Long before the advent of AIDS, with its attendant high rates of morbidity and mortality, influenza was known to be capable of mass destruction. In fact, more persons died as a result of influenza from 1918 to 1920 than have died of AIDS in its 25-year history or died of the bubonic plague in the Middle Ages.1,2
Influenza can occur sporadically as individual cases, as local epidemics, and as worldwide infectious outbreaks known as pandemics. Even in nonepidemic years, about 36,000 deaths are attributable to influenza annually in the United States.3 Although major influenza pandemics have occurred at intervals of about 20 years, an influenza pandemic has not occurred since the late 1960s.
This low incidence of pandemic influenza has tended to lull the public and health authorities into relative inaction regarding the prevention and treatment of influenza. However, recognition of transmission of new avian strains of influenza viruses from birds to humans and the fear of potential human-to-human spread of avian strains4 have rekindled interest in preventing and treating influenza.
Even more important is the recognition that infection by the avian strains carries a very high case fatality rate, even greater than that seen in the 1918 pandemic.5 Some of the reasons for this high mortality have recently been illuminated,6,7 suggesting the possibility of new potential modes of therapy.
In this article, we will briefly review the basics of influenza virology and infection; we will then discuss the available strategies for prevention and treatment.
Influenza has been recognized in epidemic form for at least 5 centuries. The Italians named the disease influenza because they noted its seasonal incidence, which they believed to be under the "influence" of the planets. Indeed, this disease peaks in the midwinter in temporal zones and in the summer in tropical areas. The common denominator may be the crowding that occurs in the cold weather in temporal zones and during the summer rainy season in the tropics.8
Although several viral and nonviral agents can cause a "flu-like" syndrome, true influenza is caused by the influenza virus. The disease is characterized by fever, cough, myalgias, and severe malaise.9 These symptoms are not caused by vi- remia, as has been commonly thought, but rather by the cascade of cytokines that occurs as a result of infection.
The infection may be self-limited, involving the upper respiratory tract, or may progress to the lungs, causing pneumonia.10 Lower respiratory tract influenza may also be self-limited or may become overwhelming, resulting in acute respiratory distress syndrome (ARDS) that requires ventilator support and is sometimes fatal. This latter outcome is more likely in elderly patients with chronic cardiopulmonary, renal, or metabolic disease; immunocompromised patients of any age; infants; and women who are pregnant.
Influenza pneumonia can also be associated with either concomitant or subsequent bacterial pneumonia. The most common cause of bacterial superinfection in patients with influenza is Streptococcus pneumoniae. However, many cases of staphylococcal pneumonia--which is otherwise rare--are preceded by influenza.
PREVENTION OF INFLUENZA
To understand the prevention and treatment of influenza, it is important to know something about influenza virology and infection (see "The influenza virus").9,11-13
The keystone of influenza prevention is vaccination. Although effective vaccines have been available for more than half a century, the number of persons vaccinated has been very suboptimal. Even now, only about 65% of persons who should be vaccinated based on criteria published by the CDC are, in fact, vaccinated (Table).
Because of drifts and shifts in strain antigenicity, and the fact that antibodies to killed vaccines are short-lived, vaccination using the projected circulating strains must be repeated annually. The vaccine typically contains 2 strains of influenza virus type A and 1 strain of influenza virus type B, chosen on the basis of strains that were isolated in the previous season, primarily in Asia and countries in the former Soviet Union. This technique of choosing strains has generally been effective; however, in the 2003-2004 influenza season, the strain that caused most infections in the United States was not represented in the vaccine.14
Two types of trivalent vaccines are available. The first type, which has been used for several decades, is an inactivated subunit preparation containing only purified hemagglutinin and neuraminidase from the selected strains. There is no living or replication-capable virus in this preparation, so it is safe for immunocompromised patients and it cannot cause influenza in vaccine recipients.
A single intramuscular dose of this vaccine should be administered to persons in the risk groups listed in the Table, starting in September of each year.15 Children 6 months to 9 years of age who have never received influenza vaccine should receive a second dose of vaccine 1 month after the first. Protective efficacy averages 70% to 80%.
The only adverse effect of this vaccine is soreness at the site of injection, and the only contraindications to vaccination are severe allergy to egg protein and a history of Guillain-Barr syndrome. The former contraindication is based on the fact that the virus is grown on the allantoic membrane of eggs, and it may retain miniscule amounts of egg antigens. The latter contraindication is based on adverse reactions to vaccination that occurred in 1976. At that time, mass immunization with a single preparation of influenza vaccine was initiated because of a threatened return of the same strain that caused the 1918 pandemic. Unfortunately, this pro-cess was associated with some apparent increase of Guillain-Barr syndrome, a complication that has not occurred in subsequent years.
A second form of vaccine was approved 3 years ago.16 This vaccine also contains the 3 influenza strains (2 type A; 1 type B), but the virus is attenuated rather than killed. It is administered by nasal spray and primarily evokes mucosal immunity. Because enrollees for the clinical trials of this vaccine were between the ages of 5 and 49 years, the vaccine is only licensed for use in this age group. There is little doubt that it would be effective in older adults, and it has been used in older patients in times of inactivated vaccine shortage.
Live attenuated vaccines, including this one, are not recommended for use in immunocompromised patients because of concern that unchecked viral infection may occur. This vaccine also appears to be about 80% effective in preventing influenza.
Two classes of drugs have been approved for the prevention of influenza. The first class is the adamantanes. Amantadine, the first of these drugs, was originally developed for the treatment of parkinsonism. Serendipitously, it proved effective in prophylaxis against influenza A outbreaks.
Amantadine and its successor rimantadine inhibit a muprotein, theM2 ion channel unique to influenza virus type A, thus disturbing the influx of hydrogen ions into the virus, a step necessary for the uncoating of the virion. Uncoating, in turn, is necessary before replication can begin.17 Similar channels exist in influenza virus type B and type C replication, but they are not affected by the adamantanes at achievable doses; therefore, these drugs have no effect against these viruses.
Before 2005, adamantanes were indicated for prophylaxis in high-risk patients who had not been vaccinated and when a type A virus was implicated in a bourgeoning outbreak. They were to be given at the outset of the outbreak and continued until the outbreak had diminished.17 Both drugs were about 80% effective in preventing influenza, although results varied with the population studied. Postexposure prophylaxis of family members was unsuccessful, apparently because of rapid emergence of viral resistance in the household.18
Unfortunately, the level of resistance to the adamantanes was found to be greater than 90% in the prevalent strain (H3N2) circulating in the United States during the 2005-2006 influenza season.19 Based on these findings, the CDC has recommended that these drugs not be used for either influenza prophylaxis or therapy until there is documentation that resistance has decreased to an acceptable level.15,2
Before that time, the recommended oral dosage of amantadine was 200 mg daily; the dosage of rimantadine for equal efficacy at lower toxicity was 100 mg daily. In older adults and patients with renal failure, the dosage of amantadine should be reduced to 100 mg daily or every other day. Adverse effects, seen mostly in elderly recipients, included confusion, somnolence, and insomnia.17 Contemporaneous administration of antihistamines, trimethoprim/sulfamethoxazole, or anticholinergics may potentiate neurologic adverse effects and lead to seizures.21
The second class of prophylactic drugs is the neuraminidase inhibitors. These drugs, as their name implies, inhibit the enzyme on the viral surface that is responsible for cleaving the sialic acid bond between the new budding virus progeny and the membrane of the infected and dying cell, thereby preventing the new viruses from being released to infect other cells.22 Unlike the fortuitously discovered role of the adamantanes, the neuraminidase inhibitors, zanamivir and oseltamivir, were designed to achieve the specific effect they exhibit.23
These drugs should be given to high-risk patients at the outset and throughout the duration of a local influenza outbreak, and they are 70% to 90% effective in preventing influenza, depending on the population studied. Unlike the adamantanes, the neuraminidase inhibitors have proved effective in household contact prophylaxis.24 Because the neuraminidase function is common to both types A and B, these drugs are prophylactically effective against both influenza virus types. Clinically significant emergence of resistance has not occurred.
Oseltamivir is well absorbed from the GI tract and is supplied as an oral medication in pill form. The dosage is 75 mg twice daily. Adverse effects are uncommon but include nausea, vomiting, bronchitis-like symptoms, abdominal pain, and dizziness. Administration with food decreases the GI adverse effects.18 During preparation of this article, unpublished postmarketing reports documented the incidence of self-injury and delirium in patients--particularly children--taking oseltamivir. A revised package insert recommends monitoring for signs of unusual behavior throughout the course of treatment.
Zanamivir is not bioavailable through the GI tract and is administered as an orally inhaled powder delivered from a metered-dose disk inhaler. The inhalation process is fairly complicated, and some patients have difficulty with self- administration. Each inhalation is calculated to deliver 4 to 5 mg of zanamivir. The prophylactic dosage, suggested on the basis of studies, is 2 inhalations, once daily for 10 to 28 days during an outbreak.25 However, given the difficulty in administration, zanamivir is not currently recommended for prophylaxis.
Intravenous zanamivir at a dosage of 600 mg twice daily has been studied and seems to be effective26 but is not FDA-approved. Although prophylactic zanamivir has proved effective in several studies, it is not recommended for prevention in chronic-care facilities or for children younger than 7 years.27
Adverse effects are rare but include increased sensitivity to sunlight; dermal flushing; rash or hives; sinusitis; diarrhea; nausea; and most important, shortness of breath, wheezing, and swollen cervical glands. Because of the respiratory adverse effects, zanamivir should be used with caution in persons with asthma or chronic obstructive pulmonary disease.18 Neither oseltamivir nor zanamivir has been adequately studied in pregnant or breast-feeding women.
Several prophylactic regimens have been suggested for these antiviral drugs. In the so-called seasonal regimen, the drug is started at the outset of the influenza season and is continued for several months until the community incidence of influenza declines. This is a very expensive protocol and has not been proved to be more effective than other regimens.
The second method is to provide the antiviral drug to family members and close contacts of an index case. The third regimen is to give the drug to coresidents of a long-term-care facility in which an outbreak has been detected.
The drugs should not be thought of as substitutes for vaccination, and vaccination should always accompany antiviral drug administration, which yields an additive effect. However, the antiviral drugs cannot be given simultaneously with the live attenuated vaccine because they will interfere with viral replication and thereby diminish the immunogenicity of this vaccine.
TREATMENT OF INFLUENZA
All 4 available anti-influenza drugs have exhibited some effectiveness in the treatment of influenza. The mechanisms of action in the therapeutic setting are identical to those in prophylaxis.
For the adamantanes, the dosage for treatment is the same as for prophylaxis; the duration of therapy is usually approximately 5 days. Before 2005, these drugs were 70% to 90% effective in decreasing the duration of illness by about 1.5 days when they were administered within 48 hours of the onset of influenza symptoms.28
It has been recognized for more than 2 decades that resistance to the adamantanes (due to point mutation at 1 of several sites in the gene for the M2 protein) can emerge during treatment.29,30 As noted above, because of the high level of resistance observed during the 2005-2006 influenza season, the adamantanes are not currently recommended.
The neuraminidase inhibitors also have been shown to be about 80% effective in reducing the severity of influenza symptoms and the duration of illness when they are administered within 48 hours of the onset of clinical disease. The dosage for oseltamivir is 75 mg orally twice daily for 5 days. The dosage for zanamivir is 2 inhalations twice daily for 5 days.
Inhaled zanamivir has been shown to reduce the incidence of lower respiratory tract infection in otherwise healthy patients with influenza A by 40%.31 In another study of patients with influenza caused by either type A or type B influenza virus, the rate of progression to lower respiratory tract infection (usually bronchitis) requiring antibiotic therapy was reduced by about 50% and the rate of hospitalizations was reduced in patients treated with oseltamivir early in infection.32 Marked reductions in disease progression and hospitalization were seen in both at-risk and otherwise healthy patients. The salutary effects were equal in patients infected with influenza virus type A or type B.
A more recent study in Japan found that oseltamivir was more effective in children with influenza A than in those with influenza B.33,34 The neuraminidase inhibitors have not been studied in epidemics involving large numbers of high-risk patients with underlying diseases. Therefore, their role in preventing deaths in these patients has not been determined.
Additional therapeutic modalities
For the symptoms of influenza--headache, myalgia, and fever--the preferred agent is acetaminophen. Salicylates should be avoided because they appear to predispose to Reye syndrome, a rapid deterioration in CNS function that can lead to coma and can be accompanied by overwhelming hepatic failure. Reye syndrome is more common in children than in adults and is associated with a mortality rate of up to 40%. Severe lower respiratory tract infection caused by influenza virus may lead to ARDS, requiring intubation and prolonged supportive therapy.
Recent highly creative studies using molecular techniques have succeeded in resurrecting the H1N1 virus that caused the 1918 pandemic. This virus has been called swine influenza virus, but its origins appear to be avian. Apparently, this virus and the H5N1 avian virus circulating now are capable of initiating a cytokine and chemokine storm, which is responsible for high morbidity and mortality.6,7 Recently, studies have shown that a DNA vaccine prepared from the reconstituted 1918 virus is protective in mice.35
A number of chemotherapeutic drugs, including corticosteroids and NSAIDs, can modulate the cytokine storm and theoretically decrease morbidity and mortality. In the face of a pandemic with an influenza A virus strain for which we do not yet have a vaccine and for which the antivirals may have minimal effect, clinical trials of the anti-inflammatory agents should be pursued with vigor.
Until recently, we had become relatively complacent about influenza because we had not experienced a major influenza pandemic in more than 40 years. The emergence of avian influenza virus as a human pathogen with potentially devastating capabilities and the studies of a regenerated 1918 virus have reawakened interest in influenza virology. Even without human-to-human spread of the avian virus, there is a more widespread appreciation for the impact that an influenza pandemic would have. This appreciation, in turn, should spur efforts at new and faster vaccine development.
In the era of worldwide air travel, we cannot afford to rely on pro- cesses that require a year or more to develop, test, and distribute a vaccine. We also must provide incentives and minimize risk for drug and vaccine developers so that innovation and production keep pace with this ever-changing virus.
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