Amy Ray, MD

MPHP 439

Health Policy On-line Chapter

4/22/06

Influenza

Introduction

Influenza is an acute viral illness which causes significant human morbidity and mortality. It is known to have caused disease for several hundred years, and in 2006, it remains at the forefront of the daily news. As threats of H5N1 or avian influenza as well as drug-resistant influenza loom large, many questions face public health practitioner, including who is at risk for disease, what medications are available to treat influenza, how can spread be thwarted. This chapter will provide the latest influenza information for the public health practitioner and clinician alike.

History

Influenza epidemics have been recognized as early as the 12^th century (1). Characterized by fever, cough, malaise, and body aches, influenza cyclically causes disease every one to three years. The high attack rate and periodicity made influenza outbreaks describable by astute observers prior to the advent of virologic techniques which later identified the virus as the causative agent. Combined with the high attack rate, the virus’ ability to change itself keeps a human population susceptible to epidemic outbreaks. In 1580, the first pandemic, or disease worldwide, was described, and since, thirty-one pandemics have been recorded. The most devastating occurred in 1918-1919, when estimates place death counts at 21 million worldwide or greater (2).

The Organism

Influenza virus is classified in the viral family Orthomyxoviridae. Disease is caused most commonly by influenza A, B, or C. The types of influenza differ in their host(s), epidemiology, and clinical features. For example, influenza A affects human, birds, swine, equine, and marine animals. It also possesses the ability to change its surface proteins, resulting in decreased immunity in a newly exposed population. Influenza B infects humans only, where influenza C infects both humans and swine.

Influenza viruses have proteins on their surface called neuraminidase and hemagglutinin by which strains are identified. Influenza A viruses have at least fifteen distinct hemagglutinins described and nine distinct neuraminidase proteins. The avian influenza which is sporadically causing disease in humans currently is commonly referred to as “H5N1”, indicating that the virus has the 5^th hemagglutin described and the first neuraminidase.

Clinical Presentation

Influenza causes an acute, usually self-limited illness which is characterized by fever, malaise, body aches, and dry cough. It affects the respiratory system primarily, including the lungs, sinuses, and nasal passages. The incubation period, or time from exposure to the virus to infection, is 1 to 2 days. It can be distinguished from other respiratory viral illnesses by the systemic manifestations of high fever for 3 days on average with accompanying headache, chills, and lack of appetite with diffuse muscles aches. A contagious illness, influenza is spread via respiratory secretions and contaminated surfaces. Humans at the extremes of age, those who are immunocompromised secondary to chronic disease or required medications, and those with underlying cardiac or pulmonary disease can suffer complications of influenza, including bacterial pneumonia, myositis or inflammation of the muscles, myocarditis or inflammation of the heart muscle, and neurological complications such as encephalitis.

Epidemiology

The epidemiology of influenza-associated morbidity and mortality is staggering. The burden of disease is usually expressed in rates of pneumonia which exceed the expected rate and in influenza-related hospitalizations and deaths during epidemics (3, 4). In temperate climates, the disease incidence follows a typical pattern of peaking in the winter months at the height of influenza season and troughs in the summer months. In the United States each influenza season approximately 10 to 20 per cent of the population is infected, and as many as 114, 000 Americans require hospitalization. Each year 36, 000 Americans die of influenza and its complications. Some authors have proposed that the number of influenza deaths in the United States is higher than what is believed secondary to underreporting, estimating the true incidence to be as high as 51, 000 per year (5).

Influenza has an attack rate of 10-40 percent; therefore, when a susceptible population is exposed to influenza, up to 40 per cent will acquire the disease. Those most at risk for infection are the very young and the elderly, and mortality is highest for the elderly. Other categories of persons at high risk for acquiring influenza include the immunocompromised such as persons with HIV/AIDS or transplant recipients and pregnant women.

An influenza epidemic is characterized by a sharp increase in disease within one location, such as city, state, or country. For influenza A, the disease peaks in 2 to 3 weeks and lasts 5 to 6 weeks. Typically, the first sign of an influenza A outbreak is an increase in the number of children with respiratory illness associated with fever, although occasionally the first sign of an outbreak will occur within a nursing home in a community. The numbers of admissions to hospitals for pneumonia, exacerbations of asthma and chronic obstructive pulmonary disease, and heart failure rise, as well as school and work absenteeism. The outbreak usually stops prior to infection of all susceptible hosts within a community for unknown reason(s), but increased awareness and infection control measures contribute to cessation of the epidemic.

Diagnosis

The influenza virus can be isolated from an infected individual’s nasal or upper airways secretions. Viral culture, or growth of the virus from a clinical specimen on special media, takes three to seven days. The most common method of diagnosis is a rapid influenza test, which tests the patient’s secretions for the presence of a viral antigen. These tests are easy to perform and results can be obtained as quickly as thirty minutes. For these reasons, the rapid influenza test(s) are widely available in the United States.

In addition to viral culture or antigen detection methods, the diagnosis is often suspected on epidemiological and clinical grounds. If influenza is known to be present in a community, when a patient presents with signs and symptoms consistent with influenza, the clinical diagnosis alone is often correct (6, 7).

Treatment

Treatment of influenza is available; however, no study has shown benefit of treatment if given 48 hours after the clinical onset of disease. In healthy human hosts, influenza viral replication is rapidly limited, especially in humans who have been exposed to influenza in the past.

The antiviral drugs active against influenza include amantadine and rimantadine, which are M2 inhibitors, and zanamivir and oseltamivir, which are neuraminidase inhibitors. The M2 inhibitors are active against influenza A only. The neuraminidase inhibitors are active against both influenza A and B. All four drugs can be used for prophylaxis after exposure to influenza. Drug resistance has occurred to both classes of medications, though rarely to the neuraminidase inhibitors (8, 9).

Prevention

The most effective means of preventing influenza is vaccination. First available in 1943 in the United States, influenza vaccines are made from inactivated virus grown within chicken eggs. The vaccine is composed of three viral strains, two influenza A and one influenza B which are thought to be likely to cause the annual influenza season. When influenza in the community matches that which is contained within the year’s vaccine, the efficacy of the vaccine is 70-90% (10, 11). The strategy for vaccination is a targeted approach, and individuals most at risk for complications of influenza and those most likely to transmit disease are the targeted recipients. Currently, the Centers for Disease Control (CDC) in the United States recommends influenza vaccination to the following groups: age>50, nursing home residents or other chronic care facilities, adults and children with chronic lung or heart disease, adults and children with diabetes, kidney dysfunction, and HIV, women who will be in the second or third trimester of pregnancy during influenza season, health care workers, children ages 6 months to 23 months, and household contacts of persons in high risk groups (including children 0 to 23 months of age) (12).

Although influenza vaccination is direly important to public health, meeting production goals and population demands is often challenging. During the fall of 2004, the citizens of the United States came to appreciate the fragility of vaccine production and supply. The supply of influenza vaccine was abruptly halved when British officials shut down an influenza vaccine manufacturing factory at Chiron Corporation due to manufacturing problems. The planned supply for the United States during the fall 2004-winter 2005 was intended to be 100 million doses, but the shutdown of the Chiron factory decreased the number to 54 million. Suddenly, the vaccine production process, vaccine suppliers, and demand for vaccine became issues of the daily news and subject for political commentary. The CDC tailored its vaccine recommendations to target babies and their caregivers, the elderly, pregnant women, children on aspirin therapy, health care workers, and others at high risk for complications and their caregivers.

The 2004 shortage of influenza vaccine highlights the current problems with vaccine supply and demand. The entire United States population was depending on two companies to supply its annual vaccine, and this episode was not the first season of vaccine shortage. If demand for influenza vaccine is high, why is shortage ever an issue? The production process is lengthy and expensive, so that when the Chiron supply was stopped in process, another “batch” could not replace it due to time constraints. It takes as long as six months after a viral strain has been identified to produce vaccine. The reasons for vaccine shortage are multiple and include fewer companies making the vaccine secondary to expense and lack of a guaranteed market, problems in the manufacturing process itself, and liability concerns.

In September 2005, the United States Government Accountability Office (GAO) submitted a report to the United States Congress entitled, “Influenza Vaccine: Shortages in 2004-2005 Season Underscore the Need for Better Preparation” (13). Within the report, the authors review the actions taken by various governmental agencies at the local, state, and federal level to deal with the shortages of influenza vaccine as well as underscore the lessons learned from the shortage. The primary action taken within all sectors of government was the redistribution of vaccine supply to those most at risk, including new CDC recommendations on recipients during the shortage. During mid-December through January, health officials then broadened recommendations to more widely serve the population.

The GAO report highlights three interrelated lessons from the influenza vaccine shortage during the 2004-2005 season. Prior to the announcement of the thwarted supply of vaccine from Chiron, the CDC had no contingency plan in order to contend with a severe shortage. A number of states utilized emergency responsiveness plans and health directives in lieu of a specific federal plan from the CDC. Although federal agencies purchased more vaccine from other suppliers not licensed in the United States market, the purchases occurred late in the season, December 2004 and January 2005, after the demand had subsided. Finally, the GAO found that communication during the crisis was not always well-coordinated between governmental agencies, resulting in public confusion about the process to acquire vaccine and eventual public disinterest as confusion grew.

The influenza season of 2004-2005 proved to be mild to moderate, and the CDC’s postseason data indicate the levels of vaccination in high-risk groups approached historical rates (14). Clearly, had the season been more severe, the lack of planning and delayed purchase of vaccine could have been disastrous. The Department of Health and Human Services agreed with the GAO in terms of the importance of contingency planning, and approval for additional suppliers of influenza vaccine is ongoing.

Avian Influenza

The shortage of United States influenza vaccine in 2004-2005 received much media as well as political attention, but in 2006, the world is on alert a different influenza, the avian flu. The H5N1 or avian influenza virus is circulating among birds across eastern Asia and Europe. The virus is making headlines because it can cause disease, albeit rarely, in humans. When the virus causes human disease, the fatality rate is high. To date, there have been 204 human cases with 113 fatalities since 2003 (15). Most of the cases have occurred in Viet Nam (93/204), followed by Indonesia and Thailand. An H5N1 influenza pandemic, or worldwide disease outbreak, is possible.

What distinguishes H5N1 from other influenza viruses is its habitat and virulence among fowl. Given that it is spread by migratory birds, it is unlikely to be contained. It can be spread from birds to mammals, and like all influenza viruses, H5N1 will continue to evolve. Most, if not all, human cases have been a result of direct contact with infected poultry. No sustained human-to-human transmission has occurred, and this mode of transmission is needed in order for H5N1 influenza to result in a pandemic.

Symptoms of avian influenza in humans are not unlike those caused by more typical human influenza, including fever, headache, body aches, and cough. More severe manifestations such as pneumonia and acute respiratory distress syndrome have occurred. The number of cases in humans may be an underestimate, as only the more severe cases are currently being reported.

Currently, there is no H5N1 vaccine for humans, although the United States National Institute of Allergy and Infectious Diseases (NIAID) is working on vaccine development based upon currently circulating H5N1. NIAID is collaborating with industry to increase the vaccine production capability and researching new types of influence vaccines (16). The neuraminidase inhibitors are active against H5N1; however, drug resistance is a concern, and additional studies are needed to confirm efficacy of these medications against H5N1 influenza.

A severe influenza pandemic whether caused by H5N1 or another influenza strain will undoubtedly take a large toll on society, including high rates of death, illness, social disruption, and economic loss. Deaths caused by pandemic influenza will depend upon the virulence of the virus, the number of infections, and the degree of preparedness. In order to prepare for a pandemic of influenza, the World Health Organization (WHO) is leading the global efforts. Keys to success are early detection of outbreaks and containment, vaccine supply, medication supply, adequate food and water stores, and clear delineation of roles and responsibilities of governments. The WHO has planned a draft protocol to the facilitate the early detection of an outbreak in order to thwart a pandemic at its start (17) The plan is extremely time-dependent and involves early detection and confirmation of the disease, rapid containment via isolation or social distancing, and mass administration of antiviral drugs within the outbreak zone in order to prevent future infections. An international stockpile of oseltamivir has been established which amounts to 3 million treatment courses which will be used in the event of sustained, person-to-person transmission. In addition to international planning, the WHO has outlined emergency preparedness goals for individual nations (18), many of whom are also stockpiling antiviral agents and coordinating governmental and private sector plans.

Conclusion

Influenza is a viral illness which causes significant morbidity and mortality. Its consequences are most harsh for those persons at the extremes of age. Successful management of future epidemics and prevention of a pandemic include early detection of disease, efficient containment, adequate and accurate vaccine supplies, medication supplies, and management of health care resources. Adequate planning for contingencies and communication among international and local agencies are fundamental, as is personal preparedness.

References

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2. Crosby AW. Epidemic and Peace, 1918. Part IV. Westport, Conn: Greenwood Press; 1976.

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5. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179–186.

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8. Monto AS, Arden NH. Implications of viral resistance to amantadine in control of influenza A. Clin Infect Dis. 1992;15:362–367.

9. Covington E, Mendel DB, Escarpe P, et al. Phenotypic and genotypic assay of influenza virus neuraminidase indicates a low incidence of viral drug resistance during treatment with oseltamivir. J Clin Virol. 2000;18:P326.

10. Meiklejohn G, Eickhoff TC, Graves P. Antigenic drift and efficacy of influenza virus vaccines, 1976–1977. J Infect Dis. 1978;138:618–624.

11. Meiklejohn G. Viral respiratory disease at Lowry Air Force Base in Denver, 1952–1982. J Infect Dis. 1983;148:775–783.

12. www.cdc.gov/mmwr/pdf/rr/rr5408.pdf

13. www.gao.gov/new.items/d05984.pdf

14. Centers for Disease Control and Prevention, “Estimated Influenza Vaccination Coverage among Adults and Children, United States, September 1, 2004-January 31, 2005, “ Morbidity and Mortality Weekly Report, vol.54, no 12 (2005): 304-307.

15.www.who.int/csr/disease/avian_influenza/country/cases_table_2006_04_21/en/index.html

16.www.pandemicflu.gov/general/#h5n1

17. www.who.int/csr/disease/avian_influenza/guidelines/pandemicfluprotocol_17.03a.pdf

18. www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_05_8-EN.pdf