Symptoms of Distress: Emerging Diseases Mary E. Wilson, MD Harvard Medical School Harvard School of Public Health Human Health and Global Environmental Change 7 February 2007
Outline • Infectious diseases are dynamic • The current global circumstances favor the appearance and spread of new infectious diseases and changes in old ones • Multiple biological and social systems interact in a changing physicochemical environment
West Nile Virus Activity: US
Themes and Examples • Themes – Local perturbations – Global linkages – Receptor populations
• Disease examples – Avian influenza – XDR-TB
The Backdrop • Population – – – – –
Size Density Mobility Location Vulnerability
• Microbial life – Abundant, resilient, diverse, capacity to undergo rapid change
)
400 350
Days to Circumnavigate ( the Globe
5
300
4
250 200
3
150
2
100 50
1
0
0 1850
1900
Year
1950
From: Murphy and Nathanson. Semin. Virol. 5, 87, 1994
2000
(
6
World Population in billions
)
Speed of Global Travel in Relation to World Population Growth
Population Size • Larger than ever (humans and food animals) 6.5 b • Drives need to develop new regions, find sources for food and water – Alter land (clear, irrigate, build roads) – Intrude on new environments
• Promotes raising animals and hunting wild animals for food • Contributes to juxtaposition of animal and human populations
Dhaka, Bangladesh: 17.9 M
Urban and Rural Population in Millions, 1950-2030 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0 (1,000,000) (2,000,000) (3,000,000) (4,000,000) 1950
1960
1970
1980
Urban Developed Rural Developed
1990
2000
2010
Urban Developing Rural Developing
2020
2030
Rio de Janeiro, Brazil
The Global Distribution of Malaria Since 1900
Hay et al. Lancet Infect Dis 2004;4:327-36.
Malaria: Population at Risk in Future • Area of world supporting malaria has declined by half during the past century • Demographic changes have resulted in 2 billion increase in population exposed to malaria risk • Even if regions affected by malaria do not expand, population projections indicate about 400 million births will occur in region by 2010 Hay SI, et al. Lancet ID 2004;4:327-36.
Geographic Latitude and Species Richness • Analysis of human parasitic and infectious disease species and latitude • Found significant negative relationship between latitude and PID species richness • Link between climatic factors and spatial pattern of human pathogens Guenier et al. PLoS Bio 2004;2:740-6.
Global Population Growth, 1750-2100
Haggett, 1995
Mumbai, India
Urban airports (3100 in 220 countries)
Colizza et al. PLoS Med 2007;4:e13.
Source of Pathogens • • • • •
Humans Animals Soil Water Arthropods
Infectious Disease Deaths by Mode of Transmission • • • •
Person-to-person Food/water/soil Insect/vector Directly from animal
WHO 1995
65% 22% 13% 0.3%
Zoonoses • “Diseases or infections which are naturally transmitted between vertebrate animals and humans” (WHO) • Diversity of animal reservoirs – Mammals, including bats – Nonmammals, including birds – Domestic and wildlife species
Microbial Threats: Zoonoses • • • • • • • • •
SARS Avian influenza vCJD (new variant Creutzfeldt-Jakob) HIV/AIDS Nipah virus West Nile virus Hantavirus pulmonary syndrome E. coli O157:H7 Monkeypox
RNA Viruses • Extremely mutable; many mutations introduced during replication • Few or no proof reading mechanisms • Can generate viral diversity • Exist as quasispecies (viruses of slightly different genetic composition) • Variants with any advantage are selected, can amplify • Can also recombine and reassort
Host Range • Number of species that can be infected with an infectious agent – Smallpox: humans only – Influenza: birds, pigs and other mammals as well as humans – Yellow fever: humans, primates, mosquitoes
Sick Chicken (Broiler)
H5N1 in Poultry/Wild Birds Since 2003
Dead Swan: Europe
Culling Chickens: Nigeria
Human Cases H5N1 as of 22 Jan 2007 272 cases, 166 deaths (2.07)
Influenza story starts with birds…..
Natural Hosts: Waterfowl • Wild birds (predominantly waterfowl) are source of all influenza A viruses in other species (reservoir hosts) • All 16 HA and 9 NA are found in birds • Replicate in respiratory and GI tracts • Virus shed in high concentrations in feces – Virus found in lakes and shores – Virus also found in respiratory tract
• Infection is often asymptomatic • Infection is common; many subtypes involved
Influenza in Birds • Most strains of influenza are not pathogenic in water birds • Viruses in wild birds show minimal change over time • After transfer to new type of host (avian or mammalian) undergo rapid evolution • Occasional outbreaks of severe in domestic, other birds
Ducks: Trojan Horse of H5N1 • In 2002, highly pathogenic H5N1 caused disease in ducks • Since then, viruses have reverted to nonpathogenicity in ducks but remain pathogenic to chickens • Can excrete virus for extended time (at least 20 days) Stealth carrier. • Potential to transmit via fecal and respiratory contamination of water Hulse-Post et al. PNAS 2005;102:10682.
Host Range Influenza Viruses • • • • •
Avian species Pigs Horses Cats (also tigers, leopards) Seals, whales – ~20% harbor seals NE US coast died of influenza H7N7 in 1979-1980
• Mink and ferrets • Nonhuman primates • Dogs
Environmental Conditions • Influenza A: survival increases at lower temperatures – Can survive indefinitely in frozen material; 4 days in water at 22oC – Max stability at low humidity
• Seasonal pattern of circulation (H5N1) peaking from October to March (mean temp 20 billion poultry produced/year
Modern Chicken Farms • • • •
May house 100,000 or more chickens Genetically similar Crowded conditions Unlikely to have contact with migratory birds (in contrast to backyard, open range, and hobby flocks)
Pathways for Spread • Birds/poultry – Trade of live birds (legal and illegal) – Trade of bird parts – Migration
• Material contaminated by birds – Shipping containers, crates; trucks – Chicken manure (fertilize fields, fish farms) – Water
• Humans
Global Markets • Raw duck tongues smuggled from China (almost 4 tons confiscated) – 20 kg intercepted in in Rio de Janeiro airport
• Importation of chicken feet from Thailand (labeled as jellyfish). – One importer in CT imported >9000 lbs since March 2004) – Sent to stores CT, GA, KT, MA, MI, MN
• H5N1 isolated from duck meat imported to S. Korea from China
Movement of Live Birds • • • •
Cock fights Bird collectors/pet birds Falconers Sending old birds to rural markets • Release of birds in religious ceremonies
Chicken for Cock Fight
Price: $4000
Hand Luggage: Flight from Thailand to Brussels
Stored in overhead compartment
Crested Hawk-Eagles from Thailand to Brussels Airport
Both infected with highly pathogenic H5N1 avian influenza EID May, 2005
Predicting the Global Spread: Analysis of Data • Analyzed data for 52 individual introduction events • Integrated data – Relatedness of viral isolates – Migratory bird movements – Imports/exports live poultry and wild birds
• Other routes – Unreported/illegal trade – Poultry products, e.g., chicken feces for fertilizer, use in aquaculture Kilpatrick et al. PNAS 2006;103:19368.
Likely Routes of Spread of 52 Introduction Events • Asia – 9/21 introductions poultry – 3/21 migratory birds
• Europe – 20/23 migratory birds
• Africa – 2/8 introductions poultry – 3/8 migratory birds Kilpatrick et al. PNAS 2006;103:19368.
Likely Routes: Western Hemisphere • >4 million migratory birds to US from south • Infected poultry more likely route of introduction into Western Hemisphere • Possible subsequent introduction into mainland US by movement of migratory birds from neighboring countries • Risk of introduction in Americas by poultry substantial • Synergy: trade and wild animal movement Kilpatrick et al. PNAS 2006;103:19368.
Global Aviation Network
(civil traffic, 500 largest airports, 100 countries)
PNAS 2004;101:15125.
Clusters • Common source of infection • Common genetic vulnerability • Person-to-person spread
Estimating Global Mortality from Pandemic Influenza • Countries with high quality vital registry data • Used data 1915-1923 • Compared death rates before, during, and after the pandemic • Calculated excess all-cause mortality Murray et al. Lancet 2006;368:2211-18.
Excess Mortality • Range: 0.2% Denmark - 4.4% India • India (9 provinces): 2.1% in Burma to 7.8% Central Provinces of Berar • US: 0.24% in WI to 1% in Colorado • Mortality concentrated in young adults • Mortality M>F (except 5/9 provinces in India) • Variance: ~50% explained by per-head income Murray et al. Lancet 2006;368:2211-18.
Expected Mortality 2004 • Assume 2004 population size, demography, other characteristics • Median estimated deaths 61 m (51-81) • Most deaths in young adults • 96% of estimated deaths would occur in developing world Murray et al. Lancet 2006;368:2211-18.
DALYs per 1000 Population, 2001
Fig 4. Lopez et al. Lancet 2006;367:1754.
Resistance • General phenomenon • Occurs in all classes of pathogens and also arthropods (to pesticides), rodents (to rodenticides), tumor cells (to chemotherapy) • Among mosquitoes, resistance reported in 125 species – Can often develop w/i few yr – Undergo several generations/yr
Antimicrobials in Environment • Use favors resistance (not just misuse) • Many agents have antimicrobial activity • Activity is far broader than the target pathogen • Activity extends beyond target population (person, partridge, or pear tree)
Antimicrobials • Activity of agents that enter the environment similar whether originally given to person, plant, or animal • Antimicrobial agents have a life span • These agents may have toxic and allergenic properties as well • We know little about impact on microbial ecology and ecosystems
Oseltamivir • Stockpiled by many countries – About 275 million courses
• To be deployed in event of outbreak • Resistance of H5N1 to it has been documented
Oseltamivir • Converted to active NA inhibitor after absorption • 70% excreted renally in active form (oseltamivir carboxylate or OC) • Up to 20% in feces (50% as OC)
Oseltamivir • Resistant to biodegradation • Hydrophilic • Predicted to enter receiving riverwater from sewage treatment works in its active form
Singer AC et al. Environ Health Perspect 2007;115:102-6.
Oseltamivir • Model predicts concentrations of OC (ml/L) capable of inhibiting virus replication in water • Sustained x several weeks • Increased risk for generation of antiviral resistance • Potential genetic exchange with viruses in wild waterfowl Singer AC et al. Environ Health Perspect 2007;115:102-6.
Drug-resistant TB • Many outbreaks in HIV-infected • Mortality 80-90% • Death: median 1-4 months after disease onset MMWR 1991;40:585.
Extensively-drug-resistant TB • • • •
Resistant to INH, and Any fluoroquinolone, and At least 3 injectable 2nd line drugs Untreatable/virtually untreatable
XDR-TB in South Africa • 53 with XDR-TB – Median age 35 yr – 55% no previous rx for TB – 67% had hospital adm w/i 2 yr
• All 44 tested were HIV-positive • 52/53 (98%) died – 70% w/I 30 d of sputum collection
• Isolates genetically similar Lancet 2006;368:1575-80.
XDR-TB, 2000-2004
Shah et al. EID March 2007
XDR-TB • Identified on 6 continents • Convergence with HIV epidemic • Reasons – Improper rx of resistant TB • • • •
Too few drugs Poor quality second line drugs Failure to assure adherence Lack of laboratory support Shah et al. EID March 2007
Final Thoughts • H5N1 ecologically entrenched in Asia • Will probably spread to rest of world • Vast populations of people, birds, other animals in which replication can occur • Probability of recombination events increases with number of hosts infected with 2 influenza A viruses
Key Points • Infectious diseases are dynamic • Influenced by physicochemical environmental, socioeconomic, cultural, political, & demographic factors • Animals are important in origin & spread • Microbes are abundant, diverse, adaptable • Current milieu (population size, density, mobility, location, vulnerability) favors emergence
