Microbiology and Pathogenesis

Influenza A, B, and C viruses are segmented, single-stranded, negative-sense RNA viruses that have on their outer surface prominent spikes formed by two surface glycoproteins, hemagglutinin (H) and neuraminidase (N). Influenza A and B viruses are major human pathogens, but influenza C virus causes only intermittent mild disease.

• Influenza A viruses are subtyped by the H and N antigens.
  • Virus attaches to sialic acid cell receptors via the hemagglutinin. Neuraminidase cleaves the virus from the cell membrane to facilitate its release from the cell.
  • Influenza A viruses undergo antigenic drift (modification of immunogenic epitopes, particularly on the H antigen), which counteracts prevailing immunity, and antigenic shift (reassortment of genes among different isolates), which results in major changes in antigens). The viruses have extensive mammalian and avian reservoirs. These features give influenza A virus the ability to cause a worldwide epidemic (pandemic).
• Influenza is transmitted by small- and large-particle droplets. Virus spread is facilitated by the coughing and sneezing that accompany the illness.

Epidemiology

Influenza outbreaks occur during cooler months. A typical outbreak begins in early winter and lasts 4-5 weeks in a given community, although its impact on the entire country lasts considerably longer.

• All of the annual influenza A epidemics in the past 50 years have been caused by H1N1 and/or H3N2 strains. H2N2 strains circulated between 1957 and 1968, and H1N1 strains circulated prior to that.
• Potentially pandemic viruses continue to emerge, mostly in Asia, with higher-number hemagglutinins (e.g., H5, H6, H7, H9). It is thought that swine serve as an important intermediary of pandemic strains: these animals can sustain simultaneous infection with swine, human, and avian influenza viruses, which facilitates reassortment of genetic segments of different viruses (enabling antigenic shift).

Clinical Manifestations

Influenza is primarily a sudden-onset respiratory illness causing rhinorrhea, sore throat, conjunctivitis, and cough. Symptoms typically begin within 48-72 h of exposure.

• Physical examination is often notable for nonlocalizing scattered rales, rhonchi, and wheezing. Localized pulmonary findings may suggest relatively complicated pneumonia with a bacterial component.
• Influenza is distinguished from other respiratory illnesses by the greater degree of accompanying fever, fatigue, myalgia, and malaise.
• Systemic symptoms generally resolve within 2-5 days, but respiratory symptoms (e.g., recurrent cough, decreased exercise performance) can persist for ≥1 month.
• Complications of influenza (respiratory and extrapulmonary manifestations) are more common among pts <5 and >65 years old, pregnant women in the second or third trimester, and pts with chronic disorders (e.g., cardiopulmonary disease, immunosuppression).
  • - Respiratory complications: Pneumonia (progressive air hunger, localized pulmonary findings on physical or radiographic examination) is the most common complication of influenza. These cases can be due to primary influenza pneumonia and/or secondary bacterial pneumonia.
    • In secondary bacterial pneumonia or mixed viral and bacterial pneumonia, illness may be biphasic, with recrudescence of fever and pulmonary symptoms following recovery from the primary influenza illness.
  • Extrapulmonary complications: The most common extrapulmonary manifestation of influenza is myositis (seen more often in influenza B). Other complications include Reye's syndrome, myo/pericarditis, and CNS disease (e.g., encephalitis, transverse myelitis, Guillain-Barré syndrome).
    • Reye's syndrome is a serious complication in children that is associated with influenza B virus (and less commonly with influenza A virus), varicella-zoster virus, and aspirin therapy for the antecedent viral infection.

Laboratory Findings

Reverse-transcription PCR (RT-PCR) of respiratory samples (e.g., throat swabs, nasopharyngeal washes, sputum) is the most sensitive and specific technique for detecting influenza.

• Rapid tests that detect viral antigens yield results quickly and can sometimes distinguish between influenza A and B viruses. These tests are highly specific but exhibit low sensitivity (50-70%).
• Serologic testing requires the availability of acute- and convalescent-phase sera and is useful only retrospectively.

Prophylaxis

Annual vaccination with either an inactivated or a live attenuated vaccine is the main public health measure for prevention of influenza.

• Vaccine strains are generated from influenza A and B viruses that have circulated during the previous influenza season and whose circulation during the upcoming season is predicted.
• For inactivated vaccines, 50-75% protection against influenza is expected if the vaccine virus and the currently circulating viruses are closely related.
• Influenza vaccination is currently recommended for all individuals >6 months of age.
• The efficacy of the live attenuated vaccine has come into question in the last few years.
• The neuraminidase inhibitors can also be used for prophylaxis, either throughout the season or, when a case is recognized in a close contact, in the short term.