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Influenza is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality is possible during seasonal epidemics, particularly among high-risk patients (eg, those who are institutionalized, at the extremes of age, have cardiopulmonary insufficiency, or are in late pregnancy); during pandemics, even healthy, young patients may die. Diagnosis is usually clinical and depends on local epidemiologic patterns. High-risk patients, their caregivers and household contacts, health care practitioners, all people ≥50 yr, and all children aged 6 mo to 18 yr should receive annual influenza vaccination. Antiviral treatment reduces the duration of illness by about 1 day and should be specifically considered for high-risk patients.
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.
Influenza antigens
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.
Antigenic drift refers to relatively minor mutations in HA and NA of influenza A and B that result in the frequent emergence of new viral strains. The result is decreased protection by antibody generated to the previous strain.
Antigenic shift refers to a major change in NA or HA that 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 causes 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 due to new influenza A serotypes may cause particularly severe disease. Influenza B viruses typically cause mild disease but can cause epidemics with moderate or severe disease, usually 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 first 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.
At-risk groups
Certain patients are at high risk of complications from influenza:
Morbidity and mortality in these patients may be due to exacerbation of underlying illness, acute respiratory distress syndrome, 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 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. GI symptoms may occur and appear to be more common with the 2009 pandemic H1N1 strain. 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.
Complications
Pneumonia is suggested by a worsening cough, bloody sputum, dyspnea, and rales. Secondary bacterial pneumonia is suggested by persistence or recurrence of fever and cough after the primary illness appears to be resolving.
Encephalitis, myocarditis, and myoglobinuria, sometimes with renal failure, develop infrequently after influenza A or B infection. Reye's syndrome (see Miscellaneous Disorders in Infants and Children: Reye's Syndrome), —characterized by encephalopathy; fatty liver; elevation of liver enzymes, ammonia, or both; hypoglycemia; and lipidemia—often occurs during 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 in different studies and they usually add little to patient management. Diagnostic tests should be done when results will affect clinical decisions. Reverse transcriptase–PCR (RT-PCR) assays are sensitve and specific and can differentiate influenza types and subtypes. If this assay is quickly available, results may be used to select appropriate antiviral therapy. These tests are also useful to determine whether outbreaks of respiratory disease are due to influenza. Cell culture of nasopharyngeal swabs or aspirates takes several days and is not useful for patient management decisions.
If patients have lower respiratory tract symptoms and signs (eg, dyspnea, rales noted during lung examination), pulse oximetry to detect hypoxemia and a chest x-ray to detect pneumonia should be done. Primary influenza pneumonia appears as focal or diffuse interstitial infiltrates or as acute respiratory distress syndrome. Secondary bacterial pneumonia is more likely to be lobar or segmental.
Prognosis
Most patients recover fully, although full recovery often takes 1 to 2 wk. However, influenza and influenza-related pneumonia are important causes of increased morbidity or mortality in high-risk patients. Use of antiviral treatment in these patients appears to reduce the incidence of lower respiratory disease and hospitalization. Appropriate antibacterial therapy decreases the mortality rate due to secondary bacterial pneumonia.
Treatment
Treatment for most patients is symptomatic, including rest, hydration, and antipyretics as needed, but aspirin is avoided in patients ≤ 18 yr. Complicating bacterial infections require appropriate antibiotics.
Drugs for influenza
Antiviral drugs given within 1 to 2 days of symptom onset decrease the duration of fever, severity of symptoms, and time to return to normal activity. Treatment with antiviral drugs is recommended for high-risk patients who develop influenza-like symptoms; this recommendation is based on data suggesting that early treatment may prevent complications in these patients.
Drugs for influenza include the following:
Neuraminidase inhibitors interfere with release of influenza virus from infected cells and thus halt spread of infection.
Adamantanes block the M2 ion channel and thus interfere with viral uncoating inside the cell. They are effective only against influenza A viruses (influenza B viruses lack the M2 protein).
Choice of antiviral drug is complicated by resistance of different influenza types and subtypes to different drugs (see Table 2: Respiratory Viruses: Drug Sensitivities of Various Influenza Strains ). If RT-PCR testing is rapidly available, results can be used to direct treatment. If RT-PCR is not available, patients may be treated with zanamivir alone or with rimantadine plus oseltamivir.
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Table 2
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| Drug Sensitivities of Various Influenza Strains |
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Virus
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Amantadine or Rimantadine
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Oseltamivir
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Zanamivir
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Influenza A viruses
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Seasonal H3N2
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Resistant
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Sensitive
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Sensitive
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Seasonal H1N1
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Sensitive
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Resistant
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Sensitive
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Pandemic H1N1
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Resistant
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Sensitive
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Sensitive
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Avian H5N1
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Resistant
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Sensitive
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Sensitive
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Influenza B viruses
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All
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Resistant
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Sensitive
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Sensitive
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Zanamivir is given by an inhaler, 2 puffs (10 mg) bid; it can be used in adults and children ≥ 7 yr. Zanamivir sometimes causes bronchospasm and should not be given to patients with reactive airway disease; some people cannot use the inhalation device.
Oseltamivir 75 mg po bid is given to patients > 12 yr; lower doses may be used in children as young as 1 yr. Oseltamivir may cause occasional nausea and vomiting. In children, oseltamivir may decrease the incidence of otitis media; however, no other data clearly show that treatment of influenza prevents complications.
Rimantadine is the preferred adamantane because it has fewer side effects and is better tolerated. Treatment is stopped 1 to 2 days after symptoms resolve or after 3 to 5 days. For rimantadine or amantadine, 100 mg po bid can be used. To avoid adverse effects due to drug accumulation, clinicians reduce the dose 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 creatinine clearance. The dose of rimantadine should not exceed 100 mg/day if patients have hepatic dysfunction. 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 patients with CNS diseases or impaired renal function, and often resolve during continued use. Anorexia, nausea, and constipation may also occur.
Prevention
Influenza infections can largely be prevented by
Prevention is indicated for all patients, but is especially important for high-risk patients and health care practitioners.
Vaccines
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 the rate of pneumonia and death by 60 to 80%. Vaccine-induced immunity is decreased by antigenic drift and is absent if there is antigenic shift.
There are 2 types of vaccine:
TIV is given by IM injection. Patients aged 6 mo to 35 mo are given 0.25 mL, and those ≥ 3 yr are given 0.5 mL. Adverse effects are usually limited to mild pain at the injection site; it lasts no more than a few days. Fever, myalgia, and other systemic effects are uncommon.
LAIV is given intranasally at a dose of 0.25 mL in each nostril. It may be used for healthy people aged 2 to 49 yr. The vaccine is not recommended for high-risk patients, pregnant women, household contacts of patients with severe immunodeficiency (eg, with hematopoietic stem cell transplants), or children who are receiving long-term aspirin therapy. Adverse effects associated with the vaccine are mild; rhinorrhea is the most common, and mild wheezing may occur. LAIV should not be given to children who are < 5 yr and have reactive airway disease (eg, known asthma, recurrent or recent wheezing episodes)
For both vaccines, children who are < 8 yr and have not been vaccinated should be given a primary dose and a booster dose 1 mo apart.
Vaccination recommendations
Annual vaccination is recommended for
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 (between November and March in the US).
Vaccination (both TIV and LAIV) should be avoided in people who
Antiviral drugs
Although vaccination is the preferred method of prevention, antiviral drugs are also effective. Prophylactic antiviral drugs are indicated when influenza is circulating in the community for patients
Antiviral drugs do not impair development of immunity from the vaccine. They can be stopped 2 wk after vaccination. If vaccine cannot be given, antiviral drugs are continued for the duration of the epidemic.
If the circulating influenza types or subtypes are unknown, patients may be treated with either zanamivir alone (in patients for whom it is not contraindicated) or with a combination of rimantadine and oseltamivir.
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 first human cases of H5N1 were discovered in Hong Kong in 1997. Spread to humans was contained by culling domestic bird populations. However, in 2003 and 2004, H5N1 infections in humans reappeared, and occasional cases continue to be reported, primarily in Asia and the Middle East. Human infections with other avian influenza strains have also been reported in Asia (H9N2), Canada (H7N3), and the Netherlands (H7N7). Although most cases occurred through exposure to infected birds, some person-to-person transmission probably occurred in the Netherlands and in Asia.
All influenza viruses are capable of rapid genetic change, raising the possibility that avian strains could acquire the ability to spread more easily from person to person via direct mutation or via recombination with human strains in a human or porcine host. Many experts are concerned that if these strains acquire the ability to spread efficiently from person to person, 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 has been > 60% in subsequent infections. 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.
Diagnosis
An appropriate clinical syndrome in a patient exposed to a person known to be infected or to birds in an area with an ongoing avian influenza outbreak should prompt consideration of this infection. History of recent travel to regions with ongoing transmission from birds to humans (eg, Egypt, Indonesia, Vietnam) plus exposure to birds or infected people should prompt testing for influenza A by RT–PCR. Culture of the organism should not be attempted.
Suspected and confirmed cases are reported to the Centers for Disease Control and Prevention (CDC).
Treatment
Treatment with oseltamivir or zanamivir at usual doses is indicated. The H5N1 virus is resistant to amantadine and rimantadine; resistance to oseltamivir has also been reported.
H1N1 Swine Influenza
H1N1 swine influenza (flu) is caused by a new strain of H1N1 influenza A virus, which genetically is a combination of swine, avian, and human influenza viruses.
Most often, pigs are infected by strains of influenza that are slightly different from those that infect people. These strains very rarely spread to people, and when they do, they very rarely then spread from person to person. The H1N1 swine flu virus is a combination of swine, bird (avian), and human influenza viruses that spreads easily from person to person. The infection is not acquired through ingestion of pork and is acquired very rarely by contact with infected pigs.
In June 2009, the World Health Organization declared H1N1 swine flu a pandemic; it has spread to > 70 countries and to all 50 US states. The majority of the deaths occurred in Mexico. The attack rate and mortality for H1N1 swine flu are higher in young and middle-aged adults and lower in the elderly than they are for seasonal flu. The pandemic entered the post-pandemic period in August 2010.
Symptoms and Signs
Symptoms, signs, and complications resemble those of ordinary influenza (see Respiratory Viruses: Symptoms and Signs), although nausea, vomiting, and diarrhea may be more common. Symptoms are usually mild, but they can become severe, leading to pneumonia or respiratory failure.
Diagnosis
Because H1N1 swine flu is the predominant strain of influenza currently circulating worldwide, the diagnosis should be considered in any patient with influenza-like symptoms.
A newly developed PCR test can detect the H1N1 virus in respiratory tract samples (eg, nasopharyngeal swabs, nasal washings, tracheal aspirates). Mildly ill patients do not require testing other than for epidemiologic or surveillance purposes; however, local hospital and public health requirements may vary. Usual rapid antigen detection tests have decreased sensitivity for H1N1 swine flu and generally have little clinical use in diagnosis.
Treatment
Treatment focuses mainly on symptom relief (eg, acetaminophen or ibuprofen for fever and aches). Antiviral drugs may be used, particularly for high-risk patients (see Respiratory Viruses: At-risk groups) and those who are seriously ill. Oseltamivir and zanamivir appear to be effective; they are most effective when started within 48 h after symptom onset. In the US, the FDA has issued Emergency Use Authorizations for the use of oseltamivir in patients < 1 yr old and the use of peramivir, an IV neuraminidase inhibitor, in severely ill hospitalized patients.
Most patients recover fully without taking these drugs.
Prevention
Vaccines for H1N1 infection have been developed. Guidelines for use of these vaccines are similar to those for use of seasonal TIV and LAIV.
Commonsense steps (eg, staying home if influenza-like symptoms develop; thorough, frequent hand washing with soap and water or an alcohol-based hand sanitizer) are recommended to reduce the spread of infection.
Last full review/revision October 2009 by Ronald B. Turner, MD
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