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Influenza

Influenza. “probably the most under-rated major pathogen in the developed world…” John Barlett, Update in Infectious Diseases Annals of Internal Medicine August 1999. Case 1. 38 year-old man presented February

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Influenza

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  1. Influenza • “probably the most under-rated major pathogen in the developed world…” • John Barlett, Update in Infectious Diseases • Annals of Internal Medicine August 1999

  2. Case 1 • 38 year-old man presented February • 2-day history of fever, chills, cough, sore throat, nasal congestion, muscle aches, headache, fatigue • Did not receive flu vaccine

  3. “Influenza-like illness” • Recent, acute onset • Fever or feverishness • Respiratory (cough, sore throat, coryza) and systemic (malaise, headache, myalgias) components

  4. Influenza in Healthy, Young and Middle-aged, Unvaccinated Adults Monto et al. Arch Intern Med 2000; 160: 3243.

  5. Recognizing influenza in hospitalized patients? Dowell et al. JID 1996; 174:456.

  6. Influenza in a Fully-Immunized Veteran COPD Population Neuzil et al. CID 2003; 36: 169.

  7. Accuracy of Clinical Diagnosis • Diagnosis from clinical signs and symptoms is of limited accuracy • Maintain a high index of suspicion during the right time of year • Other co-circulating respiratory pathogens: Adeno; RSV; Parainfluenza; Rhino; Strep; Chlamydia; Mycoplasma

  8. Seasonal Occurrence of Influenza, RSV and Parainfluenza Viruses, United States,1996-99 7/96 1/97 7/97 1/98 7/98 1/99 7/99

  9. Should I perform a diagnostic test? • Utility of test in individual patient depends on quality of sample, timing of sample, turn-around time of test • Collecting specimens still critical because it provides information about circulating influenza types • BMC: Antigen testing +/- reflex PCR [Antigen testing Sensitivity (40 - 90%) Specificity (90 - 99%).] • Typing is done at state labs

  10. How and who should be tested? • Nasopharyngeal swabs or washes on patients • Immunocompetent adults at high risk for complications who present within 5 days of illness. • Immunocompromised adults with acute febrile illness regardless of time of onset • Recently hospitalized adults with fever and respiratory symptoms regardless of time of onset.

  11. Virology of Influenza A and B • Orthomyxoviridae • Enveloped negative stranded RNA viruses • Four genera are included in this family • Influenza A and B (human pathogens) • Influenza C • Thogotovirus (sometimes called Influenza D).

  12. Subtyped based on surface glycoproteins: • 16 hemagglutinins (HA) and 9 neuraminidases (NA) • current human subtypes: H1N1, H3N2, H1N2 • Segmented genome Influenza A Viruses HA NA

  13. Antigenic Drift • H1, H2, H3 / N1 and N2 • Antigenic drift: • Both A and B • Individual point mutations

  14. Antigenic Shift • Influenza A only • Sudden appearance of a virus with a completely novel HA or HA and NA. • This occurs when a strain of Influenza A that usually infects bird or other mammals crosses over to cause human infection. • May result in emergence of pandemic strains • Asia appears to be a fertile ground for such shifts.

  15. DIRECT Mechanisms of Influenza Virus Antigenic “Shift” 15 HAs 9 NAs Non-human virus Human virus Reassortant virus

  16. Pandemic Influenza • Emergence & spread of “novel” influenza A virus • HA (or HA/NA) derived from animal viruses • Sustained and efficient human-human transmission • Near simultaneous global outbreak • Elevated rates illness & death

  17. The Great Influenza of 1918 • First wave less pathogenic (April-May), possibly beginning in Kansas and spreading by military travel throughout the world • Second wave (July-Nov) much more lethal; hemorrhagic pneumonia in young adults • Between 20-100 million deaths worldwide Barry J. The Great Influenza – Viking Press, 2004

  18. Mortality Comparisons

  19. Infectious Disease Mortality, United States - 20th Century Armstrong, et al. JAMA 1999;281:61-66.

  20. Pathogenesis of 1918 Influenza • Hemagglutinin (HA) antigen the key determinant of virulence in a mouse model • Massive inflammation in lungs with cytokine “storm” and neutrophil influx • Might immunomodulatory therapy be a useful adjunct to appropriate antivirals? Kobasa et al. Nature 2004:431:703-07

  21. Timeline of Emergence of Influenza A Viruses in Humans Avian Influenza H7 H9 H7 Russian Influenza H5 H5 H1 Asian Influenza H3 Spanish Influenza H2 Hong Kong Influenza 2009 pandemic H1 H1 2009 1918 1957 1968 1977 1997 2003 1998/9

  22. 2009 Pandemic Influenza A (H1N1)

  23. H7N9 Virus • Avian influenza, first reported from China April 1, 2013 • Over 130 infections detected. Most subjects exposure to poultry. Reported 44 deaths. • No evidence of sustained human to human transmission • If virus acquires ability for sustained human to human transmission, then high potential for a pandemic

  24. Should I use antivirals? • Amantadine and rimantadine: effective against influenza A viruses • Neuraminidase inhibitors: oseltamivir (oral), zanamivir (inhaled); effective against influenza A and B viruses • Differ in terms of pharmacokinetics, side effects, routes of administration, cost

  25. Antivirals • Neuraminidase inhibitors: Inteferes with viral release from infected cell. • Ostelamivir: 75 mg BID; $55; Approved for prophylaxis. Can use higher doses • Zanamivir: Inhalation 10 mg BID; $45 Contraindicated in people with asthma or other chronic respiratory conditions DURATION: Generally 5 days but can be longer in ill patients.

  26. Antivirals • Amantadine and rimantadine: Inteferes with M2 protein function • Amantadine: 100 mg BID; $2 (Neuro side-effects) • Rimantadine: 100 mg BID; $2; Approved for prophylaxis. • Associated with CNS toxicity • Because of wide resistance, these drugs should not be used for treatment other than special circumstances

  27. Antiviral Resistance • Resistance to all drugs have been described. • Generally single point mutations lead to resistance • CDC website provides information about % circulating variants with resistance • Durnig 2012 – 2013 season, resistance to Tamiflu was observed in less than 1% of isolates.

  28. Adverse Effects • Ostemlavir • Nausea and vomiting • Mild abdominal pain • Dosing must be modified for renal insufficiency • Zanamavir • Broncospasm • Not recommended to be used with ventilation tubing

  29. Treatment in hospitalized with severe disease • Confirmed or Suspected disease • Therapy should be initiated prior to diagnostic test results • With high clinical suspicion therapy should not be stopped even if diagnostic test is negative • For patients with severe disease therapy should be instituted even if they present after 48 hours

  30. Oseltamivir Reduces Time to Alleviation of All Symptoms Placebo Proportion with symptoms End of treatment Oseltamivir Days Treanor et al. JAMA 2000; 283: 1016.

  31. Treatment • Treatment best if initiated early • Duration of illness is reduced and return to usual activities is earlier • Treatment reduces virus shedding • None of the treatments has been shown to prevent serious influenza-related complications (bacterial pneumonia or exacerbation of chronic disease)

  32. Clinical Case 2 • 43yo man with CML, chronic phase, on interferon • 2-week history of sore throat, cough, fever/chills/ myalgias/headache, dizziness, weight loss • ?atypical pneumonia • Rx: azithromycin • (in addition to trimeth-sulfa and PCN VK)

  33. Clinical Case 2 • Returned 12 days later: worsening dyspnea, dry cough • PE: cyanosis, bilateral crackles lower lung fields • Hypoxic • BAL: Influenza A, Staph. Aureus • Blood culture + S. aureus

  34. Complications of Influenza • Secondary bacterial infection (Streptococcus or Staph. Aureus) • Myositis • CNS • Guillan Barre, transverse myelitis, aseptic meningitis • Cardiac • Myocarditis, pericarditis, MI

  35. Influenza Vaccine • Each year, vaccine formulation depends on the circulating strains. • Since 1980s vaccine have been trivalent although quadrivalent may be standard at some point • Current vaccines consist of a H1N1, H3N2 and influenza B

  36. Who Should be Immunized?Persons at High Risk for Complications • All persons aged 6 months or older • All people including pregnant women can receive the inactivated influenza vaccine (IIV) • Healthy, nonpregnant person age 2 – 49 without high risk medical conditions can receive either intranasally administered live, attenuated influenza vaccine (LAIV) (FluMist) or IIV. • Health care workers who care for severely immunocompromised persons should receive IIV.

  37. Efficacy of Inactivated Influenza Vaccine • Healthy children and adults: 70-90% in preventing culture-confirmed influenza • Elderly: 30-70% in preventing hospitalization for pneumonia and influenza • Frail elderly: 30-40% in preventing illness; 50-60% in preventing hospitalization; 80% in preventing death MMWR 2003;52: 1-36.

  38. Vaccine Efficacy 2012 - 2013 • Overall effectiveness 56% • Against H3N2 – 47% • Only 9% for individuals 65 or older • Against Flu B 67%

  39. Influenza Vaccine Effectiveness: Hospitalizations per 1000 65+ Nichol et al. N Engl J Med 1994; 331: 778

  40. Special Target Populations • Healthcare workers • Household members (including children) of persons in high-risk groups • Employees of chronic-care facilities, assisted living facilities or persons who provide home care to persons in high-risk groups • Household and close contacts of young children (< 2 years) MMWR 2003;52: 1-36.

  41. Who Should Not be Immunized? • LAIV and TIV are grown in embroyonated hens’ eggs. Therefore vaccine should not be given to those with anaphylactic hypersensitivity to eggs or other components of the influenza vaccine. (Newer vaccine formulations are now available that are egg free. Flucelvax and FluBlok) • Persons with acute febrile illness should not be vaccinated until their symptoms have abated MMWR 2003;52: 1-36.

  42. Which vaccine should I recommend/administer?

  43. Potential advantages of live vaccine? • Broad mucosal and systemic immune response • Ease of administration • Intranasal route of administration

  44. Potential disadvantages? • Expense • Limited viral replication and potential for transmission (rare) • After vaccination, antigen and PCR tests can be positive • Less experience • Storage requirements

  45. Live versus Dead • Multiple head to head randomized controlled trials. • RCT in ~5000 subjects no difference • RCT 2004/05 season in ~1300 subjects, both vaccine similar efficacy against A but IIV better than LAIV against B • RCT 2007/08 season in ~2000 subjects, IIV was more effective (72%) versus LAIV (29%) • Surveillance study 2004 – 07 IIV associated with lower healthcare associated visits compared to LAIV. Efficacy differences likely depend on year (circulating strains) and patient characteristics

  46. Clinical Case 3 • 56 yo man 14 days s/p autologous pbsct for multiple myeloma • Fever, hypoxia, respiratory failure

  47. Case 3 • Prescribed imipenem, tobramycin, levofloxacin, metronidazole • “This will cover his pulmonary pathogen for sure” • BAL: FA and culture positive for influenza A virus

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