This document outlines the lectures in a course on global health and emerging infections. The first three lectures discuss existing threats like malaria, tuberculosis, and leprosy. The third lecture focuses on new threats posed by emerging infections and examines case studies of SARS, pandemic flu, and a 2011 E. coli outbreak in Germany. The fourth lecture discusses disease eradication efforts for smallpox and current efforts for polio and guinea worm. The fifth lecture provides an overview of infectious disease diagnosis in clinical microbiology laboratories.

1. Global Health and Emerging
Infections 3: New Foes
Professor Mark Pallen
Bio303

2. Global Health and Emerging Infections
1. 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.

3. 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

4. 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

6. SARS: First pandemic ofnew 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

7. SARS: history of the epidemic
 15 Feb: 65-yr-old
professorof 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/photostrea

8. 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

9. SARS: history of the epidemic
 Carlo Urbani, Italian doctor and WHO
physician in Hanoi notifies WHO of
explosive nosocomial outbreakin
Hanoi
 Urbani's descriptionof casesoutside
Guangdong alerts healthauthorities
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

10. 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

11. 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

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

13. SARS-CoV
 Coronavirus  S protein binds host receptor
 Previously thought to be benign angiotensin-converting enzyme
group; 15% of all cases of 2 (ACE2)
common cold
 Mutations in S protein reveal
 large, enveloped, +ssRNA virus evolution of virus as epidemic
 Irregular shape, club-shaped progresses
spikes  Adaptive changes show
 Genome encodes increase affinity for human
 replicase (Orf1ab) ACE2
 structural proteins: spike [S],  Neutral changes reveal
envelope [E], membrane [M], phylogeny of HK outbreak
nucleocapsid [N]

14. 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

15. Transmission of SARS-CoV
 Human-to-human transmission
 direct or indirect contact of the mucosae with
infectiousrespiratory droplets or fomites
 Higher environmentalstability 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

16. 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

17. 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

18. 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

19. SARS epidemic: the aftermath
 SARS epidemic involved 37  rapid global dissemination
countries around the world depended on
 8,096 cases and 774 deaths  capacity for human-to-human
 Case-fatality rate ~10% transmission
 50% for >65 yrs old  the lackof awareness in hospital
infection control
 Causes of epidemic
 internationalair travel
 rapid economic growth inChina
primed demand for exotic food  unparalleled dramatic impact on
animals such as civets health care systems,economies,
and societies of affected countries
 overcrowdedcages with no
biosecurity in wet markets
 ability of virus to jump from
animals to human

20. SARS next time: are we ready?
 SARS could return if conditions  gaps still exist in
are fit for the  understanding transmissibility and
introduction,mutation, pathogenesis in humans
amplification, and transmission  screening tests
of this dangerousvirus  foolproof infection control
 animal reservoir persists in  effective antivirals and
civets, bats etc immunomodulatory agents
 safe effective vaccine
 BUT next time, we will have
 identifying immediate animal host
wherewithal to diagnose and
that transmitted the virus to caged
respond civets
 And treat and vaccinate?
 4,000 publications available
online

21. Swine Flu 2009: the first open-source epidemic?

22. Haemolytic-uraemic syndrome
 Shiga-toxin-producing E. coli (STEC)
 bloody diarrhoea; damage to kidneys and brain
 anaemia; loss of platelets

23. 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

25. “Calling International Rescue…”
Herr Doktor Holger Rohde
UKE Universitätsklinikum Hamburg-Eppendorf

26. “Calling International Rescue…”

27. UKE Hamburg
BGI-Shenzhen

28. Ion Torrent
Millions of wells reading sequences
Microchip detects release of protons
~3 hour run-time
~£500 cost per run

30. Crowd-sourcing the genome

31. 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

32. Crowd-sourcing the genome

35. 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

36. 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

37. 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?

38. 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

40. 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

41. public health in
the 21st century:
the open source
outbreak
dr. jennifergardy
bc centre for disease control
genome research laboratory

42. new technology

43. new attitudes

44. public health 2.0

45. www.globecampus.ca/blogs/nerd-girl

46. open source outbreak

47. take-home point
technological advances shift in scientists’ attitudes
public health 2.0: rapid & collaborative

48. rewind to march 2009

49. CDC
California
WHO
increased flu activity in
Mexico
pandemic!

50. 5,000 confirmed cases
100-150,000 possible
cases
at June 11, 2009

51. open source outbreak

52. sharing germs,
sharing data

53. CDC
California
WHO
increased flu activity in april 25: 1st genome
Mexico
pandemic!

54. april 26: international wiki
13 people, 8 institutes, 4 countries
http://tree.bio.ed.ac.uk/groups/influenza

55. april 26: origins of the virus calculated

56. april 30: origins data published
5 days from sequence
to open-access paper

57. CDC
California
WHO
increased flu activity in april 25: 1st genome
Mexico
may 6: 69 virus’ RNA
pandemic!

58. virus entered human population late
08/early 09

59. may 5: first major paper submitted
may 11: first major paper published

60. CDC
California
WHO
increased flu activity in april 25: 1st genome
Mexico
may 6: 69 virus’ RNA
june 11: 250+ papers
pandemic!

61. SARS, 2003
day 19
day 0 virus
one viral
isolation
genome
day 19
H1N1, 2009
day 0 virus
isolation
100+ viral genomes
where/when it arose
multiple papers
vaccine seed strain

63. technological advances
shift in scientists’ attitudes

64. genomes = easy, cheap, fast

65. human genome project
(1990)
10 years to draft
3 more to complete
$3 billion
100s of people

66. spring 2009
four weeks
$48,000 worth of
reagents stephen quake, stanford
three-person team bioengineering

67. data = easy, cheap, fast

68. the file-sharing generation
from flickr user amy and cas

70. 85% of
scientists
support
open
Mann et al, Comm. of the ACM 52(3):135. (2009

71. collaboration

73. what about H1N1?
susceptible to antivirals
not drifted from vaccine strain
displaced seasonal influenza
race between the spread of
the virus and the spread
of information

74. what about
the next
bug?

75. genome
surveillance

76. population sampling to pick
up threats before the lab or
clinic

77. months of undiscovered circulation in
people

78. sewage-nomics
from flickr user stuck in
customs

79. embrace new
technologies

80. embrace open access
and collaboration

81. don’t
embrace
anyone with
a fever
and/or cough
from flickr user jess and coli

82. oink! oink!
(thank you)