influenza virus

**Classification and structure** - Family Orthomyxoviridae. Enveloped, helical nucleocapsid, negative-sense ssRNA with a segmented genome (8 segments in influenza A and B; 7 in C). - Because the genome is negative-sense, the virion carries its own RNA-dependent RNA polymerase. It replicates in the nucleus, unlike most RNA viruses. - Types: A (humans, birds, swine, other animals; causes pandemics and is subtyped by HA and NA, e.g., H1N1, H3N2), B (humans only; epidemics; no shift), C (mild disease). - Surface glycoproteins: - **Hemagglutinin (HA):** binds sialic acid on respiratory epithelium, mediating attachment and fusion/entry. It is the main target of neutralizing antibody. - **Neuraminidase (NA):** cleaves sialic acid to release new virions and prevents clumping. It is the target of oseltamivir and zanamivir. - M2 ion channel: mediates uncoating. It is the target of amantadine and rimantadine, which are no longer used because of widespread resistance.

**Antigenic variation (high-yield)** - **Antigenic drift:** point mutations in HA and NA. Influenza A and B both undergo it. It causes yearly epidemics and is why the vaccine is reformulated annually. - **Antigenic shift:** reassortment of genome segments between different strains (e.g., human, avian, swine). Only influenza A undergoes it. It produces a novel subtype to which the population is immunologically naive, which can cause a pandemic (e.g., 1918 H1N1, 1957 H2N2, 1968 H3N2, 2009 H1N1).

**Clinical features** - Transmitted by respiratory droplets. Peaks in winter. - Abrupt onset of fever, chills, myalgia, headache, malaise, nonproductive cough, and sore throat. Systemic symptoms are more prominent than in the common cold. - Infection destroys ciliated respiratory epithelium, which predisposes to bacterial superinfection. - Complications: - **Secondary bacterial pneumonia** (most common cause of death): *S. pneumoniae*, *S. aureus* (including MRSA), *H. influenzae*. - Primary viral pneumonia and ARDS. - Myositis and rhabdomyolysis, myocarditis, and encephalopathy. - **Reye syndrome** with aspirin use in children (hepatic steatosis, hyperammonemia, encephalopathy). Avoid aspirin in children with viral illness. - Guillain-Barré syndrome (associated with infection and, rarely, vaccination). - High-risk groups: age <5 (especially <2) or ≥65, pregnancy, immunosuppression, chronic lung or heart disease, obesity, and residents of long-term care facilities.

**Diagnosis** - Clinical during an outbreak. Confirm with rapid molecular assay (RT-PCR/NAAT, preferred; high sensitivity and specificity) or rapid antigen test (lower sensitivity). - Viral culture is rarely used. - Historically, hemagglutination assays were used, and infected cells hemadsorb RBCs.

**Treatment and prevention** - **Neuraminidase inhibitors:** oseltamivir (PO), zanamivir (inhaled; avoid in asthma/COPD because of bronchospasm), and peramivir (IV). They work best within 48 hours of onset but are recommended for hospitalized or high-risk patients regardless of timing. - **Baloxavir:** inhibits the cap-dependent endonuclease (PA protein) and blocks viral mRNA synthesis. - **Vaccines:** - Inactivated (IM) quadrivalent or trivalent vaccine, recommended annually for everyone ≥6 months old. Contraindicated only with a history of severe allergic reaction to the vaccine or its components. - Live attenuated intranasal vaccine (LAIV): not for pregnant, immunocompromised, or very young (<2 years) patients, or those with asthma. - Chemoprophylaxis with oseltamivir or baloxavir can be used for high-risk exposed contacts.

**Board pearls** - Negative-sense, segmented, enveloped RNA viruses: influenza, plus bunyaviruses, arenaviruses, and others. Segmentation allows reassortment. - Other segmented RNA viruses: Bunya-, Orthomyxo-, Reo- (rotavirus; dsRNA), Arena- ("BOAR"). - Influenza is the classic cause of pandemics. Look for a healthy patient with abrupt-onset fever and myalgias in winter, then worsening after initial improvement (bacterial superinfection).