Influenza

1. Influenza By: Brian Schneider, MD Chris Taulien, MD Janet Willoughby Maynard, MD Image: http://web.tiscali.it/lacimiceonline/numero_marzo-aprile2000/Scienza%20e%20Cultura%20art%206.htm

2. Learning Objectives • Understand the etiology, epidemiology, and pathogenesis of influenza • Explain the differences between the types of influenza and their clinical significance • Understand the etiology of flu epidemics and pandemics • Recognize the clinical symptoms and complications of influenza • Understand the medications used to treat influenza and their indications • Properly identify groups which should be vaccinated

3. Definition and Overview • Acute respiratory illness caused by influenza virus • Affects the upper and/or lower respiratory tract and is often accompanied by systemic signs and symptoms • Fever, headache, myalgia, and weakness • Outbreaks of variable extent and severity occur nearly every winter • In the US, epidemics of influenza have been responsible for an average of approximately 36,000 deaths/year from 1990–1999 • Influenza A viruses can cause pandemics and did so 4 times in the 20th century • The pandemic of 1918 to 1919 caused at least 500,000 deaths in the US and over 40 million worldwide

4. Etiologic Agent • Influenza viruses are members of the Orthomyxoviridae family and are subdivided into 3 types: A, B, and C • They are distinguished by the antigenicity of their internal and external proteins • Spherical virions w/ 8 segments of RNA join together w/ nucleocapsid protein (NP) • Surrounding the RNA is an outer membrane with glycoprotein spikes • Hemagglutinin (HA) and Neuraminidase (NA) Mandell: Principles & Practice of Infectious Disease. 5th ed, 2000;1825

5. Types of Influenza Viruses • Influenza A • Further subtyped based on the surface hemagglutinin (HA) and neuraminidase (NA) antigens • Individual strains are designated according to: site of origin, isolate number, year of isolation, and subtype • Infect diverse animal species • Variation of antigenicity of the surface glycoproteins contributes to continuing epidemics of influenza in humans • Influenza B and C • Human pathogens only • Influenza B outbreaks are generally less extensive and associated with less severe disease than influenza A • The Antibodies to HA neutralize viral infectivity and thus are the major determinant of immunity

6. Antigenic Drift Results from accumulation of point mutations in the RNA segment coding for HA or NA Small changes that occur frequently Can cause disease epidemics Antigenic Shift Results from the appearance of an influenza A virus w/ HA and NA glycoproteins new to humans or possible reappearance of virus after decades of absence Due to the lack of immunity, a virulent strain can cause pandemic disease Reassortment of gene segments may occur when 2 influenza viruses co-infect one cell Antigenic Drift vs. Shift http://www.hku.hk/rss/res_proj/91/fig1.jpg

7. Epidemics vs. Pandemics • Epidemic • An outbreak of influenza confined to one geographic location • Usual pattern: begin abruptly, reach a peak in 2-3 weeks, and last about 6-10 weeks • Typically occurs in the winter months in temperate areas, but influenza activity is year round in the tropics • Overall attack rate typically averages 5-20% in adults and 40-50% in closed populations • Pandemic • Affects a wide geographic area and a diverse population • Result from emergence of new viruses capable of sustained person-to-person transmission • Example: pandemic of 1918-1919 (Spanish Influenza), associated with antigenic shifts of HA and NA

8. Pathogenesis and Pathology • Pathogenesis • Person-to-Person spread of virus containing respiratory secretions & hand-to-hand contact • The incubation averages 2 days • Initially, the virus infects ciliated columnar epithelial cells --> desquamation • Systemic symptoms are related to cytokine release • Secondary bacterial infections may develop due to altered bacterial flora, damaged bronchial epithelium, or changes in the immune system http://www.health.state.nm.us/immunize/Images/sneeze.jpg

9. Clinical Manifestations of Influenza • Influenza is characterized by abrupt onset of illness • Pts can often recall the precise time that they became ill • Systemic symptoms are usually the first manifestation • Predominance of systemic symptoms sets influenza apart from other viral respiratory infections • Fever 38-41 C • Frank shaking chills • Headache • Myalgias especially in the legs and lumbosacral area • Eye: Tearing, burning, pain on gazing laterally • Respiratory complaints begin to worsen as systemic symptoms subside • Sore throat and persistent cough • Nasal obstruction, discharge

10. Clinical Manifestations Cont’ • Physical findings are nonspecific especially in uncomplicated cases of influenza • Flushed, dry skin • Unremarkable pharynx despite severe sore throat • Mild cervical lymphadenopathy • Complicated cases are associated with frank dyspnea, hypercapnea, cyanosis, diffuse rales, wheezes and signs of consolidation • Most patients recover over the acute illness in 2-5 days and most are back to baseline at 1 week although the cough can persist for 1-2 weeks

11. Clinical Manifestations Cont’ • The overall spectrum of clinical illness is wide and can range from mild cold symptoms to severe prostration • Influenza A is responsible for more severe disease than type B • Influenza C is a minor cause of disease in humans and is associated with common cold symptoms. There is wide prevalence of serum antibody to this virus indicating that asymptomatic infection is common.

12. Complications of Influenza • Complications occur most frequently in patients > 60 years old and those with chronic medical conditions (cardiac and pulmonary disease, diabetes, renal dysfxn). Pregnancy also predisposes pt. to complications • The most significant complication is pneumonia: “primary” viral pneumonia, secondary bacterial pneumonia, or mixed viral/bacterial pneumonia • Primary viral pneumonia is most severe and least common • Occurs in pts. with cardiovascular disease, especially rheumatic heart disease with mitral stenosis • Influenza progresses relentlessly with persistent fever, dyspnea and finally cyanosis • Scant sputum production and initially few physical signs • CXR shows diffuse interstitial infiltrates +/- ARDS

13. Complications of Influenza Cont’ • Secondary bacterial pneumonia • Pt will first improve from acute influenza then suddenly worsen with fever, cough, dyspnea • Most common pathogens are S. pneumoniae, S. aureus, and H. influenzae • Usually responds to antibiotics when initiated quickly • Mixed viral and bacterial pneumonia • Most common pneumonic complication • Can show features of both types of pneumonia • Usually have less widespread involvement of lung parenchyma than with primary viral PNA

14. Complications of Influenza Cont’ • Other pulmonary complications: worsening of COPD, asthma, can present as croup in kids • Reye’s syndrome: Associated with Influenza B > A • Nausea, vomiting, hepatitis, coma, delirium, seizures • Associated with use of aspirin in influenza or varicella infection, especially in children; incidence has decreased dramatically with warnings about use of ASA in viral illness • Myositis, rhabodmyolysis, myoglobinuria are rare • Myocarditis, pericarditis (also rare complications) • Unclear association of influenza with CNS complications such as encephalitis, transverse myelitis, Guillain-Barre syndrome

15. Diagnosis of Influenza • Often a clinical diagnosis especially in the setting of an outbreak • Virus can be isolated from throat swabs, nasopharyngeal washes or sputum (nasopharyngeal washes/swabs the best) • Virus can be detected in tissue culture by 48-72h (gold standard) • More commonly the diagnosis is established by use of rapid viral tests • Rapid tests based on immunologic detection of viral antigens in secretions or presence of neuraminidase activity • Sensitivity when compared with culture has been reported from 40-80% • More sensitive earlier in course of disease and in kids who shed more virus • Specificity reported 85-100% • Cost ~ 20$/test

16. Diagnosis of Influenza Cont’ • PCR: potentially more sensitive but more labor intensive and costly • Serology is rarely useful as diagnosis is established retrospectively • Epidemiologic Diagnosis: empiric diagnosis when patients present with flu-like symptoms during an outbreak • Accuracy of clinical diagnosis in setting of outbreak 80-90% • Best clinical predictors, especially during flu season in patients 60 and older: fever and cough (Call, et al) • Clinical findings are helpful but do not confirm or exclude the diagnosis • Rapid testing did not add to cost-effectiveness of treatment if the probability of influenza was > than 25-30% (ie during an outbreak)

17. Vaccination • There are 2 types of vaccines in the US • Live attenuated nasal vaccine • Trivalent inactivated intramuscular • The vaccine stimulates neutralizing antibodies to the viral hemagglutinin and neuraminadase envelope glycoproteins • Fluzone (Aventis) and Fluvirin (Chiron) composed of either whole or subvirion components (whole is not available in US) • Fluvirin was the manufacturer with the past problem with sterility • Intranasal vaccine (LAIV, Flumist) approved for ages 5-49 by the FDA in 2003 • Uses a master attenuated cold donor virus from which reassortments of HA and N Aantigens are generated. • Adults receive one dose, kids two doses (age 5-8)

18. Vaccination Efficacy • Does the vaccine have efficacy? Yes! • The efficacy of inactivated vaccine production depends on the fit of the antigenic variants selected and will vary from season. However, in general, serological reduction is greater than clinical reduction. • Cochrane Database Rev in 2001, found that the intranasal vaccine had a 48% reduction in serologically confirmed cases versus 68% for inactivated parenteral vaccine. • Likewise, the reduction of clinical cases was 13% (intranasal) versus 24% for parenteral inactivated.

19. Vaccination Cost Effectiveness • Cost effective? Seems well established that it is cost effective in elderly and at risk groups (more later), but this is less clear in healthy adults • Study published in JAMA in 2000 looked at this over 2 years. In general, cost more to give the vaccine to healthy adults, particularly if the strain was not well matched to the circulating virus that year • Other studies have compared vaccination to other treatment strategies • More recently Cochrane Review found that vaccination of healthy adults seems to reduce serological cases of Influenza but not clinical cases nor working days lost • In general, vaccination compares well to other treatment strategies (oseltamivir, supportive care) in terms of cost • Bottom line, probably cost effective for elderly and at risk groups, but not routinely for healthy adults

20. Vaccination of the Elderly is Critical • Why??? 90% of influenza related deaths occur in the elderly • Shown to decrease outpt visits, mortality, admissions and readmissions for pneumonia in a significant fashion • 2 Key NEJM articles addressing this: • 1. Large retrospective NEJM article in 1994 drawn from elderly in an HMO population showing the vaccination group had a decreased rate of hospitalization for pneumonia and influenza and acute and chronic respiratory conditions despite more baseline chronic illnesses. • 2. This benefit was even expanded in 2003, again in NEJM where they showed that there was a decrease in cardiac dz and stroke (16%, 23%), as well as pna and influenza (29%, 32%), hospitalization (19%), and risk of death (48%, 50%). This was a retrospective analysis over two flu seasons where the vaccinated subjects were again sicker (higher rate of coexisting conditions, outpt care, and prior hosp) while the unvaccinated had more dementia and stroke.

21. Vaccine Administration • Priority groups during past shortage: • Age: >65 or b/w 6 and 23 months • Chronic medical conditions: particularly pulmonary, CV, immunosuppression, CKD, hemiglobinopathy, DM • Healthcare workers • Women who will be or are pregnant • Residents of NH and long term care facilities • Out of home caregivers and household contacts of kids < 6 months of age • Normally (no shortage) these recs also include 50-65 (b/c of relatively high prevalence of chronic medical dz in this age group).

22. Vaccination Guidelines • Data for healthcare workers? • RCTs have shown a significant reduction in serologically confirmed infections and insignificant reduction in febrile resp illness and missed days • When to vaccinate? • Annually, b/c of antigenic drift and shift and b/c immunity declines. May improve immunogenic response and there is data from a Dutch study (JAMA 2004) showing better mortality benefit with revaccination versus first time in elderly population • Vaccinate pregnant women or women who might become pregnant • Per recom. of advisory committee on Immunization Practices • Vaccinate HIV? • May not be effective (esp if CD4 count less than 200) and some reports suggest upregulation in HIV replication • Current CDC recommendation: vaccinate HIV infected pateints

23. Vaccination Administration • Administration: currently intramuscularly with 15 ug of HA per strain. • However, studies in 18-60 and 18-40 showing efficacy with 40% and 20% of normal doses when given intradermally. Involved 119 and 100 adults respectively. May not be effective for adults greater than 60 (significant difference b/w <60 and >60 in HAI (hemagglutination inhibition titer) in response to only one of three viral strains (H3N2), otherwise no significant difference b/w routes of administration in all age groups. Published in NEJM in 2004 and done to address the vaccine supply shortage. No significant increase in adverse events with intradermal administration.

24. Vaccination: Adverse Effects • IM inactivated vaccine. • Reactions generally fewer than 5%, include a low grade fever and mild systemic symptoms (myalgia, fatigue, headache) for 8-24 hours post immunization. • There is chicken egg protein in inactivated virus (desensitization, skin testing, nasal virus). Important for those with egg allergies. • Reported increase of Guillian Barre syndrome (primarily with swine vaccine in past). Reported to be one additional case per one million inoculated. • Intranasal vaccine • Reactions include runny nose, nasal congestion, HA. Swiss type of IN vaccine is linked to Bell’s palsy. Not seen in live attenuated influenza vaccine (LAIV).

25. Therapy • Symptom Treatment • Old standby’s of rest and hydration. Cough is generally self limited. • Avoid salicylates, particularly in those <18 yo for concern of Reye’s Syndrome (Multi-system disease associated with febrile illness in children with preceding ASA use that includes hepatic failure, encephalopathy, cerebral edema) • Reserve Abx’s for complications such as bacterial pneumonia, otitis media, sinusitis that generally involve such pathogens as S. pneumoniae, S. aureus, and H. influenzae • Neuraminadase inhibitors: Zanamir and oseltamivir • Block both Influenza A and Bas sialic acid analogs that competitively inhibit viral neuramindase (NA). NA has many functions. It is necessary for progeny virions to be released from the respiratory epithelial cell, prevents viral aggulutination, and promotes viral penetration into resp epithelial cell. It does this by catalyzing the cleavage between the terminal sialic acid residue and adjacent sugar • Zanamivir (Relenza) 10 mg inhaled bid for 5 days • Oseltamivir (Tamiflu) 75 mg po bid for 5 days

26. Therapy Cont’ • Influenza A specific: Amantadine and Rimantadine • Both appear to block the uncoating of the virus particle and subsequent release of viral nucleic acid into the host cell through interaction with the M2 Protein (proton channel). This interaction seems to interfere with fusion of the virion coat to cellular vacuolar membranes. • Amantadine (Symmetrel) 100 mg po bid • dose reduction in GFR <50 and age >65yo to 100 mg daily • Rimantadine (Flumadine) 100 mg po bid • dose reduction in severe hepatic dz and age >65yo to 100 mg daily • For both d/c ASAP for concerns of drug resistance, so within 3-5 days or 24-48 hours after disappearance of symptoms.

27. Therapy: EBM • Neuraminadase inhibitors: Zanamir and oseltamivir • Zanamivir thought to reduce the duration of symptoms (fever, systemic or respiratory systems) by 0.8, 0.9 days versus 0.9 and 0.4 in healthy adults and elderly, respectively. Results from meta-analysis in BMJ (2003). Seems to also reduce physician diagnosed secondary complications. Effective when started 30-36 hours within onset of symptoms. • Key side effects- Zanamivir can exacerbate asthma symptoms and oseltamivir may cause GI symptoms such as nausea and vomiting.

28. Therapy Cont’ • Influenza A drugs: Amantadine and Rimantadine • Bothamantadine and rimantadine (when initiated within 48 hrs of sxs) reduce duration of symptoms by 1 day and reduce by about 50% the severity of fever and other symptoms. • Probably not preferred as much data showing efficacy is in young and children and CNS side effects of Amantadine are more severe in the elderly. • Relatively recent study in J. of Infect Dis comparing rimantadine effect on influenza A infection showed a beneficial effect on virus shedding, sinus pain, and symptom load. • Key side effects: Amantadine-neurologic sxs (confusion, insomnia, anxiety, lightheadedness, hallucinations), d/c rates are same in rimantadine and placebo. • Overall, medication benefit greatest when given early (<30 hours) and when presenting with fever. Amantadine and rimantadine are substantially cheaper

29. Drug Prophylaxis • Amantadine and rimantadine- Reduce seroconversion, however no statistically significant effect in NH population • Appears to be no benefit from post exposure prophylaxis with Rim/Am when index case is treated with the same drug (because of high rate of resistance) • Oseltamivir (Zanamivir not approved)- Effective but need 1200 doses to prevent one case • Effective in household prophylaxis, as there appears to be little resistance • Key points: Give within 2 days of exposure, then for 7-10 days total • In a community outbreak, use drugs for the unvaccinated (takes 2 weeks to mount antibodies) • Most effective for health care workers, unvaccinated, when there is a variant (from vaccine) strain, and in HIV infected individuals

30. A note about avian influenza • While it is rare, avian influenza A can spread from poultry to humans. • The first reported case was in 1997 in Hong Kong. During this outbreak, 18 people were hospitalized and six of them died. To control the outbreak, authorities killed about 1.5 million chickens to remove the source of the virus. • Outbreaks have also been reported in the US. • Current CDC guidelines instruct people who handle poultry. • Recommendations include: protective clothing, gloves, hand washing, and respirators for all individuals who handle poultry. • The real danger to humans is when a mutant strain of avian flu is able to infect a human and then the virus is spread from person to person. • This is believed to be the source of the 1919 flu pandemic.

31. Questions • Your Uncle Fred is worried that this is going to be the year of the “really bad flu,” similar to 1918. You explain to him that pandemics of the flu are caused by: • Antigenic shifts from point mutations • Antigenic shifts from gene segment reassortment • Antigen drift from point mutations • Antigenic drift from gene segment reassortment • D. Antigenic shift is caused by point mutations in RNA (leading to epidemics), while antigenic drift is caused by reassortment of gene segments leading to new HA or NA glycoproteins (leading to pandemics)

32. Questions • (T/F) Family members of a patient w/ influenza treated with Amantadine should be given prophylaxis w/ Amantadine. • Answer: • False. If a household contact has the flu and is treated w/ rimantadine or amantadine, there appears to be no benefit to other household members receiving postexposure prophylaxis, probably because resistant virus is transmitted. In contrast, this does not appear to occur w/ oseltamivir and zanamivir. • Influenza vaccination in the elderly can: • A. Reduce hospitalization • B. Reduce Pneumonia • C. Reduce stroke • D. Reduce heart attacks • E. All of the above. • Answer: E

33. Questions • True or False: • You should always test a patient presenting with flu-like symptoms for influenza prior to initiating treatment. • Answer: • False. During an outbreak of influenza it is more cost-effective to treat empirically.

34. Questions • Your Aunt Sally calls to tell you that she thinks that she has the flu. She complains of fevers, myalgias, and fatigue. Over the next 7 days, she does not seem to be getting better. In fact, Sally has now developed shortness of breath and worsening fevers. You tell your Aunt Sally that: • She is just experiencing a severe case of the flu. • She should see her doctor in the next few days. • She should go to the emergency department to be evaluated. • Answer: • C. In a patient w/ influenza who does not seem to be getting better and develops respiratory symptoms, you should suspect either bacterial or primary viral pneumonia, two potentially deadly complications, which require urgent medical attention.

35. References • Up To Date, 2005. • Treanor, J. “Weathering the Influenza Vaccine Crisis.” NEJM 2004; 351 pg 2037-2040. • Belshe RB, et al. “ Serum Ab response after intradermal vaccination against influenza.” NEJM 2004 Nov 25; 351 (22): 2286-94. • Kenney TR, et al. “ Dose sparing with intradermal injection of influenza vaccine.” NEJM 2004 Nov 25; 351 (22): 2295-2301. • Voordouw AC, et al. “ Annual revacccination against influenza and mortality risk in community dwelling elderly persons: JAMA 2004 Nov 3, 292 (17): 2098-95. • “Prevention and control of influenza.” Recommendations of the Advisory Committee on Immunization Practices. MMWR 2004; 53 (RR06): 1. • Demicheli V, et al. “Vaccines for preventing influenza in healthy adults.” Cochrane Database of Systematic Reviews. 3, 2005 and 4, 2001. • Nichol KL, et al. “The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community.” NEJM 1994 Sept 22; 331 (12). 778-84.

36. References Cont’ • Nichol KL, et al. “Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly.” NEJM 2003 Apr 3: 348 (14). 1322-32. • Cooper NJ, et al. “Effectiveness of Neuraminidase Inhibitors in treatment and prevention of Influenza A and B: a systematic review and meta-analysis of randomized controlled trials.” BMJ 2003 June7; 326 (7401) • Doyle et al. “ Effect of Rimantadine treatment of clinical manifestations and otologic complications in adults experimentally infected with Influenza A (H1N1) virus.” J. Infectious Dis. 1998 May, 177 (5): 1260-5. • Mandell: Principles and Practice of Infectious Disease, 5th ed. 2000;1824-42. • Harrison’s: Principles of Internal Medicine, 15th ed. 2001;1125-29. • http://www.cdc.gov/flu • Call, S.A., Vollenweider, M.A et al. “Does This Patient Have Influenza?” JAMA. 2005; 293:987-997. www.stanford.edu/ group/virus/uda/