Global Health and Emerging Infections 3: New Foes

Professor Mark Pallen

Bio303

Global Health and Emerging Infections1. The Global Burden of Infection and an Old Enemy, Malaria. In this

lecture I will survey the global burden of infection, including its human and economic costs, and examine the problem of neglected tropical diseases before focusing on one of the most serious infectious threats to humanity: malaria, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection.

2. Two Old Enemies, TB and Leprosy. In this lecture I will focusing on another of the most serious infectious threats to humanity, tuberculosis, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection. I will also discuss a related mycobacterial infection, leprosy and recent progress in its control.

3. New foes. In this lecture I will describe emerging infections, their epidemiology and ecology and the threats that they pose. I will focus on three case studies: SARS, pandemic flu and the German STEC outbreak of May-June 2011

4. Operation Eradication. In this lecture, I will celebrate the global eradication of smallpox, from the campaign's beginnings in Gloucestershire to the last tragic cases here in Birmingham. I will discuss what is required for an infectious disease to be eradicated and summarise progress on disease eradication, focusing on poliomyelitis and guinea worm.

5. Lab Diagnosis of Infectious Disease. Here I will provide an overview of how infections are diagnosed in the clinical microbiology lab, focusing not just on technologies, old and new, but on practical issues and workflows crucial to optimal use of the lab.

Emerging Infectious Diseases (EIDs) diseases caused by newly identified

species/strain e.g. SARS, AIDS, Ebola, Nipah, E. coli O104:H4

new infections resulting from variant of existing organism e.g. pandemic influenza

known infection spreads to new region or population e.g. West Nile virus

re-emerging infections due to drug resistance or breakdowns in public health e.g. tuberculosis, cholera

For a full list see http://www.nature.com.ezproxyd.bham.ac.uk/nature/journal/v451/n7181/extref/nature06536-s1.pdf

Emergence Factors Human demographics and behaviour (e.g. air

travel) Changing human susceptibility (e.g. with

AIDS, cytotoxics) Climate change Economic development and land use Microbial adaptation and change Breakdown of public health measures Abnormal natural occurrences War, bioterrorism

SARS: First pandemic of new millennium Nov 2002

Initial cases in southern China

Chinese authorities slow in reporting problems; PRC later apologises

By Feb 2003 Outbreak in Guangzhou

hospitals involving patients and health care workers.

Cumulative 305 cases (105 in health care workers) & 5 deaths from unknown acute respiratory syndrome

SARS: history of the epidemic 15 Feb: 65-yr-old

professor of nephrology from Guangdong falls unwell

21 Feb: resides at “hotel M”, Metropole Hotel in Kowloon, HK

Infects 17 residents at hotel

22 Feb: admitted to hospital

CC BY-SA 2.0 John Seb http://www.flickr.com/photos/johnseb/164756503/sizes/z/in/photostream/

SARS: history of the epidemic Hotel M contacts travel

to Hanoi, Singapore and Toronto, starting new outbreaks 26 Feb: US businessman

Johnny Chen (hotel M contact) falls ill on flight to Singapore; admitted to hospital in Hanoi, dies

4 Mar: another Hotel M contact starts HK hospital outbreak

5 Mar: another Hotel M contact dies in Toronto, five family members affected

SARS: history of the epidemic Carlo Urbani, Italian doctor and

WHO physician in Hanoi notifies WHO of explosive nosocomial outbreak in Hanoi

Urbani's description of cases

outside Guangdong alerts health

authorities throughout world and accelerates research to identify virus and combat disease, saving 1000s of lives

Urbani dies on March 29, a month after seeing his first case and 18 days after falling ill on a plane to Bangkok

"If I cannot work in such situations, what am I here for - answering e-mails, going to cocktail parties, and pushing paper?" Dr. Carlo Urbani, 2003

SARS: history of the epidemic 12-15 Mar 2003

WHO issues global alert coins name “sudden acute

respiratory syndrome” calls for global collaborative

research effort 21 March

HK Scientists isolate new coronavirus from open lung biopsy; soon confirmed in US and Germany

12 April genome sequence shows this virus

is distinct from all known human pathogens

SARS: history of the epidemic Jun 2003: virus almost identical to

SARS-CoV isolated from palm civets and other game food mammals

5 Jul 2003: Lack of transmission in Taiwan signals end of human-to-human transmission

3 Sep 2003: Lab-acquired SARS-CoV infection in Singapore

Dec 2003/Jan 2004: five cases from new animal-to-human transmission in Guangzhou

17 Dec 2003: Lab-acquired SARS-CoV infection in Taiwan

25 Mar & 17 Apr 2004: Lab-acquired infection in Beijing, with secondary and tertiary spread

16 Sep 2005: SARS-CoV-like virus in horseshoe bats

 

Local transmission in Toronto, Ottawa, San Francisco, Ulan Bator, Manila, Singapore, Taiwan, Hanoi and Hong KongWithin PRC spread to Guangdong, Jilin, Hebei, Hubei, Shaanxi, Jiangsu, Shanxi, Tianjin and Inner Mongolia

SARS-CoV S protein binds host

receptor angiotensin-converting enzyme 2 (ACE2)

Mutations in S protein reveal evolution of virus as epidemic progresses Adaptive changes show

increase affinity for human ACE2

Neutral changes reveal phylogeny of HK outbreak

Coronavirus Previously thought to be

benign group; 15% of all cases of common cold

large, enveloped, +ssRNA virus

Irregular shape, club-shaped spikes

Genome encodes replicase (Orf1ab) structural proteins: spike

[S], envelope [E], membrane [M], nucleocapsid [N]

SARS Case Definition and Clinical Findings Incubation period of SARS 2-14

days Clinical history & observation

flu-like symptoms : fever >38°C, myalgia, lethargy, GI symptoms, cough, sore throat, shortness of breath

≤10 days before onset of symptoms Close contact with

probable/suspected SARS patient OR

Been in area with transmission of SARS

Chest radiography: important role 70-80% patients have abnormal

chest radiographs Now "laboratory-confirmed SARS”

possible

Transmission of SARS-CoV Human-to-human transmission

direct or indirect contact of the mucosae with infectious respiratory droplets or fomites

Higher environmental stability than other human coronaviruses 2-3 days on dry surfaces; 2-4 days in stool

Explosive outbreak affecting 100s in Amoy Garden housing estate in HK due to dried U traps in sewage drains exhaust fans generate aerosols in toilets

aerosols ascend light well connecting different floors

SARS transmitted in commercial aircraft on five flights

Origins of SARS-CoV Highly probable: origination is a cross-species

jump from civets and/or horseshoe bats to humans

Second case was chef with multiple animal contact

Phylogeny from helicase sequences

Controlling SARS Principle: to break the chain of transmission

from infected to healthy person 3-step protocol of disease confinement

Case definition and detection Prompt isolation Contract tracing

Daily health check Voluntary home isolation

Treatment interferon alfacon-1 with steroids protease inhibitors with ribavirin convalescent plasma containing neutralizing

antibody

Epidemic Containment Creation of emergency operating center Institutional support

Efficient quarantine measures 1000s quarantined in HK, Canada, SG, Taiwan Schools closed in HK, SG

Legislation International collaboration—WHO

Travel alerts and restrictions controversially WHO advised only essential visits to

Toronto Airline passengers screened for fever using thermal

imaging scans Coordination for research Agreement of countries on containment protocol

SARS epidemic: the aftermath SARS epidemic involved 37

countries around the world 8,096 cases and 774 deaths

Case-fatality rate ~10% 50% for >65 yrs old

Causes of epidemic rapid economic growth in

China primed demand for exotic food animals such as civets

overcrowded cages with no biosecurity in wet markets

ability of virus to jump from animals to human

rapid global dissemination depended on capacity for human-to-

human transmission the lack of awareness in

hospital infection control international air travel

unparalleled dramatic impact on health care systems,

economies, and societies of affected countries

SARS next time: are we ready? SARS could return if

conditions are fit for the introduction, mutation, amplification, and transmission of this dangerous virus animal reservoir persists

in civets, bats etc BUT next time, we will have

wherewithal to diagnose and respond And treat and vaccinate?

4,000 publications available online

gaps still exist in understanding transmissibility

and pathogenesis in humans screening tests foolproof infection control effective antivirals and

immunomodulatory agents safe effective vaccine identifying immediate animal

host that transmitted the virus to caged civets

Swine Flu 2009: the first open-source epidemic?

Haemolytic-uraemic syndrome Shiga-toxin-producing E. coli (STEC)

bloody diarrhoea; damage to kidneys and brain anaemia; loss of platelets

German E. coli O104:H4 outbreak

May-July 2011 >4000 cases >40 deaths Link to sprouting seeds High risk of haemolytic-

uraemic syndrome Females particularly at

risk

“Calling International Rescue…”

Herr Doktor Holger RohdeUKE Universitätsklinikum Hamburg-Eppendorf

“Calling International Rescue…”

BGI-Shenzhen

UKE Hamburg

Ion Torrent

Millions of wells reading sequencesMicrochip detects release of protons~3 hour run-time~£500 cost per run

Crowd-sourcing the genome

Crowd-sourcing the genome Within 24 hours of its release, the genome is

assembled Within two days, assigned to an existing

lineage Within five days, strain-specific diagnostic test

released Within a week, two-dozen reports on the

biology and evolution of the strain had been filed on an open-source wiki

Crowd-sourcing the genome

Take away messages Pathogens don’t bother with passports!

Not a new strain something similar seen in Germany ten years ago

and in Korea closest genome-sequenced strain was isolated

from Central African Republic in late 1990s German STEC comes from a lineage

circulating in human populations rather than from an animal source

Take away messages

Bacteria evolve quickly Virulence factors in E. coli can jump from one

lineage to another on bacterial viruses Antibiotic resistance seen where no obvious prior

use of antibiotics Infection still presents a threat even in the most

advanced societies

Take away messages Open-source genomics: propitious confluence

of high-throughput genomics crowd-sourced analyses a liberal approach to data release

Social media (e.g. blogging, Twitter) can augment usual channels of academic discourse

But have we broken the mould? appropriate for public heath emergencies… …but not for “ordinary science”?

Cite or site?

Open-source genomics

Genome sequencing brings the advantages of open-endedness (revealing the “unknown

unknowns”), universal applicability ultimate in resolution

Bench-top sequencing platforms now generate data sufficiently quickly and cheaply to have an impact on real-world clinical and epidemiological problems

Addendum: Jennifer Gardy’s slides

http://creativecommons.org/licenses/by-sa/2.0/

Attribution-ShareAlike 2.0 Generic (CC BY-SA 2.0)

http://www.youtube.com/watch?v=LmAugMSJ1-Y

public health in the 21st century: the open source outbreak

dr. jennifer gardybc centre for disease controlgenome research laboratory

new technology

new attitudes

public health 2.0

www.globecampus.ca/blogs/nerd-girl

open source outbreak

take-home point

technological advances shift in scientists’ attitudes

public health 2.0: rapid & collaborative

rewind to march 2009

increased flu activity in Mexico

California

CDC

WHO

pandemic!

5,000 confirmed cases100-150,000 possible cases

at June 11, 2009

open source outbreak

sharing germs,sharing data

increased flu activity in Mexico

California

CDC

WHO

pandemic!

april 25: 1st genome

april 26: international wiki13 people, 8 institutes, 4 countries

http://tree.bio.ed.ac.uk/groups/influenza

april 26: origins of the virus calculated

april 30: origins data published

5 days from sequence to open-access paper

increased flu activity in Mexico

California

CDC

WHO

pandemic!

april 25: 1st genome

may 6: 69 virus’ RNA

virus entered human population late 08/early 09

may 5: first major paper submitted

may 11: first major paper published

increased flu activity in Mexico

California

CDC

WHO

pandemic!

april 25: 1st genome

may 6: 69 virus’ RNA

june 11: 250+ papers

SARS, 2003day 0 virus isolation

day 0 virus isolationH1N1, 2009

day 19 one viral genome

day 19 100+ viral genomeswhere/when it arosemultiple papersvaccine seed strain

how?

technological advances

shift in scientists’ attitudes

genomes = easy, cheap, fast

human genome project (1990)

10 years to draft3 more to complete$3 billion100s of people

spring 2009four weeks

$48,000 worth of reagents

three-person teamstephen quake, stanford bioengineering

data = easy, cheap, fast

from flickr user amy and casey

the file-sharing generation

85% of scientists

support open

accessMann et al, Comm. of the ACM 52(3):135. (2009)

collaboration

what about H1N1?susceptible to antiviralsnot drifted from vaccine straindisplaced seasonal influenza

race between the spread of the virus and the spread of information

what about the next bug?

genome surveillance

population sampling to pick up threats before the lab or clinic

months of undiscovered circulation in people

sewage-nomics

from flickr user stuck in customs

embrace new technologies

embrace open access and collaboration

don’t embrace anyone with a fever and/or cough

from flickr user jess and colin

oink! oink!(thank you)