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Respiratory Infection
Influenza: New Options for Prevention and Treatment

John J. Treanor, MD, University of Rochester, Rochester, NY, William P. Glezen, MD, Baylor College of Medicine, Houston, and Keith S. Reisinger, MD, MPH, Primary Physicians Research, Pittsburgh

Infect Med 19(2):66-71, 2002. © 2002 Cliggott Publishing, Division of SCP Communications

Abstract and Introduction

Abstract

Increasingly severe influenza epidemics in the United States and the transmission of an influenza virus previously confined to avian species underscore the real possibility of a future pandemic. In recent years, however, the development of a live influenza vaccine and the availability of neuraminidase inhibitors, a novel class of antiviral agents, have improved our ability to prevent and treat influenza. Early diagnosis is important, since treatment must be started early in the disease course to be effective.

Introduction

Influenza remains a constantly reemerging health threat that requires attention to prevention as well as early diagnosis and treatment. The prospects for decreasing the toll of future epidemics have been improved by the availability of a live vaccine and a new class of antiviral agents, the neuraminidase inhibitors (NAIs). Currently available vaccines can reduce complications in children and adults with underlying medical conditions. The new live, attenuated vaccine may further reduce morbidity in children and high-risk contacts. The NAIs offer an opportunity for effective and well-tolerated treatment of influenza A and B virus infections and prevention of secondary complications. Attention to epidemiologic patterns and clinical symptoms in different age groups is the key to early intervention.

In this article, we review the characteristics of the influenza virus, the basics of diagnosis, and the role of influenza vaccines and antiviral agents in the prevention and treatment of influenza.

Characteristics of Influenza Virus

Mechanism of Viral Infection

As shown in Figure 1, the influenza virus contains 2 important surface proteins, hemagglutinin (HA) and neuraminidase (NA). Infection begins when the HA molecule attaches to sialic acid-rich glycoproteins on the surface of the cell, facilitating entry into the cell via endocytosis.[1] HA also mediates fusion between the endocytic vesicle wall and the lipid bilayer envelope of the influenza virus, allowing the release of internal viral components into the cytoplasm. Newly replicated viral material then travels back to the cell surface, where it leaves the cell by budding, but it must first free itself from surface glycoprotein receptors that contain sialic acid. The virus accomplishes this through the action of NA, an enzyme that cleaves sialic acid from the surface receptors and functionally inactivates it. The virus is then able to spread from cell to cell.[1] A third envelope protein -- known as the M2 protein -- mediates viral uncoating, freeing gene segments to migrate to the cell nucleus, where virus replication occurs.[1]

Figure 1. The influenza virus contains the surface proteins neuraminidase, hemagglutinin, and M2, which play key roles in infection and spread of the virus from cell to cell.

Antigenic Reassortment and Immunity

Protection from the influenza virus depends on the immune response to HA and NA. However, the genes for these 2 surface proteins are highly unstable, and they undergo constant variation in response to immunity in the population. HA, in particular, changes its antigenic characteristics once enough individuals have antibodies to it. The influenza virus also has a segmented genome, which is an advantage for vaccine production because it allows a ready reassortment of the anticipated virus with a "rapid grower." But reassortment can also occur in nature, leading to the emergence of pandemic strains. If a human virus reassorts with an avian virus with any of the 12 HAs that have never circulated in humans, for example, the result could be the emergence of an entirely new influenza virus to which no immunity exists.

Current Viral Patterns

Figure 2 illustrates the current classification system for the influenza virus. The first indicator is the type of influenza (A, B, or C), followed by the origin of the particular strain, the strain sequence number, and the year of isolation. Influenza type A viruses also include designations for type of HA and NA. Virtually all of the influenza viruses isolated in the United States in the 1999-2000 flu season were A/Sydney (H3N2) viruses.

Figure 2. Classification of influenza viruses includes indicators of type, origin, strain, sequence number, and year of isolation. Influenza type A viruses also include designations for hemagglutinin and neuraminidase.

Mortality and Morbidity

Extrapolations of total excess mortality from pneumonia and influenza deaths in 122 cities by the CDC suggest that each recent influenza epidemic accounted for at least 30,000 excess deaths.[2] For every flu-related death, there are 10 to 15 hospitalizations[1] and 1000 to 1500 health care visits.[3] In a 4-year analysis of hospitalizations for any acute respiratory condition that occurred throughout the entire year, including asthma and chronic obstructive pulmonary disease (COPD), influenza was the most common associated respiratory virus infection, with incidence highest among school-age children (21%) and young adults (20%).[4] CDC data indicate that the rate of hospitalizations for pneumonia among persons older than 65 years increased by 50% from 1985 to 1995, with approximately 685,000 hospitalizations in 1995.[5] The mortality rate did not increase, however, suggesting that patients were responding to treatment.

Diagnosis

Early and accurate diagnosis of influenza facilitates appropriate therapy with antiviral agents, which must be initiated within 48 hours of onset of symptoms. Accurate diagnosis also helps identify persons at higher risk for complications, such as those 50 years and older; residents of long-term-care facilities; and adults and children who have chronic pulmonary, cardiovascular, or metabolic disorders. Children and teenagers who receive long-term aspirin therapy and are at risk for Reye syndrome after influenza infection and women in the second or third trimester of pregnancy during the influenza season are other groups at higher risk.[6] Accurate diagnosis may reduce the inappropriate use of antibiotics and avoid unnecessary testing procedures in all patients.

Signs and Symptoms

Table 1 lists the most common signs and symptoms of influenza.[6] One of the hallmarks of the flu in adults is the rapid onset of symptoms: fever, cough, headache, and myalgia tend to occur within the first 12 hours. Sore throat, while common, is generally not severe. Photophobia has been prominent in some epidemics, and conjunctival injection and tearing may also occur. The triad of cough, fever, and prostration is highly predictive of influenza in middle-aged persons.[7]

The clinical picture is substantially different in children. As Figure 3 indicates, almost 90% of children present with fever and rhinitis.[7] About 40% have vomiting and diarrhea, which is extremely uncommon in adults. Atypical signs and symptoms also occur frequently in the frail elderly, in whom lassitude, confusion, and some nasal obstruction are often the only symptoms.[1] Physical findings are generally not helpful. About two thirds of patients will have some pharyngeal injection and nasal congestion. About one fourth will exhibit a minor degree of cervical adenopathy, and from 1% to 5% will have signs of a lower respiratory tract infection.[7] The most important diagnostic challenge is differentiating influenza from acute respiratory illnesses caused by other viruses, mostly rhinoviruses. Table 2 compares the significant features of each.[8]

Figure 3. Frequency of signs and symptoms in children with influenza. (From Kilbourne ED. Influenza. 1987.[7])

Community Outbreaks Support Diagnosis

When health authorities confirm an outbreak of influenza, persons with fever, muscle aches, and cough most likely will have the flu. The CDC provides weekly surveillance reports on pneumonia and influenza activity in 122 cities in the United States as part of a collaborative effort with the World Health Organization Sentinel System. This surveillance system monitors global influenza activity to determine which strains of the virus are currently circulating. This information is available through the CDC voice information system as well as its Web site (http://www.cdc.gov/ncidod/diseases/flu/weekly/htm). Because the CDC surveillance data are based on voluntary reporting, they do not provide actual infection rates. In addition, many state and county health departments do local flu surveillance.

Diagnostic tests

Diagnostic tests are typically not necessary to make an individual clinical diagnosis of influenza. However, they may be helpful in identifying the beginning or end of an outbreak or confirming a diagnosis of flu in patients with atypical presentations, such as the frail elderly or infants. Testing may also be useful in critically ill patients. Several rapid flu tests that detect live influenza virus or viral components are currently available. These tests offer good sensitivity and specificity and rapid turnaround at reasonable cost. Broad clinical use of rapid flu tests had been hampered by regulations that restricted testing to Clinical Laboratory Improvement Act (CLIA)-approved laboratories, but recently the CLIA requirement was waived for 2 of the assays. Varied reimbursement policies by health insurance companies for outpatient testing have also hampered the use of rapid flu tests.

Disease Prevention

Vaccination Rates and Response

The primary method for preventing influenza is vaccination. More than 65% of adults over age 65 years receive immunization,[9] as do the majority of residents of chronic-care facilities. However, because most of these patients have "aged" immune systems, they do not experience optimal response to the vaccine. Ironically, immunization rates are very low in the population likely to experience the greatest degree of protection from vaccination: only 30% of high-risk patients under age 65 years receive the flu vaccine.[10] Obviously, immunization rates need to be increased in high-risk patients under age 65 years, particularly those with cardiac or respiratory disease. It is also essential and safe to immunize women in the second and third trimesters of their pregnancies, as well as household contacts of high-risk patients and persons in health care facilities who have repeated contact with these patients.[10] The Advisory Committee on Immunization Practices of the CDC recently lowered its universal vaccination recommendation to include all adults 50 years and older.[10]

The cold-adapted vaccine

The current approved vaccine consists of antigens from inactivated virus. Extensive and ongoing research into the cold-adapted influenza vaccine is proving to be extremely promising. The cold-adapted vaccine was developed by growth of influenza A and B viruses at progressively lower temperatures, until it was propagated effectively at 3.8°C (25°F). This virus is then reassorted with wild virus to produce a relevant vaccine virus that will provide individuals with surface antigens for the wild-type virus and genes for attenuation from the attenuated donor virus. Infection with live, attenuated virus results in mucosal immunity, cellular immunity, and a serum antibody response.[11] The cold-adapted vaccine viruses are genetically stable and are not readily transmissible.

The live, attenuated vaccine has been shown to be safe, immunogenic, and highly effective in children and healthy, working adults.[11,12] It can be given by nasal spray to facilitate acceptance by children and other patients. Intranasal vaccine is well-suited to young children because of its ease of administration. In a multicenter study of the cold-adapted influenza vaccine in healthy children aged 15 to 71 months, vaccine recipients had a 30% reduction in the incidence of febrile otitis media compared with placebo recipients (P < .01), as well as a 29% reduction in the incidence of any febrile illness with concomitant antibiotic use (P < .001).[11] Studies are currently under way to support recommendations for its use.

Antiviral Agents

Older Agents

Amantadine and rimantadine are 2 structurally related agents whose antiviral activity against influenza virus depends on inhibiting the activity of the M2 protein. Because the influenza B virus has a different type of M2 protein, amantadine and rimantadine are effective only against the influenza A virus. Both agents have been shown to be comparably effective in prophylaxis and treatment of influenza A infection in adults.[10] Amantadine is approved for treatment and prophylaxis in children aged 12 months and older. Rimantadine is approved for prophylaxis but not for treatment in children. Treatment with these drugs begun early in the disease can reduce the duration of symptoms, including fever, and facilitate a more rapid return to normal activities. Amantadine may be associated with CNS toxicity,[10] and elderly patients who take this drug may experience seizures. Because of its significantly different pharmacokinetic profile, rimantadine is associated with fewer CNS effects. Both agents may cause mild GI side effects in some patients.[10]

One of the greatest concerns with these 2 agents is the development of resistance, particularly when they are used prophylactically. In a study reported in 1992, amantadine was administered to nursing home residents for "contact prophylaxis." That is, it was given to unaffected persons for a number of weeks following discovery of an influenza outbreak in the nursing home.[13] Persons with symptomatic disease also received treatment, with no effort to isolate treated patients from those receiving prophylaxis. About 7 days after the index case was treated with amantadine, patients receiving prophylaxis experienced transmission of virus that proved completely resistant to amantadine. Resistance emerges as a single point mutation in the virus that completely abolishes the binding capacity of either drug without any effect on transmission of disease to susceptible contacts.[14,15]

Neuraminidase Inhibitors

The ineffectiveness of amantadine and rimantadine in influenza B infections and their association with clinically significant resistance have sparked the search for better ways to treat influenza. One of the first steps forward was the ability to crystallize the NA molecule and determine its atomic structure. It was then possible to design and synthesize inhibitors that bind to amino acids in the NA molecule that are essential to its function. Alteration in even 1 of these amino acids is typically associated with significantly decreased NA activity. In addition, because these amino acids are vital to the function of the enzyme, they are conserved among all NAs of influenza viruses.[16] This includes all strains of influenza A and B viruses as well as avian influenza viruses that could be potential progenitors of pandemic infection. NAIs, therefore, represent the first clinically effective agents that offer activity against both influenza A and B viruses, including all 9 known NAs of the influenza A virus. Treatment with NAIs very rarely gives rise to resistant viruses.[16] However, it is possible to generate NA mutations in the laboratory that interfere with binding to inhibitory agents. Because these mutations occur at the enzyme binding site rather than the antigenic sites on the outside of the enzyme, they do not affect the antigenic capacity of NA.

Zanamivir and Oseltamivir

The 2 approved NAIs are zanamivir and oseltamivir. Zanamivir is an analogue of sialic acid, administered via inhalation. Oseltamivir is an oral pro-drug of GS-4071, a transitionstate analogue of sialic acid. Both agents offer comparable in vitro antiviral activity at concentrations far below those achieved with recommended dosing regimens.[17]

Treatment
In clinical trials in adults, both zanamivir[18] and oseltamivir[19-21] significantly reduced the time to alleviation of flu symptoms, the total duration of illness, and the time to resumption of normal activities when compared with placebo. The median time to alleviation of all major symptoms was 1 day (20%) shorter in 88 influenza patients given concomitant orally inhaled and intranasal zanamivir (P = .02) and 85 patients given only inhaled zanamivir (P = .05) compared with 89 patients given placebo.[18] Both intranasal and orally inhaled forms of zanamivir were administered because influenza commonly involves the lower respiratory tract. Among 85 febrile patients who began zanamivir treatment within 30 hours after symptom onset, median time to alleviation of major symptoms was 3 days sooner than in 45 patients given placebo (P = .02 in the group given inhaled zanamivir only and P .01 in the group given both intranasal and inhaled forms).[18]

Treatment with oseltamivir significantly reduced the median time to overall alleviation of symptoms by 43 hours (37%, P = .02) and 47 hours (40%, P = .01) in 226 adult patients treated within 24 hours of symptom onset with 75- and 150-mg dosages, respectively.[22] Oseltamivir reduced the total duration of illness by more than 30% (n = 245, P = .006) compared with placebo (n = 129).[20] Both oseltamivir and zanamivir reduced the rate of clinically apparent complications, such as otitis media, sinusitis, bronchitis, and pneumonia, by approximately 50%.[18,20] In children, oseltamivir also significantly reduced the median time to overall alleviation of symptoms by 36% (4.2 days in patients given placebo [n = 235] vs 2.6 days in patients given oseltamivir [n = 217], P < .0001) on the validated Canadian Acute Respiratory Infection and Flu Scale.[23] It also reduced the incidence of new cases of otitis media by 44% (26 [12%] of 217 vs 50 [21%] of 235 in the placebo group) and the use of antibiotics by 31% (68 of 217 vs 97 of 235, P = .03) in pediatric patients.[23] Resistance to oseltamivir has been found in a small percentage of children and adults at the end of therapy, but that did not alter the effectiveness of the drug.

Prophylaxis
Two double-blind, placebo-controlled, randomized, multicenter trials have studied the use of oseltamivir for seasonal prophylaxis in healthy unvaccinated adults.[19,21] One study showed that 75 mg of oseltamivir either once or twice daily for 6 weeks significantly lowered the incidence of clinical influenza.[21] In a similar study, zanamivir inhaled once daily for 4 weeks for seasonal prophylaxis also significantly lowered the rate of clinically and laboratory-confirmed influenza.[24] Zanamivir is also being studied for prophylaxis in children aged 5 to 12 years, elderly persons, and high-risk patients. Oseltamivir is approved for prophylaxis in adults and adolescents 13 years and older. In a study of seasonal prophylaxis in elderly residents of skilled nursing homes, oseltamivir reduced the incidence of clinical influenza from 4.4% (12 of 272) for the placebo group to 1% (2 of 205) for the oseltamivir group.[25] Oseltamivir also reduced the incidence of clinical influenza in household contacts of index cases from 12% (24 of 200) in the placebo group to 1% (2 of 205) in the group given oseltamivir as prophylaxis.[26]

Side Effects
Nausea occurs in about 10% of persons taking oseltamivir and is typically associated with taking the drug on an empty stomach.[27] Persons who vomit the first dose of oseltamivir may continue taking the drug but should not replace the dose vomited by immediately taking another one. All other adverse events reported in clinical trials of oseltamivir occurred with a frequency comparable with that seen with placebo.[19] Active therapy was not associated with any clinically significant changes in laboratory test values.

Zanamivir also proved to be well tolerated in clinical trials, with an incidence of adverse events comparable with that of placebo.[19,24] Bronchospasm occurred in 1 of 13 patients with mild to moderate asthma studied in a phase 1 trial.[28] In another trial of patients with asthma or COPD, the number of patients who experienced a decline in forced expiratory volume in 1 second or peak flow rate was higher in the zanamivir-treated group than in the placebo group.[28] Because of these findings and subsequent postmarketing reports, zanamivir should be used with caution in patients with underlying chronic lung disease under conditions of proper monitoring and supportive care, including ready access to short-acting bronchodilators. Patients should discontinue the drug and contact their physician if they develop difficulty in breathing.[10] There are no known clinically significant drug interactions associated with either zanamivir or oseltamivir.

Indications
Oseltamivir is indicated for the treatment of uncomplicated influenza in adults and children 1 year and older. For adults, the standard dosage of oseltamivir is one 75-mg capsule twice daily for 5 days, beginning within 2 days of onset of influenza symptoms. For children 1 year and older and adult patients who cannot swallow a capsule, oseltamivir is available as an oral suspension, with dosing based on the patient's body weight. No dosage adjustments are necessary for geriatric patients. Zanamivir is indicated for the treatment of adults and children 7 years and older. The recommended dosage of zanamivir is 10 mg (2 inhalations) orally twice daily for 5 days beginning within 2 days of symptoms. The drug has not been studied in geriatric patients. Neither agent has been adequately studied in patients with hepatic dysfunction. Zanamivir has not been adequately studied in children younger than 7 years, and oseltamivir has not been adequately studied in pediatric patients younger than 1 year.

Tables

Classic signs and symptoms of influenza


  • Rapid onset of symptoms

  • Fever (temperature usually > 37.7°C [100°F])

  • Nonproductive cough

  • Headache

  • Myalgia

  • Chills and/or sweats

  • Sore throat

  • Potentially severe, persistent malaise

  • Substernal soreness, photo-phobia, and ocular problems

From Cox NJ, Fukuda K. Infect Dis Clin North Am. 1998.[6]


Signs and symptoms of influenza versus cold


Signs and symptomsInfluenzaCold
OnsetSuddenGradual
FeverCharacteristically high, lasting 3 or 4 daysUncommon
CoughFrequent, early in onset, often marked, sometimes mucoidLess frequent, less severe, later in onset
HeadacheProminentCommon but usually not disabling
MyalgiaUsual, often severeSlight
Fatigue or weaknessMay last up to 2 to 3 weeksMild
Extreme exhaustionEarly and prominentRare
Chest discomfortCommonUncommon
Stuffy noseSometimesHallmark symptom
SneezingSometimesHallmark symptom
Sore throatSometimesSore or scratchy throat typically first symptom noted

Adapted from National Institute of Allergy and Infectious Diseases. 1999.[8]


References

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  3. Glezen WP, Decker M, Joseph SW, Mercready RG Jr. Acute respiratory disease associated with influenza epidemics in Houston, 1981-1983. J Infect Dis. 1987;155:1119-1126.
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Side Bar: Drugs Mentioned in This Article

AmantadineSymmetrel, generic
OseltamivirTamiflu
RimantadineFlumadine
ZanamivirRelenza



Dr Treanor is associate professor of medicine, infectious disease department, University of Rochester School of Medicine and Dentistry, Rochester, NY. Dr Glezen is professor of molecular virology and microbiology, Baylor College of Medicine, Houston. Dr Reisinger is medical director of Primary Physicians Research, Pittsburgh.