New WHO Phases: Issues Related to the Pandemic of a Novel A(H1N1) Virus
New WHO Phases: Issues Related to the Pandemic of a Novel A(H1N1) Virus Arnold S. Monto University of Michigan School of Public Health Ann Arbor, Michigan USA
Proposed 2008 Phases 1 - 3 Phases 5-6 Sustained H-2-H transmission Time Predominantly animal infections; Limited infections of people Geographic spread 5 - 6 4 Post Peak Post Pandemic
First Detection of Community Level Outbreaks Will Require Several Urgent Decisions Sustained H-2-H transmission Consider rapid containment Consider Phase Change to 4 Consider switch to pandemic vaccine Other
WHO Pandemic Phase Descriptions Phase Estimated probability of pandemic Description Main actions in affected countries Main actions in not-yet-affected countries Phase 4 Medium to high Human-to-human transmission of an animal or human-animal influenza reassortant virus able to sustain community-level outbreaks has been verified Rapid containment Readiness for pandemic response Phase 5 High to certain The same identified virus has caused sustained community level outbreaks in at least two countries in one WHO region Pandemic response: Each country to implement actions as called for in their national plans. Readiness for imminent response Phase 6 Pandemic in progress In addition to the criteria defined in Phase 5, the same virus has caused sustained community level outbreaks in at least one other country in another WHO region.
Community Strategies by Pandemic Flu Severity (1) Pandemic Severity Index Interventions by Setting 1 2 and 3 4 and 5 Home Voluntary isolation of ill at home (adults and children); combine with use of antiviral treatment as available and indicated Recommend Recommend Recommend Voluntary quarantine of household members in homes with ill persons (adults and children); consider combining with antiviral prophylaxis if effective, feasible, and quantities sufficient Generally not recommended Consider Recommend <ul><li>School </li></ul><ul><li>Child social distancing </li></ul><ul><li>dismissal of students from schools and school-based activities, and closure of child care programs </li></ul>Generally not recommended Consider: ≤ 4 weeks Recommend: ≤ 12 weeks <ul><li>reduce out-of-school contacts and community mixing </li></ul>Generally not recommended Consider: ≤ 4 weeks Recommend: ≤ 12 weeks
Community Strategies by Pandemic Flu Severity (2) Pandemic Severity Index Interventions by Setting 1 2 and 3 4 and 5 <ul><li>Workplace/Community </li></ul><ul><li>Adult social distancing </li></ul><ul><li>decrease number of social contacts (e.g., encourage teleconferences, alternatives to face-to-face meetings) </li></ul>Generally not recommended Consider Recommend <ul><li>increase distance between persons (e.g., reduce density in public transit, workplace) </li></ul>Generally not recommended Consider Recommend <ul><li>modify, postpone, or cancel selected public gatherings to promote social distance (e.g., stadium events, theater performances) </li></ul>Generally not recommended Consider Recommend <ul><li>modify workplace schedules and practices (e.g., telework, staggered shifts) </li></ul>Generally not recommended Consider Recommend
Progress of Asian Influenza Pandemic, February, 1957-January, 1958 Langmuir AD,Am Rev Resp Dis. 1961; 83:3.
Status of Asian Influenza in the United States and Major Routes of Spread through July 22, 1957 Military Civilian Confirmed Sporadic Cases Confirmed Outbreaks Suspect Outbreaks Arrows indicate probable spread from Foci of infection. Langmuir AD,Am Rev Resp Dis. 1961; 83:5.
Influenza Attack Rates by Age in Tangipahoa Parish, Louisiana – August, 1957 Langmuir AD,Am Rev Resp Dis. 1961; 83:5.
Weekly Incidence of Respiratory Illnesses (all ages) Per 100,000, July, 1957-June 1958 Langmuir AD,Am Rev Resp Dis. 1961; 83:8. 1957 1958 6,000 5,000 4,000 3,000 2,000 1,000 0 Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun
Clinical Influenza Attack Rates (Kansas City, 1957) and Annual Mortality Rate Pneumonia and Influenza (U.S. 1957) - 300 - 250 - 200 - 150 - 100 - 50 0 Mortality Rate per 100,000 Modified from Monto AS. Am J Med . 1987; 82:20-5.
Comparison of Amantadine and Rimantadine Structures NH 2 NH 2 Amantadine Rimantadine
Protective Efficacy of M2 Inhibitors Against Laboratory-Confirmed Clinical Influenza Monto AS, et al . JAMA. 1979; 241:1003-7. Dolin R, et al. N Engl J Med . 1982; 307:580-4.
Cases of Influenza-like Illnesses and Resistant Viruses Isolated From Case-Patients at Nursing Home B, by Living Unit Mast et al. Am J Epidemiol. 1991; 134:988-97. January February Val to Ala, position 27 Ala to Val, position 30 Ser to Asn, position 31 Demonstrated Amino Acid Changes
Trend of Adamantane-Resistant H3N2 Viruses, 1994-2005 China Japan US Hong Kong South Korea Overall 90 80 70 60 50 40 30 20 10 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Season of Isolate Collection Resistance Frequency (%) Bright RA, et al . Lancet . 2005;366:1175-81.
Efficacy of Seasonal Prophylaxis of Influenza with Zanamivir (4 weeks) and Oseltamivir (6 weeks) Monto AS, et al. JAMA . 1999; 282:31-5. Hayden FG, et al. NEJM . 1999; 341-1336-43.
Efficacy of Oseltamivir in Preventing Lower Respiratory Tract Complications (LRTCs) Leading to Antibiotic Use Percent Reduction Overall n=2413 55%* 52% 61% 55% 54% Otherwise Healthy n=1644 67% 60% 77% 63% 71% At Risk n=769 34% † 34% 30% 34% 25% LRTCs Leading to Antibiotic Use All LRTC Bronchitis Pneumonia Influenza A Influenza B * Comparison of oseltamivir vs placebo, P<.001. † Comparison of oseltamivir vs placebo, P=.02. Kaiser L, et al. Arch Intern Med . 2003; 163:1667-72.
Influenza Prevention in Household Studies with NAI’s * Prophylaxis is given ≥ 5 years. † Excludes contacts positive for influenza prior to prophylaxis. Antiviral (Study) Season (Virus) Reduction in Secondary Cases % Resistance Transmission No Treatment of Index Zanamivir (Monto et al, 2002) Oseltamivir (Welliver et al, 2001) 2000-01 (A/H3N2, B) 1998-99 (A/H3N2, B) 81% 89% — — With Treatment of Index Zanamivir* (Hayden et al, 2000) † Oseltamivir (Hayden et al, 2004) 1998-99 (A/H3N2, A/H1N1) 2000-01 (A/H3N2, B) 79% 85% No No
Ferret Transmission Model DONOR DONOR DONOR DONOR RECIPIENTS RECIPIENTS RECIPIENTS RECIPIENTS <ul><li>Four donors and 12 recipients each for wt and mt </li></ul><ul><li>Groups of four housed together in cage </li></ul>
Comparisons of Infectivity and Transmissibility of WT and MUT Pairs for NA Genotypes Isolated During Treatment Studies Herlocher, et al. 2002. Antiviral Research , 54: 99-111. Herlocher, et al. 2004. J Infect Dis , 190:1627-30. Wild type [WT] and Mutant [MUT] pairs isolated from pre- and follow-up specimens from the same subject Infectious dose Donor infection status Recipient infection status Sequence confirmation of WT or MUT NA genotype A/Sydney/5/97-like (H3N2) R292 - WT 2.3 TCID50/0.5 ml 4 of 4 12 of 12 WT *R292K – MUT Same 2 of 4 3* of 6 *Reversion to WT A/Wuhan/359/95-like (H3N2) E119 - WT 1.0 x 10 -6 Dilution of stock 4 of 4 11 or 11 WT E119V - MUT 1.0 x 10 -6 Dilution of stock 4 of 4 11 or 11 MUT A/New Calendonia (H1N1) H274 – WT 1.5 x 10 -6 Dilution of stock 4 of 4 12 or 12 WT H274Y – MUT 1.5 x 10 -5 Dilution of stock 0 of 4 @ day 7 0 of 12 @ day 7 1.5 x 10 -3 Dilution of stock 4 of 4 12 of 12 MUT
Antiviral Resistance in USA (Week 14, 2008-2009) CDC, Apr 11, 2009 Isolates tested (N) Resistant Viruses, n (%) Isolates tested (N) Resistant Viruses, n (%) Oseltamivir Zanamivir Adamantanes Influenza A (H1N1) 748 743 (99.3%) 0 729 3 (0.4%) Influenza A (H3N2) 112 0 0 108 108 (100%) Influenza B 227 0 0 N/A* N/A*
Antivirals and Health Care Workers, USA <ul><li>A fluid situation. When antivirals were in limited supply, early treatment only. </li></ul><ul><li>More recently, prophylaxis considered. </li></ul><ul><li>Where do drugs come from? </li></ul><ul><li>Are you dealing with imported cases, or local transmission? </li></ul><ul><li>If latter, greater likelihood of acquiring infection outside health care setting. </li></ul>