ANTIVIRALS: Drugs for Influenza Brent Jensen BSP © www.RxFiles.ca    Jan 2015 AMANTADINE ‐SYMMETREL Dosage by Age & Renal Function 1,2

No recognized renal dysfunction TREATMENT DOSAGE Children 1-9 yrs a 5mg/kg daily or divided BID (total daily dose not to exceed 150mg) Children >10 yrs 200mg daily or divided BID b (if less than 40 kg, give 5mg/kg per day) Adults 64 yrs 200mg daily (or 100mg BID) b (Note: 100mg daily adequate/better tolerated for prophylaxis) Adults 65 yrs 100mg daily

Renal dysfunction: CrCl * in ml/second (ml/min in brackets) Alternate dosing adjustment schedule2

>1.33ml/s (80-99 ml/min) 100mg po daily 100mg Day 1, 100mg/day starting Day 2 1.00-1.32 ml/s (60-79 ml/min) Alternating daily doses of 100mg & 50mg 100mg Day 1, 75mg/day starting Day 2 0.67-0.99 ml/s (40-59 ml/min) 100mg every 2 days 100mg Day 1, 50mg/day starting Day 2 0.50-0.66 ml/s (30-39 ml/min) 100mg twice weekly 0.33-0.49 ml/s (20-29 ml/min) 50mg three times per week

100mg Day 1, 25mg/day starting Day 2

<0.32 ml/s (10-19 ml/min) Alternating weekly doses of 100mg & 50mg

If outbreak continues, repeat 100mg dose every 7 days during the outbreak.

Hemodialysis 200mg every 7 days * Calculation of creatinine clearance (CrCl): CrCl ml/second ={(140-age) x weight (kg)} / {serum creatinine (umol/L) x 50} Female: CrCl = 0.85 x CrCl (male)

a Use in children < 1yr old has not been evaluated b Patients with history of seizures: consider reduction in amantadine dose (<100mg daily) or use alternate neuraminidase inhibitor

Antiviral AGENTS for Influenza 3,4,5 -treatment within ~48-72hr of symptom onset shortens course by ~1 day & relieves symptoms to some extent 8, conflicting data

-treat patients with severe illness or those likely to suffer complications or death due to influenza (also encourage fluids, rest & analgesics) -persons not at higher risk for complications or do not have severe influenza requiring hospitalization generally do not require antiviral meds for treatment or prophylaxis.

M2 INHIBITORS NEURAMINIDASE Inhibitors (NI) –use of NI within 48hr before or <2wk after FluMist less effective vaccine Amantadine SYMMETREL Oseltamivir TAMIFLU

on SPDP, exception Zanamivir RELENZA on SPDP, exception

Influenza coverage Influenza A only {H3N2, H1N1, H1N2} except resistance now high ( H3N2 Resistance 0.4% (1994)12.3%(2004); >70% China & Hong Kong)

Influenza A including H1N1 & Influenza B

Influenza A including H1N1& Influenza B

Route of administration Oral Oral {IV: available via compassionate use basis in USA} Oral Inhalation (<2 % oral bioavailability)

Dosage forms available 100mg capsules; 10mg/ml syrup 30,45,75mg caps; or powder for susp. 6-12mg/mL (susp has 26g sorbitol thus not use if fructose intolerance)

5mg per inhalation via Diskhaler Show & give info to use device properly. Contains lactose.

Approved for prophylaxis c

(A 10 day tx of postexposure prophylaxis with zan- or oselt-amivir results in 8% less incidence of symptomatic influenza.) 8

Currently not for prophylaxis because of resistance {Previously: “approved for - 1yr”}

Yes 13yrs 75mg po daily x 7-14day

CrCl10-30ml/min 75mg every other day or 30mg daily suspension

Kids 1-12yr 15-40kg; 30-60mg daily x 10day

Yes 7yrs d (FDA: Adult & Kids 5yr: 10mg daily x 10-28d) NOT for nebulizer/ventilator mechanical; not for reconstitution

Approved age for treatment 1yr 1yr But CNS AE in kids {<1yr (FDA >2wk) when need tx 3-3.5mg/kg BID} 7 yrs Concern: Diskhaler difficult to use in young kids Dosage for treatment (usually 5 days, but up to 10days maybe if critically ill)

Currently not for prophylaxis or treatment (because resistance has risen to > 99 %) except

if severe H5N1 or resistant/multiple A subtypes may combo tx with NI.

Adult or Kid>40kg: 75-150mg rarely po BID x 5day;Kid:<15kg: 30mg BID; 16-23kg: 45mg BID; 24-40kg: 60mg BID x5day<9mos 3mg/kg BID;≥9-<12mos 3.5mg/kg BID; CPedS max 3.5mg/kg BID NIH/FDA

2 inhalations (10mg) q12h x 5days e {IV: via Special Access Program in Canada at 1-613-941-2108;

or compassionate use USA at 1-877-626-8019}

Adjustment for renal failure YES - see above Table Treat: CrCl 10-30ml/min 75mg daily. PD: 75mg x1, 30mg in 48hrx1. HD: 75mg x1 post HD x2.

NO dose adjustment necessary.

Adverse Events CNS - lightheadedness, insomnia, irritability (less when dose for age & renal fx); GI upset, edema Use in Pregnancy not recommended.WHO

Nausea NNH=28, vomiting NNH=22, insomnia, vertigo & bronchitis, HA NNH=32, rash & liver enzymes. Rare: behaviour changes self-injury

& delirium; psychiatric events NNH=94 esp. in kids

Nasal/throat irritation, headache, GI upset, bronchitis & cough Rare ?: behaviour changes self-injury & delirium esp. in kids

Cost in Sask. for 5days ~$13 (cap); $17 (syrup) ~ $54 ~ $60 Comments/ Precautions

Check with local Medical Health Officer for current local area recommendations before prescribing!!!

Adverse CNS effects related to & progressive with high serum concentrations dosage for age, renal function & seizure history institutional outbreaks: tx 6-8wk80% preventive avian 2004 virus isolates are resistant to amantadine resistance H3N2 esp. in Asia, CDN & USACDC’06

prodrug needs liver activation dose not better nausea~10% +/- vomiting

6%; with food may help concern of resistance in kids & H1N1/H7N9 6 stockpiling: for avian

H5N1 & swine H1N1 flu

(In pregnant women recommend to give for H1N1) DI: probenecid oseltamivir levels, clopidogrel oseltamivir effect.

Compounded suspension is 10 or 15mg/ml strengths

may cause bronchospasm, in people with asthma or COPD avoid or use cautiously with access to a SABA e.g. salbutamol VENTOLIN ? an option in pregnancy due to bioavailability resistance not a great concern yet stockpiling: for avian

H5N1 & swine H1N1 flu

(In pregnant women recommend to give for H1N1) = dose if renal dysfn =non-formulary SK =not covered NIHB =prior NIHB COPD=chronic obstructive pulmonary disease fx=function GBS=GuillainBarre Syndrome SABA=short acting agonist sx=symptoms tx=treat Wks=weeks

c Prophylaxis: Institutional exposure tx at least 2wks & continued for 1 wk after the end of the outbreak; Household post-exposure 60-80% effective tx 7-10-14days may be effective. Infection: tx usually 5 days rarely 10day. (Med Letter Jan/2014) d Zanamivir trials show 80-85% effective at 1/2 of the usual dose. e Zanamivir -Recommended on first day: 2 inhalations stat; repeat after 2 hrs then begin 2 inhalations q12h the next day for 4 days. WHO: http://www.who.int/csr/disease/influenza/en/

Amantadine for prophylaxis &/or therapy within a family, facility or institution is NO longer advised because of viral resistance.7 (NACI), 8 Canada http://www.phac-aspc.gc.ca/fluwatch/ CDC http://www.cdc.gov/flu/about/season/index.htm Peramivir RAPIVAB new NI by the FDA’14 for ≥ 18yrs with sx ≤ 2 days for uncomplicated influenza, 600mg IV x1 over 15-30mins , AE: diarrhea, rash (rare SJS); DI: Flumist.

Watch units for ml/second !!!

Emphasize importance of VACCINATION! (In Canada ~20% get the flu & leads to >4000 deaths/yr) Worldwide ~400,000 deaths/yr

{Esp. for Healthy kids 6-59mos (give 2 full vaccine doses 4 weeks apart for kids <9yr who were previously unvaccinated previous H1N1: not count); People providing regular care to kids <6yr; kids on ASA long-term; if heart, renal, cancer, neuro, diabetes or lung dx; BMI ≥ 40, Aboriginals, nursing home/care facility; elderly 65; pregnant & <2wk post partum; & to protect high-risk people e.g. health care worker, if work with poultry/hog … or anyone if vaccine supply}. Efficacy to prevent is ~70%. Protection begins ~2 weeks post vaccination & persists ~6-8mos ~4mos in elderly or longer. FLUMIST preferred in healthy ages 2-6 yearsNACI’14. Contraindicated: SEVERE egg allergy 1, previous severe rxn but can give normal dose, then rest in 30mins if no rxn , serious acute febrile illness, GBS within 6 weeks post vaccination

Watch ~15-30mins post-vaccination for a reaction. CDN: VAXIGRIP ≥6mos, thimerosal only in 5ml, may contain neomycin. FLUVIRAL ≥6mos, thimerosal 5ml vial. INFLUVAC ≥18yr,thimerosal free, gentamicin. AGRIFLU: for ≥ 6mos, thimerosal free, may contain kana- & neo-mycin. FLUMIST: live attenuated LAIV intranasal 0.1ml each nostril, age 2-6-17-59, $23, CI: pregnant, immunosuppressed, asthmasevere, egg INTANZA: intradermal 0.1ml 18-59yr 9ug;>60yr or immunosuppressed 15ug; ↓antigen, ↑local rx, thimerosal free, neomycin FLUAD: for 65yr, has MF59C.1 adjuvant; 0.5ml IM deltoid; latex & thimerosal free,

may have kan & neomycin. New: quad inactive, extra B strain FLULAVALTETRA, FLUZONE QUAD ≥6mos.Coming soon CDN: FLUMIST QUAD, FLUZONE TIV Usually give 0.5mL for ≥ 6mos IM in deltoid (not Intanza & FluMist) in Oct or Nov but offer thru May. For 2014-2015: vaccine has pandemic 2009 strain A/California/07/2009 (pH1N1), A/Texas/50/2012 (H3N2) & B/

Massachusetts/2/2012 virus & non-adjuvanated. 2013-2014: 3 & 4 + B/Brisbane/60/2008 in USA strain versions.

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Extras: 1) Clinical Decision Rule for Point of Care Testing of Influenza Patients:  fever (2 points), myalgia (2 points), symptoms <48hrs (1 point), chills/sweats (1 point).  0‐2points = 8%; 3 points = 30%; 4‐6 points = 59%.   Rx Files – Drugs for Influenza References 1 Adapted from the National Advisory Committee on Immunization's Statement on Influenza Vaccination for the 2000-2001 Season. Health Protection Branch - Laboratory Centre for Disease Control (Ottawa, Canada), Vol 26 (ACS-2 ), June 1, 2000. NACI: National Advisory Committee on Immunization. Statement on seasonal trivalent inactivated influenza vaccine (TIV) for 2010-2011. CCDR 2010;36(ACS-6):1-49.

www.phac-aspc.gc.ca/publicat/ccdr-rmtc/10vol36/acs-6/index-eng.php (accessed August 30, 2010). NACI: Statement on Seasonal Influenza vaccine for 2011-2012. CCDR Sept 2011 (ACS-5) Vol 37. http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/11vol37/acs-dcc-5/index-eng.php NACI 2011: Recommendations on the use of intradermal trivalent inactivated influenza vaccine (TIV-ID). http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/11vol37/acs-dcc-4/index-eng.php NACI National Advisory Committee on Immunization. Statement on seasonal influenza vaccine for 2012–2013. www.phac-aspc.gc.ca/publicat/ccdr-rmtc/12vol38/acs-dcc-4/index-eng.php .

NACI National Advisory Committee on Immunization (NACI). Statement on seasonal influenza vaccine for 2013-2014. CCDR 2013. http://www.phac-aspc.gc.ca/naci-ccni/index-eng.php NACI: National Advisory Committee on Immunization. Statement on seasonal influenza vaccine for 2014-2015. http://publications.gc.ca/collections/collection_2014/aspc-phac/HP40-114-2014-eng.pdf (accessed August 12, 2014).

Since the 2011-12 influenza season, NACI has recommended that egg-allergic individuals may be vaccinated against influenza using TIV, without a prior influenza vaccine skin test, based on an assessment of risk for a severe

allergic reaction to guide the method of vaccination. (NACI recommendation Grade A)Footnote bb Details of the vaccine delivery protocols are found below. Because of the lack of data, the use of FluMist® in egg-allergic persons is not

recommended at this time. However, ovalbumin concentrations in FluMist® are documented to be very low and a study is currently underway to assess the use of FluMist® in egg-allergic persons. Its use will be re-evaluated when further

data become available. Although ovalbumin content in influenza vaccine manufactured in eggs may vary from year to year, between vaccine products or between lots of the same vaccine,Footnote 6363-Footnote 6565 vaccines marketed in Canada

are approved under the European specification for ovalbumin content, which is currently <1.2 µg/mL, the level associated with low risks of adverse events.Footnote 6666 An egg-allergic individual is considered to be at higher risk for severe

allergic reactions by CSACI if they have had a previous respiratory or cardiovascular reaction or generalized hives when exposed to egg, or have poorly controlled asthma. Two vaccine delivery protocols can be used for egg-allergic

individuals, depending on their level of risk for an allergic reaction.Footnote 6767 Egg-allergic individuals at lower risk for severe allergic reaction can be vaccinated for influenza using a single vaccine dose. The two-step graded protocol is

recommended for individuals who are at higher risk for severe allergic reaction. These protocols are as follows:

Full dose - A single vaccine dose without the use of a graded challenge. Individuals should be observed for 30 minutes following administration for symptom development.

Two-step graded dosing - A two-step graded process, whereby 10% of the dose is administered followed by 30 minutes of observation. If no symptoms develop, or symptoms are self-resolving, administer the remaining 90% with another 30

minute observation period. If sustained or severe reactions arise after the initial dose, the vaccine is withheld and the individual should be re-evaluated for receipt of the influenza vaccine.

***More recent studies suggest that the absolute risk of GBS in the period following seasonal and A(H1N1)pdm09 influenza vaccination is about one excess case per 1 million vaccines

2 McGeer A, Sitar D, Tamblyn S, et al. Use of antiviral prophylaxis in influenza outbreaks in long term care facilities. Can J Infect Dis 2000; 11(4): 187-192. 3 Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ. 2003 Jun 7;326(7401):1235. 4 Stiver G. The treatment of influenza with antiviral drugs. CMAJ. 2003 Jan 7;168(1):49-56. 5 Influenza Prevention 2002-2003. Med Lett Drugs Ther. 2002 Sep 2;44(1138):75-6. 6 Kiso M., Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004; 364: 759-65. (9 of 50 treated kids had resistant gene mutations, but transmissibility unknown)

Physician’s First Watch: Feb/08 A common influenza virus has developed a mutation resistant to oseltamivir (Tamiflu) has been found in U.S., Canada, & 4 European nations, the New York Times reports. A small percentage of influenza A/H1N1 — the predominant flu virus infecting people this season — is affected by the H274Y mutation. Norway appears to be hardest hit, with 75% (12 of 16) of the isolated viruses showing resistance to oseltamivir. In the U.S., Britain, Denmark, and France, roughly 3% to 5% of tested viruses showed resistance (data on Canada were not provided, but reported in Pharmacy Bulletin Board Feb 4/08 at 10%). "We don't know right now if this is a trend on the upswing or just a small blip," the CDC's chief of epidemiology and prevention told the Associated Press. Officials from the U.S. and World Health Organization told the Times they do not currently advise changes in Tamiflu use. In addition, the flu vaccine is still effective against the mutant virus. Dec/08: Clinicians should remain alert for changes in recommendations that might occur as the 2008--09 influenza season progresses. Recommendations regarding the use of antiviral medications might be revised if surveillance data indicate a substantial and widespread increase in the prevalence of oseltamivir-resistant influenza viruses in the United States. In fact, the interim CDC guidance provides advice for clinicians on how to treat patients with influenza antiviral medications this season. Clinicians can use influenza test results and information, if available, about which viruses are circulating, to help decide which antiviral(s) should be used. If H1N1 viruses are circulating in the community, or it’s not clear which viruses are circulating, health care providers are recommended to use an alternative antiviral, zanamivir (Relenza®), or to use combination therapy of oseltamivir and rimantadine. Use of zanamivir or dual therapy with oseltamivir and rimantadine would provide effective treatment against all circulating influenza viruses. In some instances, oseltamivir alone can still be used, such as when influenza B is diagnosed, or H1N1 viruses are not circulating. Dharan NJ, Gubareva LV, Meyer JJ, et al. for the Oseltamivir-Resistance Working Group. Infections With Oseltamivir-Resistant Influenza A(H1N1) Virus in the United States. JAMA. 2009 Mar 2. [Epub ahead of print] Oseltamivir-resistant A(H1N1) viruses circulated widely in the United States during the 2007-2008 influenza season, appeared to be unrelated to oseltamivir use, and appeared to cause illness similar to oseltamivir-susceptible A(H1N1) viruses. Circulation of oseltamivir-resistant A(H1N1) viruses will continue, with a higher prevalence of resistance, during the 2008-2009 season. Van der Vries Erhardl Emergence of a Multidrug-Resistant Pandemic Influenza A (H1N1) Virus. N Engl J Med 2010; 363:1381-1382. 7 Orr P; National Advisory Committee on Immunization. An Advisory Committee Statement (ACS). National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2004-2005 season. Can Commun Dis Rep. 2004 Jun 15;30:1-32. (Canada Communicable Disease Report,Volume 31 • ACS-6,15 June 2005 ,An Advisory Committee Statement (ACS), National Advisory Committee on Immunization (NACI)*† , Statement on Influenza Vaccination, for the 2005-2006 Season, http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/05pdf/acs-dcc3106.pdf )

NACI: National Advisory Committee on Immunization. Statement on seasonal trivalent inactivated influenza vaccine (TIV) for 2010-2011. CCDR 2010;36(ACS-6):1-49. www.phac-aspc.gc.ca/publicat/ccdr-rmtc/10vol36/acs-6/index-eng.php (accessed August 30, 2010).

NACI: Statement on Seasonal Influenza vaccine for 2011-2012. CCDR Sept 2011 (ACS-5) Vol 37. http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/11vol37/acs-dcc-5/index-eng.php

8 Schmidt AC. Antiviral therapy for influenza : a clinical and economic comparative review. Drugs. 2004;64(18):2031-46. Shun-Shin Matthew, Thompson Matthew, Heneghan Carl, et al. Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta- analysis of randomised controlled trials. BMJ 2009;339:b3172, doi: 10.1136/bmj.b3172 (Published 10 August 2009) Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis. 2013 Nov 21. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;4:CD008965. Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence. Jefferson T, Jones M, Doshi P, Spencer EA, et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545. Heneghan CJ, Onakpoya I, Thompson M, et al. Zanamivir for influenza in adults and children: systematic review of clinical study reports. BMJ 2014;348:g2547.

Additional sources: ACIP: Recommended Adult Immunization Schedule: United States, 2013. Advisory Committee on Immunization Practices. Ann Intern Med Jan 2013. Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis. 2010 Aug 15;202(4):563-6. ACOG-American College of Obstetricians and Gynecologists Committee on Obstetric Practice. ACOG Committee Opinion No. 608: Influenza vaccination during pregnancy. Obstet Gynecol. 2014 Sept. Alves Galvão MG, et al. Amantadine and rimantadine for influenza A in children and the elderly. Cochrane Database Syst Rev. 2008;1:CD002745 Our conclusions about effectiveness of both antivirals for the treatment of influenza A in children were limited to a proven benefit of RMT in the abatement of fever on day three of treatment. Due to the small number of available studies we could not reach a definitive conclusion on the safety of AMT or the effectiveness of RMT in preventing influenza in children and the elderly. Alves Galvao MG, Rocha Crispino Santos MA, Alves da Cunha AJ. Amantadine and rimantadine for influenza A in children and the elderly. Cochrane Database Syst Rev. 2012 Jan 18;1:CD002745. AMT is effective in preventing influenza A in children but the NNTB is high (NNTB: 12 (95% CI 9 to 17). RMT probably helps the abatement of fever on day three of treatment, but the quality of the evidence is poor. Due to the small number of available studies, we could not reach a definitive conclusion on the safety of AMT or the effectiveness of RMT in preventing influenza in children and the elderly. American Academy of Pediatrics Committee on Infectious Diseases. Antiviral therapy and prophylaxis for influenza in children. Pediatrics. 2007 Apr;119(4):852-60. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of influenza: recommendations for influenza immunization of children, 2006-2007. Pediatrics. 2007 Apr;119(4):846-51. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of influenza: recommendations for influenza immunization of children, 2008-2009. Pediatrics. 2008 Nov;122(5):1135-41. http://pediatrics.aappublications.org/cgi/reprint/122/5/1135 American Academy of Pediatrics (AAP) Committee on Infectious Diseases, Policy Statement--Recommendations for the Prevention and Treatment of Influenza in Children, 2009-2010. Pediatrics 2009 124: 1216-1226 http://pediatrics.aappublications.org/cgi/reprint/124/4/1216 American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement--recommendations for prevention and control of influenza in children, 2010-2011. Pediatrics 2010 Oct;126(4):816-26. http://aappolicy.aappublications.org/cgi/reprint/pediatrics;126/4/816.pdf American Academy of Pediatrics (AAP). Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2011-2012. Pediatrics. 2011 Oct;128(4):813-25. http://pediatrics.aappublications.org/content/128/4/813.long Anti-infective Review Panel. Anti-infective Guidelines for Community-acquired Infections. Canadian - New-2012. Toronto: MUMS Guideline Clearinghouse. http://www.mumshealth.com/ Antiviral Drugs for Prophylaxis and Treatment of Influenza. Med Lett Drugs Ther. 2005 Novt 21;47(1222):93-5. (Influenza vaccine Oct 9,2006 & also Updated Oct 23,2006 & Oct 22, 2007)

Aoki FY, Allen UD, Stiver HG, et al. The use of antiviral drugs for influenza: Guidance for practitioners 2012/2013. Can J Infect Dis Med Microbiol. 2012 Winter;23(4):e79-92 Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009;0(2009):2009.1535. Bardage C, Persson I, Ortqvist A, et al. Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden. BMJ. 2011 Oct 12;343:d5956. doi: 10.1136/bmj.d5956. Barker CI, Snape MD. Pandemic influenza A H1N1 vaccines and narcolepsy: vaccine safety surveillance in action. Lancet Infect Dis. 2013 Dec 18. Barry M. Anita. A 29-Year-Old Woman With Flu-like Symptoms: Review of Influenza Diagnosis and Treatment. JAMA. 2010;304(6):671-678. Behrman A, Offley W. Should influenza vaccination be mandatory for healthcare workers? BMJ. 2013 Nov 12;347:f6705 Belluz J. Tug of war for antiviral drugs data. BMJ. 2014 Apr 9;348:g2227. Benchimol EI, Hawken S, Kwong JC, Wilson K. Safety and Utilization of Influenza Immunization in Children With Inflammatory Bowel Disease. Pediatrics. 2013 May 6. Beigel JH, Farrar J, Han AM, et al.; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005 Sep 29;353(13):1374-85. Bhat N, Wright JG, Broder KR, et al. Influenza-Associated Deaths among Children in the United States, 2003-2004. N Engl J Med. 2005 Dec 15;353(24):2559-2567. RESULTS: One hundred fifty-three influenza-associated deaths among children were reported by 40 state health departments Blanton L, Peacock G, Cox C, et al. Neurologic disorders among pediatric deaths associated with the 2009 pandemic influenza. Pediatrics. 2012 Sep;130(3):390-6. Blyth CC, Jacoby P, Effler PV, et al; on behalf of the WAIVE Study Team. Effectiveness of Trivalent Flu Vaccine in Healthy Young Children. Pediatrics. 2014 Apr 21. Bodewes R, Fraaij PL, Kreijtz JH, et al. Annual influenza vaccination affects the development of heterosubtypic immunity. Vaccine. 2012 Dec 7;30(51):7407-10. Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet. 2005

Oct 1;366(9492):1175-81. Epub 2005 Sep 22. FINDINGS: More than 7000 influenza A field isolates were screened for specific aminoacid substitutions in the M2 gene known to confer drug resistance. During the decade of surveillance a significant increase in drug resistance was noted, from 0.4% in 1994-1995 to 12.3% in 2003-2004. This increase in the proportion of resistant viruses was weighted heavily by those obtained from Asia with 61% of resistant viruses isolated since 2003 being from people in Asia. INTERPRETATION: Our data raise concerns about the appropriate use of adamantanes & draw attention to the importance of tracking the emergence and spread of drug-resistant influenza A viruses.

Bright RA, et al. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA. 2006 Feb 22;295(8):891-4. Epub 2006 Feb 2. RESULTS: A total of 209 influenza A(H3N2) viruses isolated from patients in 26 states were screened, of which 193 (92.3%) contained a change at amino acid 31 (serine to asparagine [S31N]) in the M2 gene known to be correlated with adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same mutation. Drug-resistant viruses were distributed across the United States. CONCLUSIONS: The high proportion of influenza A viruses currently circulating in the United States demonstrating adamantane resistance highlights the clinical importance of rapid surveillance for antiviral resistance. Our results indicate that these drugs should not be used for the treatment or prophylaxis of influenza in the United States until susceptibility to adamantanes has been reestablished among circulating influenza A isolates.

Briggs GE, et al Drugs in Pregnancy & Lactation, 9th Ed. Wilkins; Baltimore, MD.2011. Brun-Buisson C, Richard JCM, Mercat A, et al. REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory Distress syndrome. Am J Respir Crit Care Med 2011;183:1200–1206. Burch J, Corbett M, Stock C, et al.. Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis. Lancet Infect Dis. 2009 Sep;9(9):537-45. Epub 2009 Aug 7. Burks AW, Jones SM, Wood RA, et al. Consortium of Food Allergy Research (CoFAR). Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012 Jul 19;367(3):233-43. Campitelli MA, Inoue M, Calzavara AJ, et al. Low Rates of Influenza Immunization in Young Children Under Ontario's Universal Influenza Immunization Program. Pediatrics. 2012 May 14. Campos MA, Alazemi S, Zhang G, et al. Influenza Vaccination in Subjects With Alpha-1 Antitrypsin Deficiency. Chest. 2007 Oct 1; [Epub ahead of print] Subjects with AATD in the United States receive adequate influenza vaccination regardless of age. However, we did not observe a significant impact of the vaccination on disease exacerbations and other respiratory outcomes during the 2003-2004 influenza season.

Canadian Society of Allergy and Clinical Immunology ADMINISTRATION OF H1N1 AND SEASONAL INFLUENZA VACCINE TO EGG ALLERGIC INDIVIDUALS http://www.csaci.ca/include/files/CSACI_H1N1_Statement.pdf Canetta SE, Bao Y, Co MD, et al. Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring. Am J Psychiatry. 2014 Jan 31. Cates CJ, Jefferson TO, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD000364. Uncertainty remains about the degree of protection vaccination affords against asthma exacerbations that are related to influenza infection. Evidence from recently published trials indicates that there is no significant increase in asthma exacerbations immediately after vaccination (at least with inactivated influenza vaccination). There is concern regarding possible increased wheezing and hospital admissions in infants given live intranasal vaccination. CDC Jan 2006 CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season http://www.cdc.gov/flu/han011406.htm (Recommendations against amantadine for influenza in 2005-06. Pharmacist’s Letter/Prescriber’s Letter 2006;22(2):220216) CDC July 2009 Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009 http://www.cdc.gov/mmwr/preview/mmwrhtml/rr58e0724a1.htm ; http://www.cdc.gov/flu/ CDC Centers for Disease Control and Prevention. Updated interim recommendations — HIV-infected adults and adolescents: Considerations for clinicians regarding 2009 H1N1 influenza. Oct 21 , 2009. (http://www.cdc.gov/h1n1flu/guidance_HIV.htm) CDC data strengthen the evidence that the risk for Guillain-Barré syndrome (GBS) associated with the 2009 H1N1 vaccine is similar to the risk seen with seasonal flu vaccines, according to an MMWR report. The CDC's analysis of data from October 2009 through March 2010 found that the incidence of GBS was 1.92 per 100,000 person-years among vaccinated individuals and 1.21 per 100,000 person-years among the unvaccinated. If final data confirm this finding, the CDC says, then this would translate to 0.8 excess GBS cases for every 1 million vaccinations — a rate comparable to that found with seasonal flu vaccination. MMWR article (Free)

CDC Prevention and Control of Influenza with Vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. http://www.cdc.gov/mmwr/pdf/rr/rr59e0729.pdf CDC Preliminary Results: Surveillance for Guillain-Barré Syndrome After Receipt of Influenza A (H1N1) 2009 Monovalent Vaccine — United States, 2009–2010 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm59e0602a1.htm Preliminary results from an analysis in EIP comparing GBS patients hospitalized through March 31, 2010, who did and did not receive 2009 H1N1 vaccination showed an estimated age-adjusted rate ratio of 1.77 (GBS

incidence of 1.92 per 100,000 person-years among vaccinated persons and 1.21 per 100,000 person-years among unvaccinated persons). If end-of-surveillance analysis confirms this finding, this would correspond to 0.8 excess cases of GBS per 1 million vaccinations, similar to that found in seasonal influenza vaccines.[2,3]

No other federal system to date has detected a statistically significant association between GBS and 2009 H1N1 vaccination. Surveillance and further analyses are ongoing. The 2009 H1N1 vaccine safety profile is similar to that for seasonal influenza vaccines, which have an excellent safety record. Vaccination remains the

most effective method to prevent serious illness and death from 2009 H1N1 influenza infection; illness from the 2009 H1N1 influenza virus has been associated with a hospitalization rate of 222 per 1 million and a death rate of 9.7 per 1 million population.

CDC Aug/10 Estimates of Deaths Associated with Seasonal Influenza --- United States, 1976—2007 http://www.cdc.gov/mmwr/pdf/wk/mm5933.pdf

CDC: Interim Guidance on the Use of Influenza Antiviral Agents During the 2010-2011 Influenza Season Nov 2010. http://www.cdc.gov/f lu/professionals/antivirals/guidance/ CDC: Antiviral Agents for Treatment and Chemoprophylaxis of Influenza Recommendations of the Advisory Committee on Immunization Practices (ACIP) Recommendations

and Reports January 21, 2011 / 60(RR01);1-24 http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm?s_cid=rr6001a1_x CDC: Update: Influenza Activity — United States, 2010–11 Season, and Composition of the 2011–12 Influenza Vaccine http://www.cdc.gov/mmwr/pdf/wk/mm6021.pdf CDC Sep/11 Maternal and Infant Outcomes Among Severely Ill Pregnant and Postpartum Women with 2009 Pandemic Influenza A (H1N1) --- United States, April 2009— August 2010 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6035a2.htm CDC: Centers for Disease Control and Prevention (CDC). Influenza vaccination coverage among pregnant women - 29 States and New York City, 2009-10 season. MMWR Morb Mortal Wkly Rep. 2012 Feb 24;61(7):113-8. CDC: Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) — United States, 2012–13 Influenza Season. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6132a3.htm CDC: Centers for Disease Control and Prevention (CDC). Influenza vaccination coverage among health-care personnel - 2011-12 influenza season, United States. MMWR Morb Mortal Wkly Rep. 2012 Sep 28;61:753-7. Chartrand C, Leeflang MM, Minion J, et al. Accuracy of Rapid Influenza Diagnostic Tests: A Meta-analysis. Ann Intern Med. 2012 Feb 27. Chen XY, Wu TX, Liu GJ, et al. Chinese medicinal herbs for influenza. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD004559. The present evidence is too weak to support or reject the use of Chinese medicinal herbs for preventing and treating influenza.

Chen Mark I. C.; Lee Vernon J. M.; Lim Wei-Yen; et al. 2009 Influenza A(H1N1) Seroconversion Rates and Risk Factors Among Distinct Adult Cohorts in Singapore. JAMA. 2010;303(14):1383-1391. Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet. 2013 Apr 25. Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian infl uenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 2013; 381: 1916–25. Chen H, Yuan H, et al. Clinical and epidemiological characteristics of a fatal case of avian infl uenza A H10N8 virus infection: a descriptive study. Lancet 2014; online Feb 5. Chen Q, Griffin MR, et al. Influenza Vaccine Prevents Medically Attended Influenza-Associated Acute Respiratory Illness in Adults Aged ≥50 Years. J Infect Dis. 2014 Oct 21. Chertow DS, Memoli MJ. Bacterial coinfection in influenza: a grand rounds review. JAMA. 2013 Jan 16;309(3):275-82. Chung, Erica Y., Huang, Lin, Schneider, Lynda. Safety of Influenza Vaccine Administration in Egg-Allergic Patients. Pediatrics 2010 125: e1024-e1030. Ciszewski A, Bilinska ZT, Brydak LB, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J. 2008 Jun;29(11):1350-8. Epub 2008 Jan 10. In optimally treated CAD patients influenza vaccination improves the clinical course of CAD and reduces the frequency of coronary ischaemic events. Large-scale studies are warranted to evaluate the effect of influenza vaccination on cardiovascular mortality.

Coffin SE, Leckerman K, Keren R, et al. Oseltamivir shortens hospital stays of critically ill children hospitalized with seasonal influenza: a retrospective cohort study. Pediatr Infect Dis J. 2011 Nov;30(11):962-6. Cohen D. Complications: tracking down the data on oseltamivir. BMJ 2009;339:b5387. Cohen Steven A., Chui Kenneth K.H., Naumova Elena N. Influenza Vaccination in Young Children Reduces Influenza-Associated Hospitalizations in Older Adults, 2002–2006. Journal of the American Geriatrics Society. Article first published online: 28 JAN 2011. DOI: 10.1111/j.1532-5415.2010.03271.x. Cohen D. Oseltamivir: another case of regulatory failure?. BMJ: British Medical Journal. 348. 2014. Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2012-2013. Pediatrics. 2012 Sep 10. Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2013-2014. Pediatrics. 2013 Sep 2. Corti D, Voss J, Gamblin SJ, et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 2011;333:850-6. Cowling BJ, Chan KH, et al. Facemasks and hand hygiene to prevent influenza transmission in households: a cluster randomized trial. Ann Intern Med. 2009 Oct 6;151(7):437-46. Cowling, BJ., Chan, KH, Fang, VJ. et al; Comparative Epidemiology of Pandemic and Seasonal Influenza A in Households N Engl J Med 2010 362: 2175-2184. Cowling BJ, Jin L, Lau EHY, et al. Comparative epidemiology of human infections with avian infl uenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confi rmed cases. Lancet 2013; online June 24. Crowe SR, Merrill JT, Vista ES, Dedeke AB, et al. Influenza vaccination responses in human systemic lupus erythematosus: impact of clinical and demographic features. Arthritis Rheum. 2011 May 19. doi: 10.1002/art.30388. Dalziel SR, Thompson JM, Macias CG, et al; Pediatric Emergency Research Networks (PERN) H1N1 working group. Predictors of severe H1N1 infection in children presenting within Pediatric Emergency Research Networks (PERN): retrospective case-control study. BMJ. 2013 Aug 12;347:f4836. Darvishian M, Bijlsma MJ, Hak E, van den Heuvel ER. Seasonal influenza vaccine effectiveness among the community-dwelling elderly: a metaanalysis of test-negative design case-control studies. Lancet Infect Dis 2014; online Nov 6. Dawood FS et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009 May 7.

Dawood Fatimah S., Kamimoto Laurie, D'Mello Tiffany A., et al. and the Emerging Infections Program Network. Children With Asthma Hospitalized With Seasonal or Pandemic Influenza, 2003–2009. Pediatrics 2011; 128:1 e27-e32; ahead of print June 6, 2011 Dawood FS, Iuliano DA, Reed C, et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis 2012; published online June 26. ( Respiratory deaths: ~ 201,200; Cardiovascular deaths: ~ 83,300) de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005 Dec 22;353(25):2667-72. Demicheli V, Jefferson T, Al-Ansary LA, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2014 Mar 13;3:CD001269. Des Roches A, Paradis L, Gagnon R, et al; on behalf of the PCIRN (Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network). Egg-allergic patients can be safely vaccinated against influenza. J Allergy Clin Immunol. 2012 Sep 26. De Wals P, Deceuninck G, Toth E, et al. Risk of Guillain-Barré syndrome following H1N1 influenza 3 vaccination in Quebec. JAMA. 2012;308(2):175- 181. (GBS cases attributable to vaccine was 2 per 1 million doses.) Diaz E, Rodriguez A, Martin-Loeches I, Lorente L, del Mar MM, Pozo JC, et al. Impact of obesity in patients infected with 2009 influenza A(H1N1). Chest. 2011 Feb;139(2):382-6. DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014 Aug 14;371(7):635-45. Dieleman J, Romio S, Johansen K, et al. Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe. BMJ 2011;343:d3908. Diggle L, et al. Effect of needle size on immunogenicity and reactogenicity of vaccines in infants: randomised controlled trial. BMJ. 2006 Sep 16;333(7568):571. Epub 2006 Aug 4. Long (25 mm) needles for infant immunisations can significantly reduce vaccine reactogenicity at each dose while achieving comparable immunogenicity to that of short (16 mm) needles. (InfoPOEMs: Using a 25-mm needle to inject the combined diptheria, pertussis, tetanus, and Haemophilus influenzae type B vaccine (ACT-Hib DTP) will result in significantly fewer injection site reactions and those that occur will be of less severe. The World Health organization recommends use of a 25-mm needle, although most physicians in the United States use the shorter 16-mm needle. (LOE = 1b) )

Dominguez-Cherit Guillermo; Lapinsky Stephen E.; Macias Alejandro E.; et al. Critically Ill Patients With 2009 Influenza A(H1N1) in Mexico. JAMA. 2009;0(2009):2009.1536. Donner B, Niranjan V, Hoffmann G. Safety of oseltamivir in pregnancy: a review of preclinical and clinical data. Drug Saf. 2010 Aug 1;33(8):631-42. Doshi P, Jefferson T, Del Mar C. The imperative to share clinical study reports: recommendations from the tamiflu experience. PLoS Med. 2012 Apr;9(4):e1001201. Doshi P. Influenza: marketing vaccine by marketing disease. BMJ. 2013 May 16;346:f3037. Duffy J, Weintraub E, Vellozzi C, et al; Vaccine Safety Datalink. Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. Neurology. 2014 Nov 11;83(20):1823-30. Dunn AG, Arachi D, Hudgins J, et al. Financial conflicts of interest and conclusions about neuraminidase inhibitors for influenza: an analysis of systematic reviews. Ann Intern Med. 2014 Oct 7;161(7):513-8. Dunning J, Baillie JK, Cao B, et al; on behalf of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Antiviral combinations for severe influenza. Lancet Infect Dis. 2014 Sep 8. Dutkowski R, Smith JR, Davies BE. Safety and pharmacokinetics of oseltamivir at standard and high dosages. Int J Antimicrob Agents. 2010 Feb 26. Earn DJ, He D, Loeb MB, Fonseca K, Lee BE, Dushoff J. Effects of school closure on incidence of pandemic influenza in Alberta, Canada. Ann Intern Med. 2011;156:173-81. Ebell MH, Afonso AM, Gonzales R, et al. Development and validation of a clinical decision rule for the diagnosis of influenza. J Am Board Fam Med. 2012 Jan-Feb;25(1):55-62. Ebell MH, Call M, Shinholser J. Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials. Fam Pract. 2013 Apr;30(2):125-33. Ehrlich HJ, Müller M, Oh HM, et al.; Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team. A clinical trial of a whole-virus H5N1 vaccine derived from cell culture. N Engl J Med. 2008 Jun 12;358(24):2573-84. Elkayam O, et al. The Effect of Infliximab and Timing of Vaccination on the Humoral Response to Influenza Vaccination in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis. Semin Arthritis Rheum. 2009 Feb 24. [Epub ahead of print] Influenza virus vaccine generated good humoral response in RA & AS patients treated with infliximab. Elkin PL, Froehling DA, Wahner-Roedler DL, et al. Comparison of natural language processing biosurveillance methods for identifying influenza from encounter notes. Ann Intern Med. 2012 Jan 3;156(1 Pt 1):11-8. EMA Jul 21// - European regulators have recommended restricting the use of GlaxoSmithKline's pandemic flu vaccine Pandemrix because of a potential risk of narcolepsy in children or adolescents. The European Medicines Agency said on Thursday that Pandemrix should only be used in people under 20 years in the absence of seasonal trivalent influenza vaccines, following its link to very rare cases of narcolepsy in young people. Engler RJ, Nelson MR, Klote MM, et al. Walter Reed Health Care System Influenza Vaccine Consortium. Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. Arch Intern Med. 2008 Dec 8;168(22):2405-14. Antibody responses to intramuscular half-dose TIV in healthy, previously immunized adults were not substantially inferior to the full-dose vaccine, particularly for ages 18 to 49 years. Significantly higher geometric mean titer responses in women were identified for all ages, regardless of dose or influenza strain. Half-dose vaccination may be an effective strategy for healthy adults younger than 50 years in the setting of an influenza vaccine shortage.

Erlewyn-Lajeunesse M, et al. Recommendations for the administration of influenza vaccine in children allergic to egg. BMJ. 2009 Sep 15;339:b3680. doi: 10.1136/bmj.b3680. Eshaghi A, Shalhoub S, Rosenfeld P, et al. Multiple influenza A (H3N2) mutations conferring resistance to neuraminidase inhibitors in a bone marrow transplant recipient. Antimicrob Agents Chemother. 2014 Sep 22. Eurich DT, Marrie TJ, Johnstone J, Majumdar SR. Mortality reduction with influenza vaccine in patients with pneumonia outside "flu" season: pleiotropic benefits or residual

confounding? Am J Respir Crit Care Med. 2008 Sep 1;178(5):527-33. Epub 2008 Jun 12. The 51% reduction in mortality with vaccination initially observed in patients with pneumonia who did not have influenza was most likely a result of confounding. Previous observational studies may have overestimated mortality benefits of influenza vaccination. Farley M, Ryan P, Lynfield R, et al. Emerging Infections Program Network. Children with asthma hospitalized with seasonal or pandemic influenza, 2003-2009. Pediatrics. 2011 Jul;128(1):e27-32. FDA Acts to Protect Public from Fraudulent Avian Flu Therapies Dec/05 http://www.fda.gov/bbs/topics/NEWS/2005/NEW01274.html FDA April /08 GlaxoSmithKline informed healthcare professionals of changes to the WARNINGS AND PRECAUTIONS sections of prescribing information for Relenza regarding information from postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who are receiving neuraminidase inhibitors, including Relenza. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Relenza to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms which can include seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. FDA June/10 notified consumers and healthcare professionals about a potentially harmful product represented as “Generic Tamiflu” sold over the Internet. FDA tests revealed that the fraudulent product does not contain Tamiflu’s active ingredient, oseltamivir, but cloxacillin, an ingredient in the same class of antibiotics as penicillin. Fell D, Platt R, Lanes A, et al. Fetal death and preterm birth associated with maternal influenza vaccination: systematic review. BJOG. 2014 Jul 10. Fineberg HV. Pandemic preparedness and response--lessons from the H1N1 influenza of 2009. N Engl J Med. 2014 Apr 3;370(14):1335-42. Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, Bresee JS, Cox NJ, Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009 Jul 31;58(RR-8):1-52. Flannery AH, Thompson Bastin ML. Oseltamivir Dosing in Critically Ill Patients With Severe Influenza. Ann Pharmacother. 2014 May 9;48(8):1011-1018. Food and Drug Administration Oct/11 (FDA) isadvising health care professionals not to use injector devices to administer influenza vaccines. Freemantle N, Shallcross LJ, Kyte D, et al. Oseltamivir: the real world data. BMJ. 2014 Apr 9;348:g2371. Friedman BC, Goldman RD. Influenza vaccination for children with asthma. Can Fam Physician. 2010 Nov;56(11):1137-9. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis. 2013 Nov 21. Esposito S, Pugni L, Daleno C, et al. Influenza A/H1N1 MF59-Adjuvanted Vaccine in Preterm and Term Children Aged 6 to 23 Months. Pediatrics 2011 0: peds.2010-1920. Gagnon R, Primeau MN, Des Roches A, Lemire C, Kagan R, Carr S, Ouakki M, Benoît M, De Serres G; PHAC-CIHR Influenza Research Network. Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine. J Allergy Clin Immunol. 2010 Aug;126(2):317-23. Alves Galvao MG, Rocha Crispino Santos MA, Alves da Cunha AJ. Amantadine and rimantadine for influenza A in children and the elderly. Cochrane Database Syst Rev. 2014 Nov 21;11:CD002745. The quality of the evidence combined with a lack of knowledge about the safety of amantadine and the limited benefits of rimantadine, do not indicate that amantadine and rimantadine compared to control (placebo or paracetamol) could be useful in preventing, treating and shortening the duration of influenza A in children and the elderly. Gao R, Cao B, Hu Y, et al. Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus. N Engl J Med. 2013 Apr 11. Gao HN, Lu HZ, Cao B, et al. Clinical Findings in 111 Cases of Influenza A (H7N9) Virus Infection. N Engl J Med. 2013 May 22. Garcia-Garcia L, Valdespino-Gómez JL, Lazcano-Ponce E, et al. Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza A/H1N1 2009: case- control study in Mexico City. BMJ. 2009 Oct 6;339:b3928. doi: 10.1136/bmj.b3928. Gelinck LB, van der Bijl AE, Beyer WE, et al. The effect of anti-tumor necrosis factor alpha treatment on the antibody response to influenza vaccination. Ann Rheum Dis. 2007 Oct 26; [Epub ahead of print] The antibody response to influenza vaccination in patients treated with anti-TNF is only modestly impaired. The proportion of patients that achieves a protective titer is not significantly diminished by the use of TNF blocking therapies. Gelinck LB, van den Bemt BJ, Marijt WA, et al. Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible. Vaccine. 2009 Apr 21;27(18):2469-74. Epub 2009 Feb 24. Gilca R, Deceuninck G, De Serres G, et al. Effectiveness of Pandemic H1N1 Vaccine Against Influenza-Related Hospitalization in Children. Pediatrics. 2011Nov;128(5):e1084-91. Gill PJ, Ashdown HF, Wang K, et al. Identification of children at risk of influenza-related complications in primary and ambulatory care: a systematic review and meta-analysis. Lancet Respir Med. 2014 Dec 3. Glezen WP. Clinical practice. Prevention and treatment of seasonal influenza. N Engl J Med. 2008 Dec 11;359(24):2579-85. Godlee F. Open letter to Roche about oseltamivir trial data. BMJ. 2012 Oct 29;345:e7305. Golovyan DM, Mossad SB. Prevention and treatment of influenza in the primary care office. Cleve Clin J Med. 2014 Mar;81(3):189-99. Goossen GM, Kremer LC, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006484. Paediatric oncology patients receiving chemotherapy are able to generate an immune response to the influenza vaccine, but it remains unclear whether this immune response protects them from influenza infection or its complications.

Greer LG, Sheffield JS, Rogers VL, Roberts SW, McIntire DD, Wendel GD Jr. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet Gynecol. 2010 Apr;115(4):711-6. Grohskopf LA, Olsen SJ, Sokolow LZ, et al; Influenza Division, National Center for Immunization and Respiratory Diseases, CDC. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) - United States, 2014-15 Influenza Season. MMWR Morb Mortal Wkly Rep. 2014;63:691-697. Håberg SE, Trogstad L, Gunnes N, et al. Risk of fetal death after pandemic influenza virus infection or vaccination. N Engl J Med. 2013 Jan 24;368(4):333-40. Haffi zulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2B/3 trial. Lancet Infect Dis 2014; online May 20 Hambidge SJ, et al. Vaccine Safety Datalink Team. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. JAMA. 2006 Oct 25;296(16):1990-7. Hambidge SJ et al. the Vaccine Safety Datalink Team. Trivalent Inactivated Influenza Vaccine Is Not Associated With Sickle Cell Crises in Children. Pediatrics. 2011 Dec 12. Han F, Lin L, Warby SC, Faraco J, Li J, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in china. Ann Neurol. 2011 Sep;70(3):410-7. Han F, Lin L, Li J, et al. Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann Neurol. 2012 Nov 9. Hansen C, Desai S, Bredfeldt C, et al. A Large, Population-Based Study of 2009 Pandemic Influenza A Virus Subtype H1N1 Infection Diagnosis During Pregnancy and Outcomes for Mothers and Neonates. J Infect Dis. 2012 Oct;206(8):1260-8. Harper SA, Bradley JS, Englund JA, File TM, et al. Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. (IDSA) Clin Infect Dis 2009 Apr 15;48(8):1003-32. http://www.journals.uchicago.edu/doi/pdf/10.1086/598513 Hatakeyama S, Sugaya N, Ito M, et al. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA. 2007 Apr 4;297(13):1435-42. In 1 (1.4%) of the 74 children who had received oseltamivir, we identified a variant with reduced drug sensitivity possessing a Gly402Ser neuraminidase substitution. We also identified variants with reduced sensitivity carrying an Asp198Asn, Ile222Thr, or Ser250Gly mutation in 7 (1.7%) of the 422 viruses from untreated patients. In this population, influenza B viruses with reduced sensitivity to neuraminidase inhibitors do not arise as frequently as resistant influenza A viruses. However, they appear to be transmitted within communities and families, requiring continued close monitoring.

Havers F, Thaker S, Clippard JR, et al. Use of influenza antiviral agents by ambulatory care clinicians during the 2012–2013 influenza season. Clin Infect Dis 2014. Hayden FG. Antiviral resistance in influenza viruses--implications for management and pandemic response. N Engl J Med. 2006 Feb 23;354(8):785-8. Hayward AC, Harling R, Wetten S, et la. Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomized controlled trial. BMJ. 2006 Dec 1; [Epub ahead of print] Hayward AC, Fragaszy EB, Bermingham A, et al; on behalf of the Flu Watch Group. Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med. 2014 Mar 17. Health Canada Nov/06 (Tamiflu warning) Informing Canadians of international reports of hallucinations and abnormal behaviour, including self harm, in patients taking the antiviral drug Tamiflu.http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2006/2006_116_e.html Heinonen Santtu, Silvennoinen Heli, Lehtinen Pasi, et al. Effectiveness of inactivated influenza vaccine in children aged 9 months to 3 years: an observational cohort study, The Lancet Infectious Diseases, Volume 11, Issue 1, January 2011 Heneghan CJ, Onakpoya I, Thompson M, et al. Zanamivir for influenza in adults and children: systematic review of clinical study reports. BMJ 2014;348:g2547. Hernandez Jaime E., Adiga Raghavendra, Armstrong Robert, et al. and on behalf of the eIND Peramivir Investigators. Clinical Experience in Adults and Children Treated with Intravenous Peramivir for 2009 Influenza A (H1N1) Under an Emergency IND Program in the United States Clin Infect Dis. (2011) 52(6): 695-706 doi:10.1093/cid/cir001 Hessen, Margaret Trexler. In the Clinic: Influenza. Ann Intern Med November 3, 2009 151:ITC5-1; doi:10.1059/0003-4819-151-9-200911030-01011. Hoen AG, Buckeridge DL, Charland KML, et al. Effect of expanded US recommendations for seasonal influenza vaccination: comparison of two pediatric emergency departments in the United States and Canada. CMAJ 2011;183:E1021-8. Holodniy M, Penzak SR, et al. Pharmacokinetics and Tolerability of Oseltamivir (Tamiflu(R)) Combined with Probenecid. Antimicrob Agents Chemother. 2008 Jun 16. [Epub ahead of print] Alternate day dosing of oseltamivir plus four times daily probenecid achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro; and this combination should be studied further. Holvast A, van Assen S, et al. Studies of cell-mediated immune responses to influenza vaccination in systemic lupus erythematosus. Arthritis Rheum. 2009 Aug;60(8):2438-47. Holvast A, et al. Safety & efficacy of influenza vaccination in systemic lupus erythematosus patients with quiescent disease. Ann Rheum Dis. 2006 Jul;65(7):913-8. Epub 2005 Dec1. In addition to a decreased antibody response, cell-mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections.

Hsu J, Santesso N, et al. Antivirals for Treatment of Influenza: A Systematic Review and Meta-analysis of Observational Studies. Ann Intern Med. 2012 Apr 3;156(7):512-24. Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet. 2013 May 29. Hughes RA, et al. No association between immunization and guillain-barre syndrome in the United kingdom, 1992 to 2000. Arch Intern Med. 2006 Jun 26;166(12):1301-4.

Hurst FP, Lee JJ, Jindal RM, et al. Outcomes Associated with Influenza Vaccination in the First Year after Kidney Transplantation. Clin J Am Soc Nephrol. 2011 Apr 28. April 28 Hurt AC, Hardie K, Wilson NJ et al. Community transmission of oseltamivir-resistant A(H1N1)pdm09 influenza. N Engl J Med. 2011 Dec 29;365(26):2541-2. Hurt AC et al. on behalf of the WHO Consultation on Pandemic Influenza A (H1N1) 2009 Virus Resistance to Antivirals. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect Dis. 2011 Dec 16. Infectious Diseases and Immunization Committee, Canadian Paediatric Society. Autistic spectrum disorder: no causal relationship with vaccines. Paediatrics & Child Health 2007;12(5): 393-5.http://www.cps.ca/english/statements/id/pidnote_jun07.htm (accessed 2007 Dec 4). http://www.cps.ca/english/statements/ID/PIDnote_Jun07.pdf Influenza vaccine 2005-2006. Med Lett Drugs Ther. 2005 Oct 24;47(1220):85-7 Influenza Vaccination in Children: Missed Second Doses & Use of Antiviral Drugs for Influenza: Canadian Guidelines. Pharmacist’s Letter Jan 2007. Influenza A/H1N1 MF59 adjuvanted vaccine in pregnant women and adverse perinatal outcomes: multicentre study. BMJ. 2013 Feb 13;346:f990. Ip DK, Liao Q, Wu P, et al. Detection of mild to moderate influenza A/H7N9 infection by China's national sentinel surveillance system for influenza-like illness: case series. BMJ. 2013 Jun 24;346:f3693. Izurieta HS, Haber P, Wise RP, et al. Adverse events reported following live, cold-adapted, intranasal influenza vaccine. JAMA. 2005 Dec 7;294(21):2720-5. Jack A. Tamiflu: “a nice little earner.” BMJ 2014;348:g2524. Jack A. Will Tamiflu recommendations change this winter? BMJ. 2014 Nov 27;349:g6742. Jackson ML, Nelson JC, Weiss NS, et al. Influenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: a population-based, nested case- control study. Lancet. 2008 Aug 2;372(9636):398-405. The effect of influenza vaccination on the risk of pneumonia in elderly people during influenza seasons might be less than previously estimated. Jackson LA, Chen WH, Stapleton JT, et al. Immunogenicity and Safety of Varying Dosages of a Monovalent 2009 H1N1 Influenza Vaccine Given With and Without AS03 Adjuvant System in Healthy Adults and Older Persons. J Infect Dis. 2012 Jul 20. Jain VK, Rivera L, Zaman K, et al. Vaccine (quadrivalent) for prevention of mild and moderate-to-severe influenza in children. N Engl J Med. DOI: 10.1056/NEJMoa1215817. Jain VK, Rivera L, Zaman K, et al. Vaccine for Prevention of Mild and Moderate-to-Severe Influenza in Children. N Engl J Med. 2013 Dec 11. (QIV was efficacious) Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 2009 Jul 28. Pregnant women might be at increased risk for complications from pandemic H1N1 virus infection. These data lend support to the present recommendation to promptly treat pregnant women with H1N1 influenza virus infection with anti-influenza drugs. Jefferson T, Rivetti D, et al. Efficacy & effectiveness of influenza vaccines in elderly people: a systematic review. Lancet. 2005 Oct1;366(9492):1165-74.Epub 2005Sep 22. (InfoPOEMs: Flu shots prevent influenza and influenza-like illness in the elderly. (LOE = 1a-) )

Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, et al. Antivirals for influenza in healthy adults: systematic review.Lancet. 2006 Jan 28;367(9507):303-13. (InfoPOEMs: Antiviral agents are only slightly effective in preventing confirmed influenza or flu-like illness. When given in the first few days of illness, the M2 ion blockers and neuraminidase inhibitors reduce the duration of illness by approximately 1 day. (LOE = 1a)) (Jefferson T, Demet al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2006 Jul 19;3:CD001265.)

Jefferson T, Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review. Lancet. 2005 Feb 26-Mar 4;365(9461):773-80. Jefferson T, Deeks JJ, Demicheli V, et al. Amantadine and rimantadine for preventing and treating influenza A in adults. Cochrane Database Syst Rev. 2004;(3):CD001169. Jefferson T, Foxlee R, Del Mar C, et al. Physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review. BMJ. 2008 Jan 12;336(7635):77-80. Jefferson Tom, Mar Chris Del, et al. Physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review. BMJ 2009;339:b3675, doi: 0.1136/bmj.b3675 (Published 22 September 2009) Jefferson T, et al. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD004879. Influenza vaccines are efficacious in children older than two but little evidence is available for children under two. There was a marked difference between vaccine efficacy and effectiveness. No safety comparisons could be carried out, emphasizing the need for standardisation of methods and presentation of vaccine safety data in future studies. It was surprising to find only one study of inactivated vaccine in children under two years, given current recommendations to vaccinate healthy children from six months old in the USA and Canada. If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required. Jefferson T, Jones M, Doshi P, Del Mar C. Possible harms of oseltamivir—a call for urgent action. Lancet. 2009 Oct 17;374(9698):1312-3. Jefferson Tom, Jones Mark, Doshi Peter, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 2009;339:b5106, doi: 10.1136/bmj.b5106 (Published 8 December 2009) . Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective.

Jefferson T, Di Pietrantonj C, Rivetti A, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2010 Jul 7;7:CD001269. Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission.

Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children - a review of clinical study reports. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965. We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non-comparable due to oseltamivir’s apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.

Jefferson T, Rivetti A, Di Pietrantonj C, et al. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev. 2012 Aug 15;8:CD004879. : Influenza vaccines are efficacious in preventing cases of influenza in children older than two years of age, but little evidence is available for children younger than two years of age. There was a difference between vaccine efficacy and effectiveness, partly due to differing datasets, settings and viral circulation patterns. No safety comparisons could be carried out, emphasising the need for standardisation of methods and presentation of vaccine safety data in future studies. In specific cases, influenza vaccines were associated with serious harms such as narcolepsy and febrile convulsions.

Jefferson T, Doshi P. Multisystem failure: the story of anti-influenza drugs. BMJ 2014;348:g2263. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr

10;4:CD008965. Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence. 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Napolitano LM, Angus DC, Uyeki TM. Critically Ill Patients With Influenza A(H1N1)pdm09 Virus Infection in 2014. JAMA. 2014 Feb 24. Neto HB, Farhat CK, Tregnaghi MW, et al.; for the D153-P504 LAIV Study Group. Efficacy and Safety of 1 and 2 Doses of Live Attenuated Influenza Vaccine in Vaccine-Naive Children. Pediatr Infect Dis J. 2009 May;28(5):365-371. Neuzil KM, et al. Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5-8-year-old children. J Infect Dis. 2006 Oct 15;194(8):1032-9. Epub 2006 Sep 11. Nicoll A, Sprenger M. Low effectiveness undermines promotion of seasonal influenza vaccine. Lancet Infect Dis. 2013 Jan;13(1):7-9. Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med. 2007 Oct 4;357(14):1373-81. During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved. Nicholson KG, Abrams KR, Batham S, et al. Immunogenicity and safety of a two-dose schedule of whole-virion and AS03(A)-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial. Lancet Infect Dis. 2011 Feb;11(2):91-101. Noah MA, Peek GJ, Finney SJ, et al. Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A(H1N1) [published online October 5, 2011]. JAMA. doi:10.1001/jama.2011.1471. Nolan T, Bernstein DI, Block SL, et al. for the LAIV Study Group. Safety and Immunogenicity of Concurrent Administration of Live Attenuated Influenza Vaccine With Measles- Mumps-Rubella and Varicella Vaccines to Infants 12 to 15 Months of Age.Pediatrics. 2008 Mar;121(3):508-516. Concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella vaccine and varicella vaccine provided equivalent immunogenicity, compared with separate administration, and was well tolerated. Nolan T, Roy-Ghanta S, Montellano M, et al. Relative Efficacy of AS03-Adjuvanted Pandemic Influenza A(H1N1) Vaccine in Children: Results of a Controlled, Randomized Efficacy Trial. J Infect Dis. 2014 May 2. Nordin JD, Kharbanda EO, Benitez GV, Nichol et al. Maternal safety of trivalent inactivated influenza vaccine in pregnant women. Obstet Gynecol. 2013 Mar;121(3):519-25. Noti JD, Blachere FM, McMillen CM, Lindsley, et al. High humidity leads to loss of infectious influenza virus from simulated coughs. PLoS One. 2013;8(2):e57485. Osterholm MT, Kelley NS, Sommer A, et al. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2011; online Oct 26.

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Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis. 2007 Oct;7(10):658-66. We conclude that frailty selection bias and use of non-specific endpoints such as all-cause mortality have led cohort studies to greatly exaggerate vaccine benefits. The remaining evidence base is currently insufficient to indicate the magnitude of the mortality benefit, if any, that elderly people derive from the vaccination programme. Simonsen L, Spreeuwenberg P, Lustig R, et al; GLaMOR Collaborating Teams. Global mortality estimates for the 2009 Influenza Pandemic from the GLaMOR project: a modeling study. PLoS Med. 2013 Nov;10(11):e1001558 Simpson CR, Ritchie LD, Robertson C, et al. Effectiveness of H1N1 vaccine for the prevention of pandemic influenza in Scotland: a retrospective observational cohort study. Lancet Infect Dis 2012; published online June 26. Siriwardena AN, Gwini SM, Coupland C. 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Wong KK, Jain S, Blanton L, et al. Influenza-associated pediatric deaths in the United States, 2004-2012. Pediatrics. 2013 Nov;132(5):796-804. Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus, Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z, Hayden FG, et al. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med. 2008 Jan 17;358(3):261-73. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, Clinical Aspects of Pandemic 2009 Influenza A (H1N1) Virus Infection. N Engl J Med 2010 362: 1708-1719. Wu J et al. Safety and effectiveness of a 2009 H1N1 vaccine in Beijing. N Engl J Med 2010 Dec 16; 363:2416. Xiao-Feng Liang, Li Li, Da-Wei Liu, et al. Safety of Influenza A (H1N1) Vaccine in Postmarketing Surveillance in China. February 2, 2011 (10.1056/NEJMoa1008553) Yu H, Cowling BJ, Feng L, et al. Human infection with avian infl uenza A H7N9 virus: an assessment of clinical severity. Lancet 2013; online June 24. Yu Hongjie, Liao Qiaohong, Yuan Yuan, et al. Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China. BMJ 341:doi:10.1136/bmj.c4779 (Published 28 Sept 2010). Yu H, Wu JT, et al. Eff ect of closure of live poultry markets on poultry-to-person transmission of avian infl uenza A H7N9 virus: an ecological study. Lancet 2013; online Oct 31. Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, et al.. Effectiveness of Maternal Influenza Immunization in Mothers and Infants. N Engl J Med. 2008 Sep 17. [Epub ahead of print] Inactivated influenza vaccine reduced proven influenza illness by 63% in infants up to 6 months of age and averted approximately a third of all febrile respiratory illnesses in mothers and young infants. Maternal influenza immunization is a strategy with substantial benefits for both mothers and infants. WEBSITES & Updates: Update: Influenza Activity --- United States, September 28--November 29, 2008 During September 28--November 29, 2008, influenza activity remained low in the United States. Of the few influenza viruses characterized thus far this season, most are antigenically related to the strains included in the 2008--09 influenza vaccine. Oseltamivir-resistant influenza A (H1N1) viruses have been detected, but currently available data are insufficient to predict their prevalence for the 2008--09 season. This report summarizes U.S. influenza activity* since the last update (1) and reviews new influenza vaccine recommendations for the current season. During September 28--November 29, 2008, approximately 150 World Health Organization (WHO) and National Respiratory and Enteric Virus Surveillance System collaborating laboratories in the United States tested 24,657 respiratory specimens for influenza viruses; 365 (1.5%) were positive (Figure 1). Of these, 282 (77.3%) were influenza A viruses, and 83 (22.7%) were influenza B viruses. One hundred twenty-eight (45.4%) of the 282 influenza A viruses were subtyped; 112 (87.5%) of these were influenza A (H1) viruses, and 16 (12.5%) were influenza A (H3) viruses. Influenza-positive tests have been reported from 26 states in eight of the nine surveillance regions since September 28. Enhanced surveillance for oseltamivir-resistant viruses is ongoing at CDC. Alternatives for antiviral treatment in the context of widely circulating oseltamivir-resistant viruses have been suggested. These treatment options, which might include preferential use of zanamivir or therapy with a combination of antivirals for certain patients, have been outlined in the ACIP 2008 influenza recommendations.†† Currently, the neuraminidase inhibitors oseltamivir and zanamivir remain the recommended medications for treatment and chemoprophylaxis of influenza. Clinicians should remain alert for changes in recommendations that might occur as the 2008--09 influenza season progresses. Recommendations regarding the use of antiviral medications might be revised if surveillance data indicate a substantial and widespread increase in the prevalence of oseltamivir-resistant influenza viruses in the United States. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5749a3.htm?s_cid=mm5749a3_e

CDC Flu Update:

http://www.cdc.gov/flu/

http://www.cdc.gov/flu/about/season/index.htm

Public Health Agency of Canada- FluWatch:

http://www.phac-aspc.gc.ca/fluwatch/

Swine Flue Outbreak – 2009 (Mexico & worldwide extension) http://www.who.int/mediacentre/news/statements/2009/h1n1_20090427/en/index.html http://www.cdc.gov/swineflu/