-9. Abstract: http://amedeo.com/lit.php?id=15522680
  29. Hoffmann C, Kamps BS. Drugs. In: Influenza Report 2006; Wuppertal 2006. Available from http://InfluenzaReport.com/ir/drugs.htm
  30. Hoffmann C, Korsman S, Kamps BS. Treatment and Prophylaxis. In: Influenza Report 2006; Wuppertal 2006. Available from http://InfluenzaReport.com/ir/tp.htm
  31. IHR 2005. International Health Regulations 2005. Available at: http://www.who.int/gb/ebwha/pdf_files/WHA58/WHA58_3-en.pdf
  32. Imuta F, Toyoda M, Toyoda T. New application method of zanamivir with a straw. Pediatr Int 2003; 45: 366-7.
  33. Johnson NP, Mueller J. Updating the accounts: Global mortality of the 1918-20 "Spanish" influenza pandemic. Bull Hist Med 2002; 76: 105-15. Abstract: http://amedeo.com/lit.php?id=11875246
  34. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004; 364: 759-65. Abstract: http://amedeo.com/lit.php?id=15337401
  35. Korsman S. Vaccines. In: Influenza Report 2006; Wuppertal 2006. Available from http://InfluenzaReport.com/ir/vaccines.htm
  36. Lipatov AS, Govorkova EA, Webby RJ, et al. Influenza: emergence and control. J Virol 2004; 78: 8951-9. Full text at http://jvi.asm.org/cgi/content/full/78/17/8951?view=long&pmid=15308692
  37. Longini IM Jr, Halloran ME, Nizam A, Yang Y. Containing pandemic influenza with antiviral agents. Am J Epidemiol 2004; 159: 623-33. Abstract: http://amedeo.com/lit.php?id=15033640
  38. Longini IM Jr, Nizam A, Xu S, Ungchusak K, Hanshaoworakul W, Cummings DA, Halloran ME. Containing pandemic influenza at the source. Science. 2005 Aug 12;309(5737):1083-7.
  39. McKimm-Breschkin J, Trivedi T, Hampson A, et al. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother 2003; 47: 2264-72. Full text at http://aac.asm.org/cgi/content/full/47/7/2264?view=long&pmid=12821478
  40. Moscona A. Oseltamivir resistance--disabling our influenza defenses. N Engl J Med 2005; 353: 2633-6. http://amedeo.com/lit.php?id=16371626 - Full text at http://content.nejm.org/cgi/content/full/353/25/2633
  41. Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005; 352: 1839-42. Full text at http://content.nejm.org/cgi/content/full/352/18/1839
  42. PPHSN 2004. Pacific Public Health Surveillance Network Guidelines for Influenza Preparedness & Control and Influenza Pandemic Preparedness (Part II). Prepared in Consultation with the PPHSN Influenza Specialist Group (ISG). Available at: http://www.spc.org.nc/phs/pphsn/Publications/Guidelines/Influenza/PPHSN_Influenza_pa ndemic-guidelines-partII-final_draft-oct04.pdf
  43. Stilianakis NI, Perelson NS, Hayden FG. Drug resistance and influenza pandemics. Lancet 2002; 359: 1862-3.
  44. Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature 2005; 437: 889-93. Full text at http://www.nature.com/nature/journal/v437/n7060/pdf/nature04230.pdf
  45. Thanhnien 2005. http://www.thanhniennews.com/healthy/?catid=8&newsid=10854
  46. USDHHS 2005. United States Department of Health and Human Services 2005. Draft pandemic influenza preparedness and response plan. Annex 9: Communication and education. Available at: http://www.hhs.gov/nvpo/pandemicplan/annex9.communication.pdf
  47. van Dalen PJ, Wijdenes C. Preparing for the next influenza pandemic. Neth J Med 2005; 63: 337-8. Full text at: http://www.zuidencomm.nl/njm/getpdf.php?id=436
  48. Vardi A, Levin I, Berkenstadt H, et al. Simulation-based training of medical teams to manage chemical warfare casualties. Isr Med Assoc J 2002; 4: 540-4. Abstract: http://amedeo.com/lit.php?id=12120468
  49. WCWHO 2005. The Writing Committee of the World Health Organisation (WHO) Consultation on Human Influenza A/H5. Avian Influenza A (H5N1) Infection in Humans. N Engl J Med 2005; 353: 1374-85. Full text at http://content.nejm.org/cgi/content/full/353/13/1374
  50. Webster RG, Peiris M, Chen H, Guan Y. H5N1 outbreaks and enzootic influenza. Emerg Infect Dis 2006; 12: 3-8. Available at: http://www.cdc.gov/ncidod/EID/vol12no01/05-1024.htm
  51. Webster RG. Wet markets--a continuing source of severe acute respiratory syndrome and influenza? Lancet. 2004 Jan 17;363(9404):234-6.
  52. WHO 2004: Informal consultation on influenza pandemic preparedness in countries with limited resources. Kuala Lumpur, Malaysia 23-25 June 2004. Department of Communicable Disease Surveillance and Response. http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2004_1/en/in dex.html
  53. WHO 2005a: Geographical spread of H5N1 avian influenza in birds - update 28. Situation assessment and implications for human health. 18 August 2005. http://www.who.int/entity/csr/don/2005_08_18/en/index.html
  54. WHO 2005b: Geographical Spread of H5N1 in Birds-update 34: 20 October 2005. http://www.who.int/csr/don/2005_08_18/en/index.html
  55. WHO 2005c: Situation Updates: Accessed on January 25, 2006. http://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_01_25/en/ind ex.html
  56. WHO 2005d: WHO global influenza preparedness plan: The role of WHO and recommendations for national measures before and during pandemics. Available at: http://www.who.int/entity/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_ 5/en/index.html
  57. WHO 2005e: Checklist for influenza pandemic preparedness planning 2005. http://www.who.int/csr/resources/publications/influenza/FluCheck6web.pdf
  58. WHO 2005f: Avian influenza: assessing the pandemic threat. http://www.who.int/csr/disease/influenza/WHO_CDS_2005_29/en/index.html.
  59. WHO 2005G: WHO Statement. Available at: http://www.who.int/mediacentre/news/statements/2005/s08/en/index.html
  60. WHO 2006. World Health Organisation Writing Group. Nonpharmaceutical interventions for pandemic influenza, international measures. Emerg Infect Dis. 2006; 12: 81-7. Full text at http://www.cdc.gov/ncidod/EID/vol12no01/05-1370.htm
  61. Yen HL, Herlocher LM, Hoffmann E, et al. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother 2005; 49: 4075-84. Abstract: http://amedeo.com/lit.php?id=16189083

 
 
 
 
     Design:

 
 
 

 
General Disclaimer | IR Alert