1. Influenza Update Eliane Haron, M.D.

2. Influenza Viruses • Orthomyxoviruses • Enveloped, RNA viruses • Estimated to measure 80-120 nm in diameter • Subtypes A, B and C • Mainly A and B cause significant infection in humans. • Subtype C can cause mild infection without seasonality

5. Influenza – Surface Glycoproteins • Hemaglutinin • Sialic acid receptor-binding molecule, which binds to sialic acid residues present on the surface of respiratory epithelial cells. • Mediates entry of the virus into the target cell • 16 types H1-H16 • Mainly H1, H2, H3 cause disease in humans

6. Influenza- Surface Glycoproteins • Neuraminidase • Responsible for cleavage of the newly-formed virions from the host cell. • Inhibition of this protein halts viral replication. • 9 types N1-N9 • Mostly N1 and N2 are involved in human infections

10. Current circulating virus • Since 1977, AH1N1 and A/H3N2 have circulated along with influenza B viruses • In 2001-2002 a novel reassortment strain A/H1N2 appeared but did not cause extensive outbreaks • In 2004-2005, influenza A isolates were mostly A/H3N2

11. Influenza - Transmission • Usually transmitted by direct contact and inhalation of large infectious droplets produced during coughing and sneezing • Hands and other objects can get contaminated with infected respiratory secretions, and subsequent contact with mucosal surfaces can transmit the virus • Close contact needed (<3 feet) • Droplet precautions in hospitalized patients • For 5 days in normal hosts • For the duration of illness in immunocompromised patients

12. Clinical Manifestations • Uncomplicated Influenza • Abrupt onset of fever, HA, myalgias, malaise along with respiratory symptoms particularly cough and sore throat. • Illness usually improves/resolves in 3-7 days • Occasional post infectious asthenia

13. Clinical Manifestations • Complications • Primary Influenza Pneumonia • Secondary Bacterial Pneumonia • Strep. pneumoniae; Staph aureus • Exacerbation of fever and respiratory symptoms after initial improvement of influenza symptoms • Other complications • Myositis, • CNS involvement: encephalitis, transverse myelitis, aseptic meningitis, Guillan-Barre’ syndrome. • Myocarditis and pericarditis (rare).

14. Influenza- Diagnosis • Clinical Diagnosis • Clinical diagnosis is straightforward during a flu epidemic • In sporadic cases, symptoms can be indistinguishable from other acute respiratory infections • Laboratory Diagnosis • Viral cultures of respiratory secretions (nasal washes, sputum, throat swab, BAL) • Rapid detection tests (EIA, IF, PCR) • Serologic tests

15. Influenza- Treatment • Adamantanes (Amantadine/Rimantadine) • Inhibition of viral uncoating inside the host cell due to interaction with the M2 protein of susceptible viruses • Active against Influenza A, • No activity against Influenza B • Both drugs have shown a decrease in clinical symptoms and a reduction in the levels and duration of viral shedding • Need to be started within 48 hours of symptoms • Resistant isolates can develop

16. Influenza- Treatment • Amantadine • Dose: • 100mg PO q12hs x 5days for rx acute infection • 100mg PO q12hs x 10 days post exposure, 2-4 wks post vaccine • Excreted unaltered in urine • Needs dose correction in renal insufficiency • CNS side effects such as insomnia, dizziness, difficulty concentrating, seizures • Main use: Treatment and prophylaxis

17. Influenza- Treatment • Rimantadine • Dose: • 100mgPO q12hs x 7 days for rx acute infection • Less than 15% excreted unchanged in urine • Dose should be decreases by half in ESRD, hepatic insufficiency and in elderly patients • Considerably less CNS side effects than amantadine

18. Influenza- Treatment • Neuraminidase Inhibitors: • Zanamivir and Olseltamivir • Active against Influenza A and B viruses • Must be given within 48hs of development of symptoms • Mechanism of action: mimic the natural substrate, fitting into the neuraminidase site of the virus • Halts viral replication by impeding release of new formed virions.

19. Mechanism of Action of Neuraminidase Inhibitors Moscona, A. N Engl J Med 2005;353:1363-1373

20. Influenza- Treatment • Zanamivir • Dose: two 5mg inhalations twice daily x 5 days • Powder for inhalation • Highly concentrated in respiratory tract when inhaled • No bio-availability • Only 5%-15% of the drug is absorbed and excreted in the urine • Side effects: mainly bronchospasm, cough

21. Influenza- Treatment • Oseltamivir • Dose: • 75mg PO q 12hs x 5 days for Rx • 75 mg PO daily for prophylaxis • Good oral bioavailability (capsule or suspension) • Mainly excreted in the urine • Needs dose correction for renal insufficiency • Side Effects: nausea, vomiting, diarrhea

24. Influenza - Prevention

25. Influenza Vaccine • 2005-2006 vaccine strains • A/NewCaledonia/20/99 (H1N1) • A/California/7/2004(H3N2) • B/Shanghai/361/2002

26. Coverage 2004-2005 Season • Children 6-23 months old: 48.4% • Adults ≥ 65 years old: 62.7% • Non-priority adults: 8.8% (2003-2004: 17.8%) Centers for Disease Control and Prevention, MMWR, 2005.

27. Priority Groups For Influenza Vaccination, 2005-2006 • Children 6-23 months of age • Adults >50 years • Persons 2-64 years of age with underlying chronic medical conditions • Women who will be pregnant during influenza season

28. Priority Groups For Influenza Vaccination, 2005-2006 • Residents and staff of nursing homes and long-term care facilities • Children 6 months-18 years of age on chronic aspirin therapy • Healthcare workers with direct, face-to-face patient contact • Household contacts and out-of-home caregivers of persons in a high-risk group

29. Inactivated Influenza VaccineRecommendations • Persons with the following chronic illnesses should be considered for inactivated influenza vaccine: • pulmonary (e.g., asthma, COPD) • cardiovascular (e.g., CHF) • metabolic (e.g., diabetes) • renal dysfunction • hemoglobinopathy • immunosuppression, including HIV infection

30. New Chronic Disease Risk Group (2005-2006) • Conditions (e.g. cognitive dysfunction, spinal cord injuries, seizure disorders or other neuromuscular disorders) that can: • Compromise respiratory function • Compromise the handling of respiratory secretions • Increase the risk of aspiration

31. Live Attenuated Influenza Vaccine Approved by FDA June 2003

32. Live Attenuated Influenza Vaccine (LAIV) Indications • Healthy* persons 5–49 years of age • Household contacts of persons at increased risk of complications of influenza • Health care workers *Persons who do not have medical conditions that increase their risk of complications of influenza

33. LAIVPersons Who Should not be Vaccinated • Children <5 years of age* • Persons >50 years of age* • Persons with underlying medical conditions* • Pregnant women* • Persons immunosuppressed from disease (including HIV) or drugs* *These persons should receive inactivated influenza vaccine

34. LAIVPersons Who Should not be Vaccinated • Children or adolescents receiving long-term therapy with aspirin or other salicylates* • Severe (anaphylactic) allergy to egg or other vaccine components • History of Guillain-Barre´ syndrome *These persons should receive inactivated influenza vaccine

35. Avian Influenza • Caused by Influenza A viruses • Can affect domestic poultry and wild birds • Migratory birds are considered the natural reservoir of influenza viruses

37. Avian Influenza • Two forms of infection in birds • Low Pathogenicity • Mild disease, ruffled feathers, drop in egg production • Can go undetected • High Pathogenicity • Dramatic bird disease affecting multiple organs • Spreads rapidly through poultry flocks • High mortality, usually within 48 hours

39. Implications of Avian Influenza in Human Health • Direct Infection • Virus crosses from birds to humans, causing severe disease in humans • Birds shed large amounts of virus in their feces • Caused by direct contact with poultry or objects/surfaces contaminated with poultry feces • Exposure during slaughter, de-feathering, butchering and preparing for cooking most likely • No evidence of transmission through cooked foods

40. Implications of Avian Influenza in Human Health • Transformation of the virus into a form that is highly infectious to humans and can spread easily from person to person • Adaptive mutation • Reassortment • Will trigger a pandemic given lack of immunity of the population

41. The Two Mechanisms whereby Pandemic Influenza Originates Belshe, R. B. N Engl J Med 2005;353:2209-2211

47. Avian Influenza A(H5N1) in Humans • Affects younger population; very high mortality • Incubation may be longer (up to 8 days) • Clinical presentation includes high fever, and an influenza-like illness with lower tract respiratory symptoms, pleuritic chest pain, diarrhea, vomiting, abdominal pain, bleeding from gums and nose • CXR with diffuse, patchy, multi-focal infiltrates • Progression to respiratory failure and ARDS requiring ventilatory support • Labs: leukopenia, lymphopenia, thrombocytopenia, elevated LFTs, renal function tests • Virologic diagnosis: • Viral cultures or viral RNA in pharyngeal samples (rather than nasal). • Viral loads higher than A(H1N1) or A(H3N2) viruses • Commercial rapid antigen tests less sensitive in detecting A(H5N1)

48. Proposed Mechanism of the Cytokine Storm Evoked by Influenzavirus Osterholm, M. T. N Engl J Med 2005;352:1839-1842

49. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO 29 November 2005

50. Belshe, R. B. N Engl J Med 2005;353:2209-2211