Influenza: Introduction of the Neuraminidase Inhibitors
 

Table of Contents

          Introduction
          Epidemiology
               Attributable Deaths
               Who Gets the Flu?
               Who Is at Risk of Death?
          Mechanisms of Immunity
               The Antigenic Proteins
               Antigenic Drift
               Antigenic Shift
          Diagnosis
               Rapid, Accurate Diagnosis: Why Is It Important?
               Clinical Presentation
               Pretest Probability Always a Linchpin
               Laboratory Techniques
          Treatment
               The Influenza Vaccine: Safe and Effective
               Antiviral Agents
          Summary
          References
 

Introduction

Until recently, supportive care, monitoring, and treatment for secondary complications, and, of course, chicken soup were the primary modalities for treating people infected with influenza virus. Now the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir phosphate (Tamiflu) join the antimembrane drugs rimantadine and amantadine as options for treatment of this common, costly, and deadly disease. Effective diagnostic and therapeutic modalities are needed now more than ever. The rate of hospitalization (although not death) for pneumonia and influenza has increased despite the increased influenza vaccination rates in individuals older than 65 years. At a satellite symposium preceding the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, noted experts reviewed the epidemiology of influenza, as well as its diagnosis and complications, and the drugs and vaccine used to curb its impact.

Epidemiology

Attributable Deaths

The death tallies during pandemic years are the most dramatic occurrences associated with the influenza virus. All totaled, nearly 650,000 excess pneumonia deaths are attributed to the 3 most recent pandemics (Table 1).

     Table 1. Excess Pneumonia Death Attributed to Recent Pandemics*

       *Data are from Cox and Subbarao.[1]

Kanta Subbarao, Chief of the Molecular Genetics Section, Influenza Branch, Centers for Disease Control and Prevention (CDC), pointed out that the virus continues to kill during nonpandemic years. The number of excess pneumonia deaths attributable to the virus during recent interpandemic years nearly equals the number of deaths attributable to the recent pandemics. From the 1957 pandemic to the present, influenza virus infection has lead to just more than 600,000 deaths.[1]

Who Gets the Flu?

Small children have the highest rates of medically attended illness during influenza epidemics, whereas the highest rates of hospitalization and death occur in those older than 65 years, according to extensive studies of disease patterns conducted by Paul Glezen and his group in Houston, Tex.[2] Children are often the first population group affected. Thus, local epidemics are often heralded by increases in primary school absenteeism and visits to pediatricians for febrile illness.

Influenza is also a common experience in adults. From 5% to 40% of the general population gets the flu, depending on the severity of the influenza season. Because of the resulting employee absenteeism and other indirect effects of influenza, it is estimated that the total economic burden in the United States can be as high as $12 billion in some years. Approximately 80% of that figure accrues from indirect costs and 20% from direct medical costs associated with diagnosis and treatment.[3]

Who Is at Risk of Death?

The risk of death from influenza infection is highest in individuals older than 65 years with 1 or more risk factors for severe illness and in those aged 45 to 64 years with 2 or more risk factors for severe illness.[4] In individuals older than 65 years with 1 or more risk factors, the rate of hospitalization is approximately 300 per 100,000 individuals. The rate of hospitalization (although not death) for pneumonia and influenza has increased despite the increase in influenza vaccination rates in individuals older than 65 years, which has exceeded 60%.

Recently, a retrospective review of the Tennessee Medicaid database established that there is an increased risk of hospitalization in women who are in the second or third trimester of pregnancy during the influenza season.[5,6]

Mechanisms of Immunity

The Antigenic Proteins

The immune response to influenza virus is directed at 2 proteins present on its outer coat: hemagglutinin and neuraminidase. The hemagglutinin protein binds with sialic acid residues on the host cell's surface. It is necessary for viral entry into the host cell. The neuraminidase protein enzymatically cleaves sialic acid residues, and it is necessary for the spread of virus particles from cell to cell. Without neuraminidase, the virus aggregates but does not spread.

Antigenic Drift

People who have contracted the flu do not have protective immunity for life because of changes in these 2 viral antigens that elicit the immune response in humans. Antigenic drift refers to the accumulation of point mutations in the hemagglutinin and neuraminidase proteins that results in slight antigenic variation, allowing the virus to escape immunity acquired from previous influenza infections. It is thought that 2 or more amino acid changes in 2 or more of the 5 main antigenic sites on hemagglutinin are sufficient to result in a significant antigenic change.

Antigenic Shift

The other mechanism of antigenic variation is referred to as antigenic shift. Antigenic shift occurs when viruses bearing novel combinations of hemagglutinin and neuraminidase proteins enter human populations. This may occur by direct introduction into humans from an animal host (mostly water fowl) or by the reassortment of proteins between animal and human influenza A viruses. These new viruses can be very virulent and are responsible for the severe, worldwide epidemics known as pandemics.

The CDC and the World Health Organization (WHO) maintain a large worldwide surveillance system to detect and characterize new strains as quickly as possible. Currently circulating are variations of the H1N1 virus that caused the 1917 pandemic, variations of the H3N2 strain of the 1968 pandemic, and the influenza B virus (which changes by antigenic drift but not shift). Thus, the 1999-2000 trivalent inactivated virus vaccine was composed of isolates representative of these strains. The components for the North American flu vaccine for the 2000-2001 flu season were selected in mid February by WHO: an A/Moscow/10/99(H3N2)-like virus, an A/New Caledonia/20/99(H1N1)-like virus, and a B/Beijing/184/93-like virus.

Diagnosis

Rapid, Accurate Diagnosis: Why Is It Important?

There are several reasons why rapid diagnosis of influenza is highly desirable. First, without a diagnosis, specific therapy cannot be initiated when it is most helpful, during the first 2 days of illness. Second, secondary complications could be anticipated or prevented in patients, and primary prevention with antiviral prophylaxis might avoid the disease in the patient contacts. Finally, rapid and accurate diagnosis would help obtain an early picture of local influenza activity and possibly reduce inappropriate prescribing of antibacterial drugs.

Clinical Presentation

Sudden onset of fever, nonproductive cough, and systemic symptoms such as myalgias and malaise constitute the typical clinical presentation of influenza in adults, according to a review of the data presented by Jonathan Solsky of Roche Laboratories. The clinical presentation of influenza A and B is similar, although influenza B may be less severe overall. In children, fever is the most predominant symptom, and malaise and myalgias are not reported as frequently, simply because young children may not be able to describe these symptoms. However, influenza in children is usually associated with markedly decreased levels of activity and behavioral changes that are indicative of the presence of these symptoms. In many case series, nausea has been a more prominent symptom of influenza in children than it is in adults. In the elderly, the presentation of influenza may be blunted, with less marked fever and systemic symptoms and a more gradual onset. However, the rates of complications are markedly increased in this age group.[7]

Pretest Probability Always a Linchpin

The diagnosis of influenza is still as much an art as a science. Differentiating this disease from other acute respiratory viral and bacterial conditions requires clinical acumen in conjunction with the clinical clues outlined above.

Knowledge of local epidemiologic patterns of infection is a powerful aid to physicians faced with the task of ferreting out who has the flu and who may have other upper respiratory tract infections. Data suggest that the clinical diagnosis can be made with greater than 80% confidence during recognized regional influenza epidemics.[8]

In addition to the worldwide surveillance program outlined above, the CDC administers a surveillance program that includes data from the WHO collaborating laboratories, sentinel physicians, statistical reports from 122 US cities, and reports from state health departments. This highly accurate system is designed to gather data on strains for vaccine formulation and to develop accurate data for assessing the health impact of influenza. Data from the system generally lags several weeks behind real time, which limits its usefulness as a tool for physicians attempting to diagnose patient's conditions at the point of care.

Laboratory Techniques

The gold standard of diagnosis is currently viral culture, generally done on nasopharyngeal swab or aspirate, throat swab, or sputum samples. Viral culture is highly accurate and results in isolation of the virus, which can then be characterized further. However, culture requires access to a cell culture laboratory, is expensive, and usually does not provide a result for several days, limiting its utility for individual patient management.

Three rapid tests were available at the time of the presentation, including the Directigen Flu A, the Biostar optical immunoassay (FLU OIA), and the Z-stat Flu test (Table 2) The Directigen Flu A test has been available the longest and uses monoclonal antibody enzyme-linked immunosorbent assay techniques to directly detect virus in clinical samples. Published data suggest that this test has a sensitivity of between 67% and 96% compared with culture, depending on the type of sample and population analyzed.[9] The test takes approximately 20 minutes and costs around $19. The Directigen Flu A test currently only detects influenza A, although modifications to detect influenza B using similar technology are in development.

     Table 2. Rapid Laboratory Tests for Office-Based Diagnosis of Influenza

The Biostar optical immunoassay (FLU OIA) also uses monoclonal antibodies to detect viral antigen in the sample. Available data on this test are limited, but sensitivity rates of 75% to 90% have been reported.[10] The test detects both influenza A and B but does not differentiate between the two. Test time is approximately 15 minutes, and the cost is around $16.

The Z-stat Flu test uses a novel detection method. A colorimetric assay of viral neuraminidase activity determines the presence of the virus. The Z-stat Flu test detects both influenza A and B, with a sensitivity of approximately 62% compared with culture. The price is approximately $17 to $18.

None of the tests are eligible for CLIA waiver under current rules because they are classified as of moderate complexity or greater. They are also usually not reimbursed by health insurers, making them relatively less attractive for use in the office setting. However, the current rapid tests can be useful in the clinical microbiology laboratory. Two tests currently in development are the GLORIA (Gold-Labeled Optical Rapid Immunoassay) test being developed by Roche and the Quick View test being developed by Quidel. A reverse transcriptase polymerase chain reaction test is also in development.[11]

Treatment

The Influenza Vaccine: Safe and Effective

The currently available inactivated influenza vaccine for prevention of influenza is safe and effective and probably our most important tool in reducing morbidity, mortality, and economic losses due to flu, according to Dr. Peter Gross of Hackensack Medical Center. He reviewed a recent meta-analysis of influenza vaccine efficacy in the elderly.[12] This analysis concluded that overall the efficacy of inactivated vaccine in the prevention of respiratory illness is 56%; for prevention of pneumonia, 53%; for prevention of hospitalization, 50%; and for prevention of death due to influenza, 68%.

There are also multiple individual case-control studies that support the efficacy of influenza vaccine in elderly and high-risk populations.[13-16] These studies demonstrate that influenza vaccination dramatically decreases all-cause mortality in the elderly and other high-risk groups.

Nichol and colleagues[17] demonstrated that inactivated influenza vaccine was effective at preventing febrile respiratory illness of all causes during the influenza season among working adults. This reduction was associated with a significant economic benefit because of the work absenteeism prevented by vaccination. Their report estimated that vaccination would be associated with approximately $5 in direct medical cost savings and $40 in indirect cost saving per person vaccinated. Recently, these authors performed a similar analysis of vaccination of working adults with the experimental live, cold-adapted influenza vaccine. Their analysis has shown that this vaccine is also effective in prevention of severe febrile respiratory illness in adults.[18,19]

Antiviral Agents

The 2 classes of antiviral agents currently available for prevention and treatment of influenza are the older antimembrane drugs (M2 inhibitors: amantadine and rimantadine) and the newer neuraminidase inhibitors (zanamivir and oseltamivir).[20,21] The M2 inhibitors have been available for many years and are clearly efficacious. However, they act only against influenza A viruses, and they frequently and rapidly induce resistance (Table 3). In contrast, antiviral resistance appears to arise infrequently in individuals treated with neuraminidase inhibitors, and resistant strains have decreased replicative fitness compared with their wild-type counterparts.[22] By binding to and inactivating the viral neuraminidase enzyme, the neuraminidase inhibitors interfere with the release of the virus from the cell.

     Table 3. Classes and Names of Influenza Antivirals

Dr. Gross reviewed data on the safety and efficacy of zanamivir.[23-25] Zanamivir is well tolerated. Patients with the flu taking the drug experienced approximately 1 fewer day of flu symptoms. Zanamivir is delivered topically. The standard treatment dose is 2 inhalations (10 mg) twice a day for 5 days.

Oseltamivir phosphate is an ethylester prodrug of another neuraminidase inhibitor, oseltamivir carboxylate (GS4071).[26,27] Oseltamivir reduces the severity of flu symptoms by approximately 40% and also reduces rates of secondary complications. Oseltamivir reduced infection of patient contacts by approximately 89%, but prophylaxis is not an indication currently approved by the Food and Drug Administration. The dose of oseltamivir for treatment is 75 mg orally twice a day for 5 days.

Summary

The testing of a new approach to vaccination -- the cold-adapted, live, attenuated vaccine -- and the approval of 2 new drugs for the treatment of influenza -- oseltamivir and zanamivir -- promise to provide physicians with new tools to battle an old enemy.

References

   1.Cox NJ, Subbarao K. Influenza. Lancet. 1999;354:1277-1282.
   2.Glezen WP. Emerging infections: pandemic influenza. Epidemiol Rev. 1996;18:64-76.
   3.Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med. 1995;333:889-893.
   4.Barker WH, Mullooly JP. Pneumonia and influenza deaths during epidemics. Arch Intern Med. 1982;142:85-89.
   5.Neuzil KM, Reed GW, Mitchel EF Jr, Griffin MR. Influenza-associated morbidity and mortality in young and middle-aged women. JAMA. 1999;281:901-907.
   6.Neuzil KM, Reed GW, Mitchel EF, et al. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol. 1998;148:1094-1102.
   7.Cox NJ, Fukuda K. Influenza. Infect Dis Clin North Am. 1998;12:27-38.
   8.Treanor JJ. Influenza virus. In: Mandell GL, Bennett GE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone; 1999:1823-1849.
   9.Kaiser L, Briones MS, Hayden FG. Performance of virus isolation and Directigen Flu A to detect influenza A virus in experimental human infection. J Clin Virol. 1999;14:191-197.
  10.Covalciuc KA, Webb KH, Carlson CA. Comparison of four clinical specimen types for detection of influenza A and B viruses by optical immunoassay (FLU OIA test) and cell
     culture methods. J Clin Microbiol. 1999;37:3971-3974.
  11.Pregliasco F, Mensi C, Camorali L, Anselmi G. Comparison of RT-PCR with other diagnostic assays for rapid detection of influenza viruses. J Med Virol. 1998;56:168-173.
  12.Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med.
     1995;123:518-527.
  13.Fedson DS, Wajda A, Nicol JP, Hammond GW, Kalser DL, Roos LL. Clinical effectiveness of influenza vaccination in Manitoba. JAMA. 1993;270:1956-1961.
  14.Bernstein E, Kaye D, Abrutyn E, et al. Immune response to influenza vaccination in a large healthy elderly population. Vaccine. 1999;17:82-94;
  15.Tasker SA, Treanor JJ, Paxton WB, Wallace MR. Efficacy of influenza vaccination in HIV-infected persons: a randomized, double-blind, placebo-controlled trial. Ann Intern Med.
     1999;131:430-433.
  16.Wilde JA, McMillan JA, Serwint J, et al. Effectiveness of influenza vaccine in health care professionals: a randomized trial. JAMA. 1999;281:908-913.
  17.Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med. 1995;333:889-893.
  18.Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA.
     1999;282:137-144.
  19.Treanor JJ, Kotloff K, Betts RF, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness
     following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine. 1999;18:899-906.
  20.Winquist AG, Fukuda K, Bridges CB, Cox NJ. Neuraminidase Inhibitors for treatment of influenza A and B infections. Morb Mortal Wkly Rep. 1999;48(RR14):1-9.
  21.Cox NJ, Hughes JM. New options for the prevention of influenza [editorial]. N Engl J Med. 1999;341:1387-1388.
  22.Barnett JM, Cadman A, Gor D, et al. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies.
     Antimicrob Agents Chemother. 2000;44:78-87.
  23.Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis.
     1999;180:254-261.
  24.Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999;282:31-35.
  25.Calfee DP, Peng AW, Cass LM, et al. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother.
     1999;43:1616-1620.
  26.Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.
     JAMA. 1999;282:1240-1246.
  27.Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. 1999;341:1336-1343.