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Influenza
is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality
is possible during epidemics, particularly among high-risk patients (eg,
those who are institutionalized, at the extremes of age, have cardiopulmonary
insufficiency, or are in late pregnancy). Diagnosis is usually clinical
and depends on local epidemiologic patterns. High-risk patients,
their caregivers and household contacts, health care practitioners,
and all children aged 6 to 24 mo should receive annual influenza
vaccination. Antiviral treatments include the neuraminidase inhibitors
zanamivir and oseltamivir, which are effective for both influenza
A and B, and amantadine and rimantadine, which are effective only
against influenza A.
Influenza refers to illness caused by the influenza viruses, but the term is commonly and incorrectly used to refer to similar illnesses caused by other viral respiratory pathogens. Influenza viruses are classified as types A, B, or C by their nucleoproteins and matrix proteins. Influenza C virus infection does not cause typical influenza illness and is not discussed here.
Hemagglutinin (HA) is a glycoprotein on the influenza surface that allows the virus to bind to cellular sialic acid and fuse with the host membrane. Neuraminidase (NA), another surface glycoprotein, enzymatically removes sialic acid, promoting viral dispersion from the infected cell. Relatively minor mutations in HA and NA of influenza A and B result in the frequent emergence of new viral strains (antigenic drift). The result is decreased protection by antibody generated to the previous strain. In contrast to antigenic drift, a major change in NA or HA occurs in influenza A (antigenic shift) at infrequent intervals (10 to 40 yr during the last century); as a result, the population has no immunity to the new virus, and pandemic influenza may occur.
Epidemiology
Influenza produces widespread sporadic illness yearly during fall and winter in temperate climates. Epidemics in the US occur about every 2 to 3 yr, most often caused by influenza A viruses. Pandemics caused by new influenza A serotypes may cause particularly severe disease. Influenza B viruses typically produce mild disease but can cause epidemics with moderate or severe disease, usually occurring in 3- to 5-yr cycles. Although most influenza epidemics result from a single serotype, different influenza viruses may appear sequentially in one location or may appear simultaneously, with one virus predominating in one location and another virus predominating elsewhere.
Seasonal epidemics often occur in 2 waves—the 1st in schoolchildren and their household contacts (generally younger people) and the 2nd mostly in housebound or institutionalized people, particularly the elderly.
Influenza viruses may be spread by airborne droplets, person-to-person contact, or contact with contaminated items. Airborne spread appears to be the most important mechanism.
Patients with underlying cardiopulmonary disease, metabolic disease (especially diabetes mellitus) that requires regular medical attention, renal insufficiency, hemoglobinopathies, or immunodeficiency are at increased risk for severe disease. Women in the 2nd or 3rd trimester of pregnancy, children < 24 mo, and adults > 65 yr are also at increased risk. Morbidity and mortality in these patients may be due to exacerbation of underlying illness, primary influenza pneumonia, or secondary bacterial pneumonia.
Symptoms and Signs
The incubation period ranges from 1 to 4 days with an average of about 48 h. In mild cases, many symptoms are like those of a common cold (eg, sore throat, rhinorrhea); mild conjunctivitis may also occur. Typical influenza in adults is characterized by the sudden onset of chills, fever, prostration, cough, and generalized aches and pains (especially in the back and legs). Headache is prominent, often with photophobia and retrobulbar aching. Respiratory symptoms may be mild at first, with scratchy sore throat, substernal burning, nonproductive cough, and sometimes coryza. Later, lower respiratory tract illness becomes dominant; cough can be persistent, raspy, and productive. Children may have prominent nausea, vomiting, or abdominal pain, and infants may present with a sepsis-like syndrome. After 2 to 3 days, acute symptoms rapidly subside, although fever may last up to 5 days. Cough, weakness, sweating, and fatigue may persist for several days or occasionally for weeks.
Pneumonia is suggested by a worsening cough, purulent or bloody sputum, dyspnea, and rales. Secondary bacterial pneumonia is suggested by persistence or recurrence of fever, cough, and other respiratory symptoms in the 2nd wk.
Encephalitis, myocarditis, and myoglobinuria develop infrequently, usually during convalescence. The cause is unclear, but they occur more frequently after influenza A pandemics. Reye's syndrome (see Miscellaneous Disorders in Infants and Children: Reye's Syndrome), characterized by encephalopathy, fatty liver, hypoglycemia, and lipidemia, is strongly associated with epidemics of influenza B, particularly in children who have ingested aspirin .
Diagnosis
The diagnosis is generally made clinically in patients with a typical syndrome when influenza is known to be present in the community. Although many rapid diagnostic tests are available, their sensitivities and specificities vary widely among different studies. The use of rapid tests to select patients who might benefit from antiviral therapy remains controversial. Definitive diagnosis requires cell culture of nasopharyngeal swabs or aspirate or acute and convalescent antibody titers. This testing takes several days or more and is useful primarily for establishing the presence of influenza in the community and detecting antigenic changes.
Patients with lower respiratory tract signs and symptoms, such as dyspnea, hypoxia, or rales on lung examination, should have a chest x-ray to detect pneumonia. Primary influenza pneumonia typically appears as diffuse interstitial infiltrates or as acute respiratory distress syndrome. Secondary bacterial pneumonia is more likely to be lobar or segmental.
Prognosis
and Treatment
Most patients recover fully, although full recovery often takes 1 or 2 wk. However, influenza and influenza-related pneumonia are important causes of death in high-risk patients, young children, the elderly, and those with chronic disease. The efficacy of antiviral treatment in these cases is unknown. Appropriate antibacterial therapy decreases the mortality rate from secondary bacterial pneumonia.
Treatment for most patients is symptomatic, including rest, hydration, and antipyretics as needed, but aspirin is avoided in children. Complicating bacterial infections require appropriate antibiotics.
Antiviral drugs given within 1 to 2 days of symptom onset decrease symptom duration slightly. Treatment with antiviral drugs is generally recommended in high-risk patients who develop influenza-like symptoms, but proof of benefit in such patients is lacking.
Resistance to amantadine and rimantadine develops frequently during treatment, and resistance to either drug makes both ineffective. Resistance that develops during treatment does not affect the efficacy of treatment for the index patient but may result in transmission of resistant virus to contacts. Resistance to oseltamivir and zanamivir occurs but is not clinically relevant. In children, oseltamivir may decrease the incidence of otitis media; however, no other data indicate that treatment of influenza prevents complications.
Amantadine and rimantadine inhibit virus penetration or uncoating. They are effective against influenza A viruses but not against influenza B. Treatment is stopped after 3 to 5 days or 1 to 2 days after symptoms resolve. For both drugs, 100 mg po bid can be used. To avoid adverse effects due to drug accumulation, the dose is reduced for children (2.5 mg/kg bid to a maximum of 150 mg/day for children < 10 yr or 200 mg/day for children ≥ 10 yr). In patients with impaired renal function, dose is adjusted according to the creatinine clearance. The dose of rimantadine should not exceed 100 mg/day if hepatic dysfunction exists. Dose-related nervousness, insomnia, or other CNS effects occur in about 10% of people receiving amantadine and in about 2% of people receiving rimantadine . These effects usually occur within 48 h after starting the drug, are more prominent in the elderly and in those with CNS diseases or impaired renal function, and often resolve during continued use. Anorexia, nausea, and constipation may also occur.
The NA inhibitors zanamivir and oseltamivir are effective against both influenza A and B. The dose of zanamivir is 2 puffs (10 mg) bid. Oseltamivir is given at 75 mg po bid for patients > 12 yr. The dose is decreased in younger patients. These drugs have relatively few adverse effects. Zanamivir should not be given to patients with underlying reactive airway disease because of possible bronchospasm due to the inhalation route. Oseltamivir may produce occasional nausea and vomiting.
Prevention
Influenza infections can be prevented by annual vaccination. Chemoprophylaxis with antiviral agents is also useful in certain situations. Prevention is indicated for all patients, but is especially important for high-risk patients and health care practitioners.
Vaccination:
Vaccines are modified annually to include the most prevalent strains (usually 2 strains of influenza A and 1 of influenza B). When the vaccine contains the same HA and NA as the strains in the community, vaccination decreases infections by 70 to 90% in healthy adults. In the institutionalized elderly, vaccines are less effective for prevention but decrease pneumonia and death by 60 to 80%. Vaccine-induced immunity is decreased by antigenic drift and is absent if there is antigenic shift.
Vaccination is indicated for patients > 65 yr; patients with cardiopulmonary disorders; residents of chronic care facilities; patients who are under routine medical care for chronic metabolic diseases (eg, diabetes mellitus), renal failure, hemoglobinopathies, or immunosuppression; children on long-term aspirin therapy; and women who will reach the 2nd or 3rd trimester of pregnancy during influenza season (between November and March in the US). Household contacts and people who care for these high-risk patients should also be immunized. Vaccination of all children 6 to 24 mo of age and their household contacts is also recommended. Influenza vaccine is given annually to maintain antibody titers and allow vaccine modification to compensate for antigenic drift. Vaccine is best given in the fall, so that antibody titers will be high during the winter influenza season.
Inactivated influenza vaccines are given by IM injection. Adults receive a single 0.5-mL dose. Because children have had fewer opportunities for exposure to influenza virus, both a primary and a booster dose (0.5 mL each for children 3 to 10 yr, 0.25 mL each for children 6 to 35 mo) 1 mo apart are recommended unless vaccination has been administered in prior years. Adverse effects associated with the vaccine are usually limited to mild pain at the injection site that lasts no more than a few days. Fever, myalgia, and other systemic effects are uncommon. The vaccine is contraindicated in patients who have a history of anaphylactic reactions to chicken or to egg protein.
A live attenuated influenza vaccine has recently become available in the US for healthy people between age 5 and 50 yr. The vaccine should not be given to patients in high-risk groups, pregnant women, household contacts of patients with immunodeficiency, or children who are receiving chronic aspirin therapy. The vaccine is given intranasally at a dose of 0.25 mL in each nostril. Children between 5 and 8 yr who have not been previously vaccinated with the live attenuated vaccine should receive a 2nd dose at least 6 wk after the 1st dose. Adverse effects associated with the vaccine are mild, most often rhinorrhea.
Antiviral
drugs:
Vaccination is the preferred method of prevention, but antiviral drugs are also effective. Antiviral drugs are indicated for patients who have been vaccinated only within the previous 2 wk, patients for whom vaccination is contraindicated, and patients who are immunocompromised and thus may not respond to vaccination. Drugs do not impair development of immunity from the vaccine. Antiviral drugs can be stopped 2 wk after vaccination. If vaccine cannot be given, antiviral drugs are continued for the duration of the epidemic.
Amantadine and rimantadine prevent influenza A, which accounts for most influenza illness. The NA inhibitors zanamivir and oseltamivir prevent both influenza A and B. Prophylactic doses of these antivirals are the same as treatment doses except for oseltamivir , for which the prophylactic dose is 75 mg once/day.
Avian
Influenza
Avian influenza
(bird flu) is caused by strains of influenza A that normally infect
only wild birds (and sometimes pigs). Infections due to these strains
have recently been detected in humans.
Most human infections are caused by strains of avian influenza type H5N1, but H7N7, H7N3, and H9N2 have caused some human infections. Infections with these strains are asymptomatic in wild birds but can cause highly lethal illness in domestic birds.
The 1st human cases were discovered in Hong Kong in 1997. Spread to humans was contained by culling domestic bird populations. In 2003 and 2004, however, humans were infected with avian influenza strains in several Asian nations (H9N2 and, continuing into 2005, H5N1), Canada (H7N3), and the Netherlands (H7N7). Although most cases occurred through exposure to infected birds, some human-to-human transmission probably occurred in the Netherlands and may have occurred in Asia.
All influenza viruses are capable of rapid mutation, raising the possibility that avian strains could acquire the ability to spread more easily from person-to-person. This could occur by direct mutation or by recombination with human strains in a human or porcine host. Many experts are concerned that, should these strains acquire the ability for efficient human-to-human spread, an influenza pandemic could result.
Human infection with avian influenza H5N1 strains can cause severe respiratory symptoms. Mortality was 33% in the 1997 outbreak and almost 80% in the 2004 outbreak. Infection with the H7 strains most commonly causes conjunctivitis, although in the Netherlands outbreak a few patients had flu-like symptoms and one patient (of 83) died.
An appropriate clinical syndrome in the setting of exposure to a known infected individual or exposure to birds in an area with an ongoing avian influenza outbreak should prompt consideration of this infection. History of recent travel to Asia with exposure to birds or infected individuals should prompt testing for influenza A by reverse transcription–PCR. Culture of the organism should not be attempted. Suspected and confirmed cases are reported to the Centers for Disease Control and Prevention.
Treatment with oseltamivir or zanamivir at usual doses is indicated. The strain of H5N1 in the 2004 outbreak is resistant to amantadine and rimantadine . Containment is achieved by culling infected flocks.
Last full review/revision November 2005
Content last modified November 2005
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