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Global Health and Emerging Infections 1The Global Burden of Infection and an old foe Malaria
Professor Mark Pallen
Bio303
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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.
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http://www.facebook.com/pages/Bio303-Module/159615697415445
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Infection: the Global Challenge In most developed countries infectious
diseases cause far fewer deaths than non-infectious diseases Worldwide, infectious disease accounts for >15%
of all deaths Even in developed countries new diseases are
emerging e.g. West Nile fever, SARS, German STEC
Effective control of infectious disease remains a challenge
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http://www.who.int/healthinfo/global_burden_disease/en/
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Malaria Complex and deadly mosquito-borne
infectious disease caused by a eukaryotic apicomplexan protists from genus Plasmodium most serious forms caused by P. falciparum P. vivax, P. ovale, P. malariae cause milder, usually
non-fatal disease in humans naturally transmitted by the bite of a female
Anopheles mosquito
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Malaria Leading cause of morbidity and mortality
world-wide, especially in pregnant women and children
>40% of world population, 3.3 billion people at risk in 109 countries
~250m cases worldwide in 2008 ~1m deaths in children (≥80% in tropical Africa)
Economic burden highest in Africa ≥ US$12 bn per year in direct losses (illness,
treatment, premature death) much more in lost economic growth
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Malaria in the Headlines"It was the day after my birthday when the symptoms first started. I put it down to that I'd been drinking vodka the night before, because I'm not a regular drinker. I put it down to just a big hangover. It got gradually worse and worse." "I was exhausted and having flushes, goose bumps one minute – blue lips, blue fingertips, blue toes – to then being boiling hot. My skin was wet. I couldn't breathe properly.” “I had no liver function, no kidney function, I was swollen with the fluid, I had no oxygen in my blood, I literally had 24 hours to get fluid out of my body, otherwise my insides were going to pack in. You know how sometimes you feel ill and say, 'I feel like I'm dying'? Well, I actually felt like I was dying. I asked the nurse outright – was I going to die? She said, 'There's a possibility.' "
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http://en.wikipedia.org/wiki/File:Plasmodium_lifecycle_PHIL_3405_lores.jpg
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Life Cycle in Mosquito Primary host and transmission
vector is female Anopheles young mosquitoes bite humans
and ingest gametocytes in blood meal gametocytes differentiate into male
or female gametes gametes fuse in gut into ookinete penetrates gut lining to produce
oocyst in gut wall oocyst ruptures, releases
sporozoites that migrate to salivary glands
sporozoites injected into human bloodstream with saliva when mosquito feeds
http://en.wikipedia.org/wiki/File:Malaria.jpg
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http://upload.wikimedia.org/wikipedia/commons/7/7c/MalariacycleBig.jpg
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Life cycle in Humans: Exoerythrocytic Phase sporozoites enter bloodstream within 30 mins infect hepatocytes in liver multiply asexually and asymptomatically for
6–15 days differentiate into thousands of merozoites rupture hepatocytes and escape into blood
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Life cycle in humans: erythrocytic phase merozoites infect
erythrocytes then multiple rounds of
asexual reproduction (ring forms, trophozoites, schizonts, merozoites)
cell lysis and reinfection (hence cyclical fever)
some merozoites differentiate into male and female gametocytes
http://en.wikipedia.org/wiki/File:IEcycle.PNG
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species-specific features P. vivax and P. ovale
hypnozoites remain dormant in liver for months-years, then reactivate and produce merozoites
P. falciparum adhesins on erythrocyte surface stick to walls of
small vessels responsible for haemorrhage and infarction in
placental and cerebral malaria
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Malaria and History co-evolved with anthropoid lineages in Africa
controversies as to source of human infection carried by “out of Africa” migration to Old World
periodic fevers recorded throughout history China in 2700 BCE; 2nd C BCE describe Qinghao
plant (Artemisia annua) as remedy Hippocrates in the 5th C BCE
carried to New World by explorers, missionaries, slaves Jesuits bring back Peruvian Cinchona bark (source
of quinine) historically associated with miasmas rising
from marshes malaria=“bad air”
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Malaria and History 1880: parasites first seen in blood
in by French army surgeon, Alphonse Laveran
awarded 1907 Nobel Prize mosquito as vector suspected by
Laveran and by Patrick Manson
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Malaria and History 20 August 1897, Secunderabad,
India Ronald Ross, an Indian army surgeon, spies oocysts of P. falciparum in stomach tissue of mosquito artificially fed on malaria patient, Hussain Khan
By July 1898, Ross has confirmed mosquito link with bird malaria, revealing parasite entire life cycle including presence in mosquito's salivary glands
Awarded 1902 Nobel Prize
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Malaria and History
"This day relenting GodHath placed within my
handA wondrous thing; and God
Be praised. At his command,
Seeking his secret deeds
With tears and toiling breath,
I find thy cunning seeds,O million-murdering Death.
I know this little thing
A myriad men will save,O Death, where is thy
sting?Thy victory, O Grave?"
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Malaria and History 1898: Grassi, Bignami Bastianelli describe
developmental stages of human malaria parasites in anopheline mosquitoes
1899: mosquitoes fed on a patient in Rome sent to London, fed on two volunteers; both develop malaria
1930s: de Meillon in South Africa shows that malaria controlled by frequent spraying of walls and ceilings of dwellings with pyrethrins
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Malaria and History 1934: chloroquine discovered by Hans
Andersag, at Bayer IG Farben established as effective and safe antimalarial in
1946 1939: insecticidal properties of DDT
discovered by Paul Müller in Switzerland Müller wins 1948 Nobel Prize
1947: Henry Shortt and Cyril Garnham, working in London, show phase of division in liver precedes development of parasites in blood With American clinician, Wojciech Krotoski, later
showed P. vivax could remain dormant in liver for several months
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Control of Malaria: History In 1900, >77% of world population (1.6bn) in
140 countries at risk of malaria 3.1m deaths, ~90% outside sub-Saharan Africa
National Malaria Eradication Program, 1947-52 eradicated malaria from USA >4.6M houses sprayed: 1947 15,000 cases; 1950
2,000 cases Sardinia 1947-51
75,000 to 9 cases
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Global Malaria Eradication Campaign 1950s–1970s
Spearheaded by WHO and US epidemiologist Fred Soper and involved ≥50 countries Heavy use of of DDT to spray houses twinned with case
finding and treatment in four successive steps: preparation, attack, consolidation, and maintenance
Reduced world population at risk of malaria to ~50% by 1975 Countries with temperate climates and seasonal
transmission eradicated malaria Sri Lanka, >2m cases in 1958 to 17 in 1963
Then bounced back to 500,000! Negligible progress in e.g. Indonesia, Afghanistan,
Haiti, and Nicaragua most of Sub-Saharan Africa excluded!
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Global Malaria Eradication Campaign 1950s–1970s
Failure due to Darwinian evolution of resistance to DDT and
drugs wars and massive population movements lack of sustained funding from donor countries lack of community participation
WHA abandoned eradication in 1967 Focus on control No mention of “E word” for decades
Now ~40% of world population at risk
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Roll Back Malaria Initiative instigated by WHO's Director General
in 1998, launched by WHO, UNICEF, UNDP and the World Bank
2006 RBM Change Initiative to strengthen response to emerging challenges in global malaria control
2007: Gates calls for eradication!
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Global Malaria Action Plan (2008) Universal coverage for all populations at risk with
locally appropriate interventions for prevention and case management by 2010
Reduce global malaria cases from 2000 levels by 50% in 2010 and by 75% in 2015
Reduce global malaria deaths from 2000 levels by 50% in 2010 and to near zero preventable deaths in 2015
Eliminate malaria in 8-10 countries by 2015 and afterwards in all countries in the pre-elimination phase today
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International funding for malaria control up from ~US$0.3bn in 2003 to US$1.7bn in 2009 due largely to the emergence of the Global Fund and greater commitments by the US President’s Malaria Initiative, the World Bank and other agencies. This increase in funding is resulting in dramatic scale-up of malaria control interventions in many settings and measurable reductions in malaria burden
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Control of Malaria Effective medicines and relatively inexpensive
preventive measures available But these reach only a small proportion of those in
need, mainly because of poverty Last decade: new medicines and approaches
developed for case management selective vector control epidemic detection and control
challenge of producing widely available vaccine that provides high level of protection for sustained period yet to be met
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Malaria Control: Intervention Points
Kill asexual forms (ACT)Cure disease
Kill sexual forms (primaquine)Prevent spread to
mosquito
Early DiagnosisrDT
Prevent BitesNetsRepellentsClose doors/windowsKill adult mosquitoes
Prevent Disease with Vaccine?
Prevent Transmission with Genetic Manipulation?
Prevent BreedingRelease sterile malesRemove breeding sitesLarvicidesPARASITE
VECTOR
HOST
Chemoprophylaxis for travellers
Early and Effective Treatment
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Vector Control Measures AIM: to protect individuals against infective
mosquito bites and at community level to reduce intensity of local malaria transmission
Nets and Sprays
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Insecticide-Treated Nets (ITN) Long-Lasting
Insecticidal Nets (llins) Do not require
retreatment Maintain biological
efficacy against vector for ≥3 years
In Africa alone, 140 million nets were distributed between 2006 and 2008
http://www.flickr.com/photos/dfid/2944998010/DFID Some rights reserved
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Indoor Residual Spraying (irS) Insecticides are
sprayed on walls of homes DDT back in fashion “weapon of mass
survival” If breeding sites are
few, fixed and easy to find larviciding and environmental management can be used
http://www.flickr.com/photos/27337026@N03/2589248767/ some rights reserved
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Vector Control: alternative approaches Sterile insect technique
method of biological control: millions of radiation-sterilised male insects released, compete with wild males for female insects
successfully been used to eradicate screw-worm fly in areas of North America
suitable for mosquitoes in Africa? Transgenic parasite-resistant mosquitoes?
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Malaria Case Management: Diagnosis Malaria confirmed by
parasitological diagnosis with either microscopy or a rapid diagnostic test (rDT)
Microscopy Giemsa staining of thick
and thin films: cheap and low(ish) tech
BUT requires well-trained, competent microscopists and rigorous maintenance of functional infrastructure and QC
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Malaria Rapid Diagnostic Tests immunochromatographic
assays detect malaria antigens in 5–15 µL blood with mAb impregnated on a test strip; coloured test line obtained in 5–20 min; “pregnancy test for malaria”.
require no capital investment or electricity, simple to perform and easy to interpret
BUT expensive
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Malaria Case Management: iPTp intermittent
preventive treatment for pregnant women (iPTp) to prevent malaria infection in high transmission settings give ≥ 2 doses of
sulphadoxine-pyrimethamine (SP)
regardless of presence of parasites
given from 2nd trimester, preferably 1 month apart
http://www.flickr.com/photos/hdptcar/2530914336/Some rights reserved hdptcar
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Malaria Case Management: Treatment AIMS to reduce morbidity and mortality by
ensuring rapid, complete cure preventing progression to severe, potentially fatal
disease preventing malaria-related anaemia and negative
impact of malaria on foetus to curtail transmission of malaria by reducing
parasite reservoir
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Malaria Case Management: Treatment Artemisinin-based combination therapies
(ACTs) now recommended treatment against P. falciparum malaria
Chloroquine and primaquine against P. vivax malaria.
Prophylaxis to prevent malaria in travellers to malaria-endemic countries
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Malaria Case Management: Threats Early evidence of resistance to artemisinins Continued use of artemisinin monotherapy
major factor in parasite resistance Surveillance of therapeutic efficacy over time
is an essential component of malaria control Genotyping to distinguish relapse from
reinfection
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New Drugs Against Malaria?
Medicines for Malaria Venture (MMV)
http://www.nature.com/clpt/journal/v85/n6/full/clpt200951a.html
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Developing a Vaccine?
Anti-blood-stage vaccine difficult because of Antigenic diversity in
parasite Parasite mechanisms
that evade host responses
Huge biomass of parasites
BUT we know that in endemic areas repeated infection results in control of blood-stage parasitaemia and effective immunity
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Developing a Vaccine? Vaccines Against Pre-Erythrocytic Parasite
Stages? Some success with whole-cell irradiated and
genetically attenuated parasites Subunit vaccines targeting circumsporozoite
antigen: RTS,S vaccine in phase III trials Transmission Blocking Vaccines (TBVs)?
BUT would not protect the vaccinated individual
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Are we winning?
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Will we win? Complete interruption of malaria transmission
is likely to require additional, novel tools, especially in high-transmission situations
Malaria control today relies heavily on limited number of tools, in particular artemisinin derivatives and pyrethroids which could be lost to resistance at any time
Development of new tools for vector control and other preventive measures, diagnosis, treatment and surveillance remains a priority
We need world peace and development!
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Will we eradicate malaria? In my
lifetime? No
In your lifetimes or your children’s lifetimes? Maybe, with
your help?
http://www.youtube.com/watch?v=5LdXy7nZXY4
“Death by mosquito bite? No! Not in the 21st Century, we are not having that!” Bono
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Any Questions?