2009 Pandemic Influenza: What Did We Learn and Where Do We ... · 2009 H1N1 Influenza Basics in...
Transcript of 2009 Pandemic Influenza: What Did We Learn and Where Do We ... · 2009 H1N1 Influenza Basics in...
5/5/2010
1
2009 Pandemic Influenza:What Did We Learn and
Where Do We Go from Here?
C H R I S N E L S O N , M . D .
A S S O C I A T E P R O F E S S O R O F P E D I A T R I C S
D E P A R T M E N T O F P E D I A T R I C S
D I V I S I O N O F I N F E C T I O U S D I S E A S E S
U N I V E R S I T Y O F K E N T U C K Y C H A N D L E R M E D I C A L C E N T E R
L E X I N G T O N , K E N T U C K Y
Overview
2009 H1N1 Influenza Basics in Review
Characteristics of the 2009-2010 Pandemic
How Prepared Were We?
What Lessons Did We Learn? What Lessons Did We Learn?
Present State of the Pandemic
What Does the Future Hold?
2009 H1N1 Influenza Basics in Review
2009 Novel H1N1 Influenza Virus
Genetically distinct from previous Seasonal Influenza A H1N1 virus
Direct descendant of H1N1 Influenza virus that caused major human pandemics from 1918-1953
Had not circulated in the human population since 1957 Had not circulated in the human population since 1957 (52 years) but re-emerged from Mexican swine in March of 2009 to cause human pandemic
Contains human (20%), avian (30%) and swine (50%) influenza RNA gene segments, combined through genetic reassortment
Image Courtesy NewScientist.comImage Courtesy NewScientist.com
Antigenic Drift and Shift
Antigenic drift Minor point mutations in the genes coding for
hemagglutinin and neuraminidase glycoproteins that make the new, mutated circulating influenza viruses just different enough to your immune system from previously different enough to your immune system from previously encountered influenza strains that you can get sick with these “new” influenza strains.
Primary reason for annual vaccination
5/5/2010
2
Antigenic Drift and Shift
Antigenic Shift Abrupt, major changes to influenza A glycoproteins
occur, producing a novel new influenza A virus subtype that has not previously circulated in the human populationpopulation
Occurs through genetic “Reassortment”
Responsible for majorMixing of human and animal influenza A genes (usually occurs in swine- so-called “mixing vessels”) to create a new influenza A virus (called a reassortant virus)
epidemics and pandemics
Reassortment
Reassortment in Action
New New EnglEngl J Med.J Med. 2009;361:2252009;361:225--229229
WHO Pandemic Phases
Characteristics of the 2009-2010 Pandemic
5/5/2010
3
2009 H1N1 Influenza Pandemic Timeline
Pandemic Timeline Events February 24, 2009: a 6 month-old girl from northern Mexico develops a
Flu-like illness (later designated as “patient zero”) Early March, 2009: a respiratory illness sickens 60% of the town of La
Gloria, Veracruz, Mexico March 17, 2009: first confirmed case of H1N1 swine origin Influenza in
Mexicoh fi fi d f i i i i fl i March 28, 2009: first confirmed case of H1N1 swine origin influenza in a 9
year-old girl in Imperial County, California April 26, 2009: US declares Public Health Emergency April 27, 2009: WHO issues statement declaring Phase 4 Pandemic June 11, 2009: WHO declares Phase 6 Pandemic July 1, 2009: H1N1 cases in every state in US October 24, 2009: President Obama declares US State of National
Emergency Halloween, 2009: US Pandemic reaches its peak April, 2010: Resurgence in Southeast US and Hawaii, but only local, not
widespread activity; our much-anticipated “spring peak”
5/5/2010
4
Pandemic Flu 1918-1919 US Map at the Height of the 2009 Pandemic
2009 H1N1 Pandemic Flu Facts
Hospitalization rates for ages 5-17 were 2-5x that usually seen for seasonal Flu
Peak Flu activity the week of October 24-31 was highest ever recorded by CDCCDC estimates from Apr 2009 Feb 2010 CDC estimates from Apr 2009-Feb 2010: 59 million cases (Nl. 15-60 million annually) 265,000 hospitalizations (Nl. 200,000 ann.) 12,000 deaths (Nl. 36,000 ann.) 90% patients dying from H1N1 Flu had underlying medical
conditions (asthma, COPD, DM, Chronic Cardiovascular disease, morbid obesity, neurocognitive/neuromuscular disorders, pregnancy)
2009 H1N1 CDC Estimate
U.S. Cases
0-17 years ~19,000,000
18-64 years ~34,000,000
65 years and older ~6,000,000
U.S. Cases Total ~59,000,000 (Nl. Avg.15-60 million)
U.S. Hospitalizations
0-17 years ~85,000
18-64 years ~154 00018 64 years 154,000
65 years and older ~26,000
U.S. Hospitalizations Total ~265,000 (Nl. Avg. 200,000)
U.S. Deaths
0-17 years ~1250
18-64 years ~9200
65 years and older ~1550
U.S. Deaths Total ~12,000 (Nl. Avg. 36,000)
Source: CDC; data for period April 2009 through February 2010
5/5/2010
5
H1N1 Influenza Mortality at UK
Age Gender Underlying Diagnoses DOD
53 F Lymphoma 8/30/09
63 F COPD 10/6/09
48 M HIV/AIDS 10/8/09
41 M Multiple Myeloma 10/8/09
72 F COPD; History of Breast Cancer 10/23/09
47 F Lung Cancer 10/25/09
36 M Hepatitis B, Liver Failure, CHF 11/2/09
74 F Cirrhosis; History of CVA 11/2/09
57 M Lymphoma, s/p Bone Marrow Transplant
11/3/09
17 M Congenital Heart Disease 11/20/09
How Prepared Were We?
How Prepared Were We?
US Dept of Health and Human Services Report, 2009 Disaster preparedness of individual hospitals has improved
significantly throughout the country since the start of the HPP
The emergence of Healthcare Coalitions is creating a foundation for U.S. healthcare preparedness
Healthcare planning for catastrophic emergencies is in early stages; progress will require additional assistance and direction at the national level
Surge capacity and capability goals, assessment of training, and analysis of performance during actual events and realistic exercises are the most useful indicators for measuring preparedness
Hospitals Rising to the Challenge: The First Five Years of the U.S. Hospital Preparedness Program and Priorities Going Forward http://www.upmc-biosecurity.org/website/resources/publications/2009/pdf/2009-04-16-hppreport.pdf
How Prepared Were We?
US Dept of Health and Human Services Report, 2010
US hospitals should participate in a healthcare coalition that prepares and responds collaboratively to common medical disasters and Catastrophic Health Events (CHE)
Neighboring healthcare coalitions should establish links to Neighboring healthcare coalitions should establish links to enable regional exchange of health-care information and assets during a CHE
Triage sites should be established outside of hospitals and healthcare responders should be trained in CHE triage
The Next Challenge in Healthcare Preparedness: Catastrophic Health Events, January 2010http://www.upmc-biosecurity.org/website/resources/publications/2010/pdf/2010-01-29-prepreport.pdf
How Prepared Were We?
US Dept of Health and Human Services Report, 2010
The resources of the private sector should be harnessed to develop a patient transportation system for a CHE
Crisis standards of care should be expanded and promoted within and across stateswithin and across states
A national plan for various healthcare sector roles, responsibilities and actions in response to a CHE should be developed
The Next Challenge in Healthcare Preparedness: Catastrophic Health Events, January 2010http://www.upmc-biosecurity.org/website/resources/publications/2010/pdf/2010-01-29-prepreport.pdf
How Prepared Were We?
2005, 2007 Surveys of Hospital Infectious Disease Emergency Preparedness (all 50 U.S. States surveyed)
Most respondents had: a surge/influx of infectious patients plan and had
participated in disaster drills
24/7 IPAC support and an infection preventionist on their disaster committee
a prioritization plan for vaccine and antiviral medications
Rebmann T, et al. Am J Infect Control 2007;35:25-32, Rebmann T, et al. Am J Infect Control 2009;37:1-8
5/5/2010
6
How Prepared Were We?
• Many were stockpiling N95 respirators antiviral medications
• Less than 25% of facilities had: stockpiled ventilators, surgical masks, or patient linens; those that
did had <7 days worth of supplies
Cross-trained their staff to deal with absenteeismCross trained their staff to deal with absenteeism
Convened their ethics committee to discuss preparedness issues
Developed policies/procedures for altered standards of care during disasters
Rebmann T, et al. Am J Infect Control 2007;35:25-32, Rebmann T, et al. Am J Infect Control 2009;37:1-8
What Lessons Did We Learn?
Lessons Learned
2009 H1N1 Influenza Epidemiology is different than seasonal Influenza Predilection for young age (5-17 yrs) group and pregnant women 25% develop GI symptoms Many infected individuals experienced mild, non-debilitating symptoms which
facilitated spread in schools and the workplace Increased mortality in morbidly obese individuals
I fl i d ti d di t ib ti th d d t b Influenza vaccine production and distribution methods need to be modernized
Key supply stockpiles are critical (antivirals, masks, etc.) It could have been much, much worse
Low virulence virus, did not mutate like 1918 ancestor (yet) This was not Avian Influenza
Important to be prepared, have a detailed Pandemic Plan Stay current with and respond to rapidly changing situations and be
able to rapidly disseminate information throughout organizations
Lessons Learned
We need enhanced national and international surveillance in both human and animal populations Would allow for early detection and possible anticipation of next
pandemic strain to emerge
Could facilitate vaccine development earlier in the evolution of a new d ipandemic
Lesson Re-Learned: Both seasonal and pandemic influenza viruses are capable of causing tremendous morbidity and mortality
Public trust in and acceptance of influenza vaccine continues to be an issue
Edwards, KM. Infectious Diseases in Children, March 2010
Influenza-Like Illness (ILI)
Rapid Onset of Temperature >100.0 F Cough Sore throat
In the absence of a known cause other than influenza
Additional symptoms associated with seasonal and Novel H1N1 Influenza that should be assessed in patients presenting with ILI: Fatigue, body aches, chills, congested/runny nose,
headache 24% of patients with H1N1 Flu will also have
vomiting and/or diarrhea
2009 H1N1 Influenza Symptom Progression
UK physician, previously healthy, only underlying condition: exercise-induced asthma
Day #1: 11/4/09, 4 pm; Scratchy throat Day #2: 11/5/09; awoke with congestion, mild sore
throat, but spent a productive day at work Day #3: 11/6/09 awoke with congestion a bit worse, decided to stay
home 10 am: rapid onset of cough, diffuse myalgias and chills 11:30 am: IMG Clinic for assessment (Temp 99.4°F),
PCR testing and oseltamivir Rx for presumed influenza Progressed to severe myalgias, fatigue, grossly
productive cough, TMax 100.2°F that evening
5/5/2010
7
2009 H1N1 Influenza Symptom Progression
UK Physician Day #4: 11/7/09; Influenza A RT-PCR resulted positive.
Worsening of all symptoms with addition of nausea, repeated fever spikes, TMax 101.2°F
Day #5: 11/8/09; continuation of sx’s, TMax 100.4°F, slight easing of sx’s by evening except productive cough
Day #6: 11/9/09; almost complete resolution of myalgias, but continued grossly productive cough, afebrile all day
Day #7: 11/10/09; chills, fever 100.4°F at 3 am, but no further daytime fevers and myalgias completely resolved; cough less productive
Day #8: 11/11/09; afebrile >28 hours, occasional scant productive cough, returned to work
Lessons Learned
Flu happens even when you are very careful You can be infected with this particular Flu virus
for hours to days before developing classic influenza symptoms, unwittingly spreading it to others; this is unlike most seasonal Fluot e s; t s s u e ost seaso a u
Who said Novel H1N1 is a milder illness? Nausea with this Flu virus makes oral hydration
and oral antipyresis and analgesia a real challenge; with vomiting and diarrhea, maintenance of hydration would be impossible
Flu is awful- GET YOUR VACCINE!
Present State of the Pandemic
Present Situation
Remain at WHO Pandemic Phase 6 99.4% typed influenza isolates submitted to CDC this season
are 2009 Pandemic H1N1 What happened to “seasonal” Flu?
H3N2 likely gone Previous seasonal H1N1 replaced by new Pandemic H1N1 strain
2009 Pandemic H1N1 virus has still not significantly mutated 2009 Pandemic H1N1 virus has still not significantly mutated (yet)
2009 Pandemic H1N1 antiviral susceptibility has remained very stable: 99.8% susceptible to oseltamivir 100% susceptible to zanamivir
Although delivery was late, the new H1N1 vaccine was highly immunogenic and safe
March-April 2010 has brought resurgent Flu activity in Southeast US and Hawaii but only local activity is being seen
Present US Situation
What Does the Future Hold?
5/5/2010
8
The Future
Development of antiviral resistance
Advances in treatment IV peramivir
Lung bypass Lung bypass
Advances in Prevention New Flu vaccine technology
Mandated Flu vaccination for healthcare workers
The Future: Antiviral Agents for Influenza
Adamantanes/M2 Ion Channel Inhibitors Amantadine (Symadine, Symmetrel) Rimantadine (Flumadine)
Neuraminidase (sialidase) Inhibitors Oseltamivir (Tamiflu) Oseltamivir (Tamiflu) Zanamivir (Relenza)
RNA Polymerase Inhibitors Ribavirin (Copegus, Rebetol, Ribasphere, Vilona and
Virazole) Taribavirin (Viramidine)
Peramivir IV; emergency use authorization (EUA) by FDA 10/25/09
Peramivir
Only intravenous influenza antiviral medication available Peramivir is authorized for the following patients who are
admitted to a hospital: Adult patients for whom therapy with an IV agent is clinically
appropriate, based upon one or more of the following: patient not responding to either oral or inhaled antiviral therapy, or drug delivery by a route other than IV (e.g. enteral oseltamivir or
inhaled zanamivir) is not expected to be dependable or is not feasible, or
the clinician judges IV therapy is appropriate due to other circumstances.
Pediatric patients for whom an IV agent is clinically appropriate because: patient not responding to either oral or inhaled antiviral therapy, or drug delivery by a route other than IV (e.g. enteral oseltamivir or
inhaled zanamivir) is not expected to be dependable or is not feasible
Artificial Lung
Artificial Lung
Double Lumen catheter
Portable pump system
CO2/O2 gas exchanger
Right Int. Jugular placement into SVC/IVCp /
Advantages over ECMO Decreased cost
Increased portability
Longer-term use capability
Fewer skilled healthcare staff required
Still Investigational
ACIP on Flu Vaccination 2010-2011
2010-2011 Flu Vaccine Components
2009-2010 Seasonal Vaccine 2010-2011 Vaccine
A/Brisbane/59/2007 (H1N1) A/California/7/2009 (H1N1)*
A/Brisbane/10/2007 (H3N2) A/Perth/16/2009 (H3N2)
*2009 H1N1 Pandemic Influenza virus
Universal Influenza Vaccination Recommended 50% of adults aged 19-49 have indication for annual vaccination
Vaccinating the entire population would simplify current complicated recommendations that create confusion
Public education on vaccine efficacy and safety needed
B/Brisbane/60/2008 (Victoria lineage) Same strain retained
CDC/ACIP Home Page: http://www.cdc.gov/vaccines/recs/ACIP/default.htm
5/5/2010
9
The Future: New Influenza Vaccines
Present vaccine production technology 1931: Flu virus first grown in fertilized chicken’s eggs
1940’s: US Military developed first influenza vaccines using egg inoculation method
Production technology in the US using inoculation of chicken Production technology in the US using inoculation of chicken eggs has not changed significantly since the 1940’s
The Future: New Influenza Vaccines
Present egg-based vaccine production technology: Egg shell punctured
Influenza virus injected into allantoic fluid surrounding embryoy
Puncture site re-sealed
Egg incubated to allow infection to progress
Eggs harvested, progeny virus purified and inactivated, vaccination produced
The Future: New Influenza Vaccines
Alternative strategies for Influenza vaccine development: Live cell culture-based methodology
First described mid-1990’s
Live seed virus inoculated into live tissue culture
Virus attaches to, invades and multiplies in cells
Cells harvested, virus purified and inactivated
Vaccine formulated and distributed
e.g. Optaflu from Novartis
The Future: New Influenza Vaccines
Live cell culture-based methodology advantages over embryonated chicken egg production method: Cleaner production process
Eliminates reliance on procuring chicken eggs
Production can be scaled up much more quickly to respond to a pandemic (egg: 3-6 months vs. cell-based: 1-2 months)
Avoids egg allergy issue presently a problem with egg-based vaccines
Five vaccine companies have been awarded large HHS contracts in 2006 to develop cell culture vaccines (Baxter, GlaxoSmith-Kline, Novartis, Sanofi-Pasteur) One has terminated its contract, another placed its efforts on hold
One company (Sanofi Pasteur) will stick with egg-based method methodology (presently makes most US Flu vaccine)
The Future: New Influenza Vaccines
Hemagglutinin synthesis using baculovirus to produce an influenza virus-like particle (VLP) Genes (hemagglutinin (HA), or combinations of hemagglutinin,
neuraminidase, and M1 matrix protein) are extracted from influenza virus and inserted into a baculovirus
Caterpillar (Fall Army Worm) cells are infected with Caterpillar (Fall Army Worm) cells are infected with baculovirus and begin producing hemagglutinin proteins
Proteins are extracted and formulated in phosphate buffered saline without preservatives or adjuvants
Phase I and II trials have demonstrated safety and efficacy in healthy adults, the elderly and non-Hodgkin’s lymphoma pts.
FluBlok™ (Protein Sciences Corporation, Meriden, CT)
Lakey DL. J Infect Dis 1996 174(4):838-41Treanor JJ J Infect Dis 2006;193(9):1223-8Safdar A. J Infect Dis 2006;194(10):1394-7
Bright, RA, et al. Vaccine 2007;25(19):3871-8
The Future: New Influenza Vaccines
Recently-discovered alternative viral proteins targeted by the human immune system 10 human antibiodies have been identified that target the stalk
(rather than the head) portion of the hemagglutinin (HA) protein
Studies in mice infected with lethal doses of influenza given 3 of these 10 antibodies neutralized 80 100% of infectionsthese 10 antibodies neutralized 80-100% of infections
Influenza HA stalk proteins are highly conserved among all influenza viruses (human and animal) and are very genetically stable
These results could lead the way to: Influenza vaccines that do not need to be reformulated each year (no need
to consider antigenic shift or drift)
Production of monoclonal HA stalk protein neutralizing antibodies that could be used to treat patients with serious and life-threatening influenza infections
Sui J. Nat Struct Mol Biol. 2009;16(3):265-73
5/5/2010
10
The Future: New Influenza Vaccines
Intradermal delivery of influenza vaccine Developed in an attempt to improve immunogenicity of influenza
vaccination, particularly in older adults in whom immune response to vaccine often is attenuated
May be more effective than intramuscular delivery due to stimulation f d d iti ll hi h i li d ti ti llof dendritic cells, which are specialized antigen presenting cells
Clinical trial of adults >60 years of age demonstrated higher antibody titers, seroprotection rates and seroconversion rates compared with those receiving intramuscular Flu vaccine
Higher rates of local injection site reactions, particularly redness but not pain, were seen with intradermal vaccination vs. intramuscular vaccination
Example: Intanza®/ID-flu® (Sanofi-Aventis)Holland D, et al. J Infect Dis 2008;198(5):650-8
The Future: New Influenza Vaccines
Dosage alterations of influenza vaccine High (60 mcg HA) vs. standard (15 mcg HA) dose vaccine
study in adults >65 years of age: Improved seroconversion rates
Increased mean HA inhibition titers
Increased mild-moderate local reactions with high dose vaccine
“Split” (half) dose vaccination Produces equivalent protective HA titers (>1:40) when compared
to full-dose vaccine in adults who have previously been vaccinated
Equal or higher titers among women 18-49 years of age vs. men who receive full dose vaccine
Unacceptably low titers in some subjects 50-64 years of age
Falsey AR. J Infect Dis 2009;200(2):172-80Keitel WA. J Infect Dis. 2008;198(7):1016-8Engler RJ. Arch Intern Med. 2008;168(22):2405-14
The Future: New Influenza Vaccines
Adjuvanted vaccines Adjuvant
Definition: A vaccine adjuvant is a substance that is added to the vaccine to increase the body's immune response to the vaccine; an adjuvant often allows for p ; jsmaller amounts of the inactivated virus or bacterial components to be used in the production of a vaccine
Rationale: A major problem with the development of an effective vaccine against avian influenza (H5, in particular) has been poor immunogenicity in humans; this has rekindled interest in adjuvant use in influenza vaccines
Sources: CDC, UpToDate
The Future: New Influenza Vaccines
Adjuvanted Vaccines Examples:
Aluminum salts, such as aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate are the only adjuvants currently licensed for use in the US
US-licensed vaccines containing aluminum salt adjuvants: US licensed vaccines containing aluminum salt adjuvants: hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTaP, Tdap) Haemophilus influenzae type b (Hib), human papillomavirus (HPV) and pneumococcus
Oil (squalene)-in-water emulsions such as MF59® (Novartis)
Seasonal influenza/MF59® (Fluad®) H5N1, MF59-adjuvanted vaccine, egg-derived
(AFLUNOV®/FOCETRIA®)
H5N1, MF59-adjuvanted vaccine, cell culture-derived (OPTAFLU®
platform)
The Future: Mandated Influenza Vaccination
Study-proven benefits of vaccinating HCW: Decreased absenteeism
Decreased mortality among patients (nursing home setting)
Financial savings to healthcare institutions
Vaccination rates in US healthcare workers: 40-40%4 4
Organizations supporting mandatory Flu vaccination Infectious Diseases Society of America (IDSA)
National Patient Safety Foundation (NPSF)
US Department of Defense mandates flu vaccine for: All military healthcare providers
All civilian healthcare personnel who provide direct patient care in department of defense treatment facilities
The Future: Mandated Influenza Vaccination
Healthcare Institutions mandating annual Flu vaccine: Cook Count Health and Hospitals System (Chicago)
Barnes-Jewish Healthcare, St. Louis, Hospital Corporation of America (HCA), many others*( ), y
How it is done: Gentle Approach- use of declination form to opt out, decliners
must wear surgical masks for duration of Flu season and are terminated if they do not comply with mask usage
Get-Tough Approach- opt out only for religious reasons, allergy to egg or previous vaccine, Guillan-Barre; refusal to accept vaccination results in termination of employment
*Immunization Action Coalition’s Honor Roll: http://www.immunize.org/laws/influenzahcw.asp
5/5/2010
11
The Future: Final Thoughts…
Enhanced Influenza Surveillance in Human and Animal Populations
Expedited vaccine approval by FDA, production by pharmaceutical companies and delivery by the
tgovernment
Improved antiviral stockpiles and rapid delivery
Public education
Avian influenza: the specter on the horizon
Helpful Resources
UK Healthcare Pandemic Influenza Primer, Assessment Algorithm, FAQ’s: http://www.uky.edu/EM/swineflu.htm (click “For Medical Professionals”)
CDC Seasonal Influenza Website: http://www.cdc.gov/flu/ CDC 2009 Novel H1N1 Influenza Website:
http://www.cdc.gov/h1n1flu/ World Health Organization (WHO) Website: g ( )
http://www.who.int/csr/disease/swineflu/en/index.html Kentucky Department of Public Health Site:
http://healthalerts.ky.gov/ Flu.Gov: http://www.flu.gov/ Helpful Pandemic Planning Tools: CDC Pandemic Influenza Planning Checklist for Hospitals:
http://www.flu.gov/professional/hospital/hospitalchecklist.pdf CDC Pandemic Influenza Planning Checklist for Medical Offices:
http://www.pandemicflu.gov/professional/pdf/medofficesclinics.pdf CDC’s 10 Action Steps for Medical Offices and Outpatient Facilities:
http://www.cdc.gov/h1n1flu/10steps.htm