Influenza

Etiology
Influenza viruses are RNA viruses and members of the Orthomyxoviridae family. Influenza A, B, and C viruses constitute separate genera distinguished by antigenic characteristics of the nucleoprotein (NP) and matrix (M) proteins. Influenza A viruses are further subtyped by surface hemagglutinin (H) and neuraminidase (N) antigens. Strains are designated according to site of origin, isolate number, and subtype. Influenza A and B viruses are the major human pathogens and are morphologically similar. Virus attaches to cell receptors via the hemagglutinin. Neuraminidase degrades the receptor and plays a role in the release of virus from infected cells after replication has occurred. Antibodies to the H antigen are the major determinants of immunity, while antibodies to the N antigen limit viral spread and contribute to reduction of the infection.

Epidemiology
Influenza outbreaks occur each year but vary in extent and severity. Until 25 years ago, there were influenza A epidemics or pandemics every 10?15 years due in part to the propensity of the H and N antigens to undergo periodic antigenic variation. Major changes are called antigenic shifts and are associated with pandemics. Minor variations are called antigenic drifts. The segmented genome of influenza virus allows for reassortment. It is believed that pandemic strains may result from reassortment between human and animal strains of influenza virus. Infection due to avian strains has been documented (e.g., recent infections due to influenza virus A/H5N1), but disease spread has been limited. Epidemics begin abruptly, peak over 2?3 weeks, last 2?3 months, and then subside rapidly. They take place almost exclusively during the winter months in temperate climates but occur year-round in the tropics. The morbidity and mortality associated with influenza outbreaks continue to be substantial, particularly among persons with comorbid disease. Chronic cardiac and pulmonary disease and old age are prominent risk factors for severe illness. Influenza B viruses have a more restricted host range and do not undergo antigenic shifts, although they do exhibit antigenic drift. Outbreaks are less extensive and less severe than those of influenza A, occurring most commonly in schools and military camps. Influenza C causes subclinical infection.

• type A: pandemy or epidemy or sporadic / type B: localized outbreak (epidemy) or sporadic

Pathogenesis
Influenza is acquired from respiratory secretions of acutely ill individuals through aerosols generated by coughs and sneezes and possibly by hand-to-hand contact or other personal or fomite contact. Virus then infects the respiratory epithelium. Ciliated columnar epithelial cells are initially involved; the virus replicates within 4?6 h and spreads quickly to infect other respiratory cells. Cells undergo degenerative changes, become necrotic, and desquamate. Extrapulmonary sites of infection are rare, but cytokine induction causes systemic symptoms. The host response involves production of humoral antibody (detectable by the second week of infection), local IgA antibody, cell-mediated immunity, and interferon. Host defenses are responsible for cessation of viral shedding 2?5 days after disease onset.

Clinical Features
? Systemic symptoms: abrupt onset of headache, fever, chills, myalgia, malaise
? Respiratory tract symptoms: cough and sore throat that can become more prominent as systemic symptoms subside
? Physical findings are minimal in uncomplicated disease.

Complications
Complications are more common among pts >64 years old, pregnant women, and pts with chronic disorders (e.g., cardiac or pulmonary disease, diabetes, renal diseases, hemoglobinopathies, or immunosuppression).
? Pneumonia: the most significant complication of influenza. Pts can have tachypnea, cyanosis, diffuse rales, and signs of consolidation.
1. Primary viral: least common but most severe. Acute influenza progresses relentlessly, with persistent fever, dyspnea, cyanosis, and hemoptysis; CXR may show diffuse infiltrates. ARDS can result. Cultures of respiratory secretions yield high viral titers. Primary pneumonia is especially common among pts with cardiac disease, particularly mitral stenosis.
2. Secondary bacterial: usually due to Streptococcus pneumoniae, Staphylococcus aureus, or Haemophilus influenzae. Pts improve over 2?3 days of illness and then have a recurrence of fever and clinical signs of bacterial pneumonia (e.g., cough, sputum production, and consolidation on CXR).
3. Pts can have features of both primary and secondary pneumonia.
? Extrapulmonary complications
1. Reye's syndrome: associated with influenza B more often than with influenza A; also associated with varicella-zoster virus infection and with aspirin use. Aspirin should not be given to children with acute viral respiratory infections.
2. Miscellaneous: Myositis, rhabdomyolysis, and myoglobinuria are rare despite the prevalence of severe myalgia. Myocarditis and pericarditis, encephalitis, transverse myelitis, and Guillain-Barr? syndrome have been reported.

Laboratory Findings
During acute influenza, tissue culture of virus from throat swabs, nasopharyngeal washes, or sputum usually gives a positive result within 48?72 h. Rapid tests for viral nucleoprotein or neuraminidase are highly sensitive, with a specificity of 60?90%. Serology requires the availability of acute- and convalescent-phase sera and is useful only retrospectively.

Treatment
? Symptom-based therapy (e.g., acetaminophen, rest, hydration)
acetaminophen for the relief of headache, myalgia, & fever / codeine-containing compounds for troublesome cough
? Antiviral agents
1. Amantadine and rimantadine (200 mg/d for 3?7 days) are used to treat influenza A; if their administration is begun within 48 h, the duration of systemic and respiratory symptoms is reduced by ~50%. Amantadine causes mild CNS side effects (e.g., jitteriness, anxiety, insomnia, difficulty concentrating) in ~5?10% of pts. Rimantadine has fewer CNS side effects and is equally efficacious.
2. The neuraminidase inhibitors zanamivir (10 mg inhaled bid for 5 days) and oseltamivir (75 mg bid PO with food for 5 days) are used to treat influenza A and B. The drugs decrease the duration of signs and symptoms by 1?1.5 days if therapy is begun within 2 days of illness onset. Zanamivir may exacerbate bronchospasm in asthmatic pts, while oseltamivir has been associated with nausea and vomiting (reactions whose incidence is reduced if the drug is given with food).
3. Antiviral resistance is common with amantadine and rimantadine but infrequent with neuraminidase inhibitors.
4. Antiviral treatment has been tested in healthy adults with uncomplicated influenza but not in pts with severe disease.

Prophylaxis
? Vaccination: Influenza vaccine is derived from the influenza A and B viruses that have circulated during the previous influenza season. If the currently circulating virus is similar to the vaccine strain, 50?80% protection is expected. Influenza vaccination is recommended for any individual >6 months of age who is at increased risk for complications (Table 109-1). The commercially available vaccines are inactivated and may be given to immunocompromised pts. A live attenuated influenza vaccine given by intranasal spray has recently been approved and can be used for healthy children and adults up to 49 years of age.
? Chemoprophylaxis: Efficacy rates in preventing illness are 70?100% for amantadine or rimantadine (100?200 mg/d) and are 84?89% for oseltamivir (75 mg/d PO) or zanamivir (10 mg/d inhaled). Prophylaxis is useful for high-risk individuals who have not received vaccine and are exposed to influenza; it can be administered simultaneously with the inactivated vaccine.

Recommendations for Influenza Vaccination
Table 109-1
Recommendations for Influenza Vaccinationa
?
?
Persons at increased risk for complications

?Residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions


?Children and adolescents (6 months to 18 years old) who are receiving long-term aspirin therapy and therefore may be at risk for developing Reye's syndrome after influenza infection
?Women who will be in the second or third trimester of pregnancy during the influenza season
?
Persons 50 to 64 years of age
?Included because of increased prevalence of high-risk conditions
?
Persons who can transmit influenza to those at high risk
?Physicians, nurses, and other personnel in both hospital and outpatient-care settings, including medical emergency response workers (e.g., paramedics and emergency medical technicians)
?Employees of nursing homes and chronic-care facilities who have contact with patients or residents
?Employees of assisted-living and other residences for persons in groups at high risk
?Persons who provide home care to individuals in groups at high risk
?Household members (including children) of persons in groups at high risk
?

aVaccination of healthy children 6 to 23 months of age is encouraged.
?
?
Centers for Disease Control and Prevention: MMWR S1(RR-3):1, 2002.