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“Now I lay me down to sleep.I pray the Lord my soul to keep.If I should die before I wake,I pray to God my soul to take.If I should live for other days”

A Child’s Prayer

How Much has Changed

Why has Infectious Disease Mortality Changed?

•Vaccines

•Antibiotics

•Sanitation

Last smallpox outbreak in US, 1947. New York

Last person with smallpox in the U.S. 1948

Last case of smallpox

(Variola minor),

Somalia, 1977

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Why do we Vaccinate?

• Hemophilus B• Was the leading cause of

acquired retardation

• We now vaccinate a low prevalence disease

• Targeted more at risk population• Teens

• Group Living

• Splenectomized

• MSM in CA

“Antibiotics are the magic weapons of deliverance” Future and Past New Infectious Diseases are Nothing New

• Between 5,000 and 6,000 years ago, Neolithic farming communities in Europe dramatically declined. Now, however, a team of researchers in Sweden has found a new strain of plague that they say may have been partially responsible.

• However, the discovery that the plague reached northern Europe far earlier suggests that the disease arrived before the Eurasian migrants (previously believed to be the source of plague).

• The study suggests that the plague started as a human disease in "mega-settlements" of 10,000 to 20,000 people built starting about 6,000 years ago. Poor sanitation and the concentration of people, animals and food may have allowed the plague to develop into a dangerous disease.

Rasmussen, S, Cell 2018

Emerging Organisms – Continuing Change2001-2005

Human bocavirus

Human coronavirus HKU1HTLV-3

HTLV-4

Human coronavirus

SARS coronavirus

Cryptosporidium hominis

Baboon CMV

Human metapneumovirus

Cryptosporidium felis

Whitewater Arroyo virus

1996-2000

Brachiola algerae

Ehrlichia ewingii

Nipah virus

TT virus

Brachiola vesicularum

Menangle virus

Anthropophthera

Laguna Negra virus

Andes virus

Australian bat lyssavirus

BSE/CJD agent

Ehrlichia canis

Juquitiba virus

Metorchis conjunctus

Trachipleistophorahominis

Usutu virus

1991-1995

Bayou virus

Black Creek Canal virus

Cote d’Ivoire Ebola virus

Hepatitis G virus

New York virus

Anaplasmaphagocytophila

Hendra viru

Human herpesvirus 7

Human herpesvirus 8

Sabia virus

Bartonella elizabethae

Encephalitozoon intestinalis

Gymnophalloides seoi

Sin Nombre virus

Bartonella henselae

Dobrava-Belgrade virus

Ehrlichia chaffeensis

Encephalitozoon hellemGuanarito virus

Nosema ocularum

1985-1990

Banna virus

Gan gan virus

Reston Ebola virus

Semliki Forest virus

Trubanaman virus

Vittaforma corneae

C. amycolatu

European bat lyssavirus1

Hepatitis C virus

Barah Forest virus

Piobirnavirus

Hori virus

Sealpox virus

Suid herpesvirus

Cyclospora cayetanensis

European bat lyssavirus 2

Human herpesvirus 6

HIV- 2

Kasokero virus

Kokobera virus

Rotavirus C

1981-1985

Borna disease virus

Enterocytozoon bieneusi

Pleistophora ronneafiei

Human torovirus

Rotavirus

B Scedosporiumprolificans

Candiru virus

C. canimorsu

Helicobacter pylori

Hepatitis E virus

Human adenovirus F

HIV

Borrelia burgdorferi

HTLV-2 Seoul virus

1980

Microsporidian africanumHTLV -1

Puumala virus

Factors Affecting Emerging and Re-emerging Infections• Climate change

• Politics

• Population growth

• Technology

• Poverty

• Myths and conspiracy theories

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Animal Pathogen Evolution – Will Continue to Change

Ebola, Lassa, Marburg, Lyme, Flu, SARS, etc

Diagram courtesy of Wolfe et al. 2007

JAMA. 1997;277:904-908

Disease of Changes in Nature and Population

JAMA. 1997;277:904-908

JAMA. 1997;277:904-908

Dengue - Reasons for pandemic

• Population growth• Urbanization and chaotic growth• Spread of vector mosquitoes• Expansion of plastics and tires• Rapid world-wide travel• Cessation of effective mosquito control• Developing insecticide resistance

Aedes aegypti

• Dengue transmitted female Primarily a daytime feeder

• Bites in and outdoors from early morning

• “Nervous feeders” –> high transmission rate

• Lives around human habitation

• Flies < 200 meters generally

• Lays eggs and produces larvae preferentially in artificial containers

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Reinfestation by Aedes aegypti

1930s 1970 1998

2003: 20 megacities of > 10 mil. people ; 75% developing world

Civet cat

SARS -

• Animal to human transmission

• Engineering of modern buildings

• Transportation and technology development

• Mythology

SARS

Vent stack

SARS outbreak in Canada – The Rest of the Story

“I don’t think this is SARS”

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Factors Affecting Emerging and Re-emerging Infections

• Politics

• Technology

Foreign Policy March 27, 2012

“Perform genetic engineering work on these viruses, with the eventual aims of manipulating smallpox virulence factors and inserting genes of other viruses into smallpox to create chimera viruses. The purpose of creating chimera viruses was to design new organisms which would have a synergistic effect and/or evade current vaccines or treatments. One of the first chimera viruses planned involved the insertion of Venezuelan equine encephalomyelitis (VEE) genes into smallpox….”

PerspectiveVolume IX, Number 1 (September-October 1998)

ISCIP

The Macabre Part of ID

Molecular Biology Institute outside of Moscow

Entrance to Vektor

Microbiologist Housing at Vektor

Exposure Chambers, ARVI Tartastan

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Hantavirus

• A young, physically fit Navajo man with shortness of breath died very rapidly in New Mexico

• The young man's fiancée had died a few days before

• An additional five young, healthy people were identified who all died after acute respiratory failure

• Virus genes linked to the pulmonary syndrome, a previously unknown type of hantavirus. (Sin Nombre Virus)

Hantavirus

• Later that year:• Louisiana bridge inspector who had not traveled to the Four Corners area developed HPS.

Another hantavirus, named Bayou virus

• 33 y/o Florida man with HPS symptoms. Had not traveled to the Four Corners area. Another hantavirus, named the Black Creek Canal virus

• New York 1993 - New York-1

• 1913, Russian clinical records from eastern Siberia describe hemorrhagic fever with renal syndrome (HFRS)• Chinese literature - similar disease dating to about A.D. 960

• Wars disrupt normal interface

Why Did Hanta Emerge?Climate/Population Changes

• Drought for several years.

• Heavy snows and vegetation boom

• Predators became scarce after prey numbers limited

• These factors allowed deer mice population to increase ten fold in May 1993 contrasted to May of 1992. • 30% of the deer mice tested showed evidence of infection with

hantavirus.

Zika virus

Changes• Mobility• Mutation• Population• Sanitation

Zika virus

Zika Virus in Polynesia –Relation to Guillain-Barre

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Zika Likely Spread to Brazil by Tongan Soccer Team

Zika virus –Remarkable Affinity for Neural Tissue in Fetus

Risk of Microcephaly after Maternal ZikaInfection in 1st Trimester

• Brasil et al: 22% of pregnancies in cohort of symptomatic women in Brazil

• Cauchemez et al: 1% of pregnancies all infected women in French Polynesia

• Johansson et al: 1 – 13% of all affected neonates born in Bahia*

Rodrigues, Lancet. 2016.Johansson et al NEJM 2016

Changing Malaria Risk in Kenya

• Climate change• Population

PopulationNairobi metro 7 millionKenya -50 million

Malaria Growth and Temperature.

Shapiro LLM, Whitehead SA, Thomas MB (2017) Quantifying the effects of temperature on mosquito and parasite traits that determine the transmission potential of human malaria. PLOS Biology 15(10): e2003489.

What is Cholera?• Bacterial fecal oral infection

• Toxin mediated diarrhea

• Massive fluid and electrolyte derangements

• Not invasive

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Cholera in Yemen• Population

Disruption• Breakdown of

Public Health• Malnutrition

“Under pressure from Peru's powerful fishing industry, President Alberto K. Fujimori, his wife, Susana, and his ministers of fisheries and of agriculture went on television eating ceviche…….. Trying to revive tourism, the President also played host to 20 foreign correspondents for a lunch of ceviche and sashimi at a beachfront restaurant.

Within days, hospital admissions for cholera soared. One patient reportedly was the Fisheries Minister, Felix Canal.

The Peruvian government stopped chlorinating drinking water supplies in the country following the publication of U.S. EPA reports on the health risks of disinfection byproducts (DBPs), out of concern for this newly recognized hazard.

Within months, a cholera epidemic swept through the country, eventually causing 1.3 million cases of illness and 13,000 deaths

Cholera in Peru

Cholera Outbreak Peru

• Bilge emptied into Lima harbor• DNA testing of the Latin American cholera strain shows that it is genetically similar—

although not identical—to a cholera strain common in Bangladesh

• The El Ni ˜no warming effect on ocean waters can promote plankton blooms, in which cholera bacteria can thrive, especially with high levels of sewage that provide needed nutrients to the microbes.

• strain of cholera isolated from patients in Peru, Vibrio cholerae O1, El Tor, has been found to produce an exopolysaccaride that can make the bacteria more resistant to chlorine.

• Undercooked seafood, raw (e.g., ceviche)

• Irrigation with sewage water

Cholera Outbreak Peru• Flat water system

• Erratic chlorination

• Lack of toilets – seepage into system

• Testing deteriorated

• Slums along the river

• Strain of cholera isolated from patients in Peru, Vibrio cholerae O1, El Tor, has been found to produce an exopolysaccaride that can make the bacteria more resistant to chlorine.

Fleming’s Nobel Prize Address

“. . .the thoughtless person playing with penicillin

treatment is morally responsible for the death of the

man who finally succumbs to infection with the

penicillin-resistant organism. I hope this evil can be

averted.”

New York Times 1945 Jun 26, p21.

Antibiotic Resistance – Bacteria Live in a Competitive Environment

• Many mechanisms• Enzymes destroy antibiotic (beta-lactamase)• Binding with target is altered (E. faecium, VRE)

• Penetration is reduced (VISA)• Antibiotic is removed from cell (efflux pumps)

• Innate, such as intracellular organisms• Biofilms

• Abscess formation

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Factors Promoting Antibiotic Resistance• Increased antimicrobial use in the community and hospitals,

in veterinary medicine and agriculture• 8 million kg used for animals annually

• 22,000 kg used for fruit trees annually in the U.S.

• In 1954, two million pounds of antibiotics were produced in the US. Today > 50 million pounds.

• > 100 million courses of antibiotics in the US annually.

• Empiric antibiotics

• Prolonged and broad-spectrum antibiotic courses

• Repeated antibiotic courses

Antibiotics Used in Veterinary Applications• For treatment of disease.

• For metaprophylaxis.

• For growth enhancement.• In cattle: bacitracin, tetracyclines, lasalocid, monensin• In swine: asanilic acid, bambermycin, erythromycin,

penicillin, tiamulin, virginiamcin

Antibiotics Used in Veterinary Applications• Antibiotics selected have generally not been used in

humans.• This has changed with glycopeptides for instance.• Resistance may not correlate with only the type of

antibiotic used.• Macrolide and glycopeptide genes were linked when the

macrolide (tylosin) was stopped in Denmark, and virginiamycinwas continued.

• Efflux pumps.

Antibiotics Used in Veterinary Applications

• Linkage to resistance in human pathogens is identified, but not well-understood.

• Concerns with veterinary resistance• The widespread presence of resistance genes.

• Studies in bacteria from the pre-antibiotic era.

• Development of resistance vectors such as plasmids permits wide dissemination of resistance.• This reduces the genetic cost of maintaining resistance.

0

5

10

15

20

25

30

35

40

Germany France

1985

1989

1993

1997

Outpatient Antibiotic Use, Daily Defined Doses/1000

Harbarth, Emerg Infect Dis

2002;8:1460.

0

10

20

30

40

50

60

France Germany

Pen R

Pneumococcus

Pen I

Pneumococcus

Erythro R

Pneumococcus

Harbarth, Emerg Infect Dis

2002;8:1460.

Contrast in Pneumococcal Resistance between

Germany and France

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How

Would

You treat

This

Patient?

CRE – Carbapenemase Resistant Enterobacteriaceae

• Carbapenemases exist in gram-negative bacilli, mainly Enterobacteriaceae and Pseudomonas aeruginosa. • More common in lactose-fermenting species of

Enterobacteriaceae (e.g., K. pneumoniae and E. coli)

• Less common in non-lactose fermenting Enterobacteriaceae (e.g. Serratia marcescens, Enterobacter) and P. aeruginosa.

CRE• Enterobacteriaceae can be resistant to

carbapenems by mechanisms other than a carbapenemase• Eg, extended-spectrum cephalosporinase, such as

an AmpC-type enzyme or an ESBL, combined with porin loss.

• Negative by the MHT (and KPC PCR). • All carbapenem-nonsusceptible Enterobacteriaceae

produce a broad-spectrum β-lactamase, and are therefore an infection control concern.

• Plasmid transmission is greatest concern

States with CP-CRE in 2006

https://www.ihaconnect.org/Quality-Patient-Safety/Documents/Webinars/CfC-cre-

webinar-presentation-2014-09-25-final.pdf

Current States with CP-CRE

http://www.cdc.gov/hai/organisms/cre/TrackingCRE.html

CRE

Modified Hodge Test (MHT)Measles - Mythology

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Measles – Ro Measles

Duuuhh!

Marin Pertussis Outbreak• 2010 saw the largest epidemic of B. pertussis in California

in more than 50 years

• Marin County was at the epicenter of the epidemic

• All patients with a positive PCR for B. pertussis at from March 1-October 31, 2010

• Example of mutational changes, policy changes and myhtology

Results• 171 patients with B. Pertussis were identified

• 132 age <18, and 103 age <=12.

• Vaccination rates of patients in the <=12 age group: • 85% fully vaccinated• 7% under vaccinated

• 8% never vaccinated.

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Case and Testing Rates By Age

0

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Test

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-Years

Age in Years

Pertussis attack rate and PCR Testing rate per 100,000 Person-Years

Rate of Pertussis PCR Testing Per 100,000Person-Years

Attack Rate in cases per 100,000 Person Years

Results

Table 3. Attack Rate in Vaccinated and Under and Unvaccinated Patients

Age GroupAttack Rate in

Vaccinated Persons*

Attack Rate in Under and

Unvaccinated Persons*

P-Value

2-7 359 606 0.57

8-12 2453 3211 0.43

13-18 452 2189 0.009

2-18 1011 2073 0.01

*Per 100,000 person-years

Analysis

Table 1. Vaccine Effectiveness by age.

Age Group (Years)

PPV PCVEffectiveness

(%)Effectiveness: 95%

Confidence Intervals

2-7 91% 86% 41% 21-54%

8-12 89% 86% 24% 0-40%

13-18 89% 62% 79% 73-84%

2-18 90% 81% 51% 44-58%

* PPV= Proportion of the Population fully Vaccinated

PCV= Proportion of Cases fully Vaccinated

Why the Pertussis Outbreak

• In 1996 wP was change to aP• Had fewer side effects

• Durability of aP vaccine never tested – only 18 months f/u

• Change in vaccine strategy made without the above knowledge

• Organism may have mutated to make it evade vaccine somewhat

• Unvaccinated pockets of children are incubator for epidemics

History

• Named after the Ebola River in the DRC (formerly

Zaire), near the first epidemics.

• Two species were identified in 1976: • Zaire ebolavirus (ZEBOV) and

• Sudan ebolavirus (SEBOV)

• Case fatality rates of 83% and 54% respectively.

• Additional species continue to be identified.

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Hemorrhagic Fever Virus Distribution in Africa Examples of Interspecies Transmission

Lassa Virus Ebola Virus Marburg Virus

Photos courtesy of Travel Approved (for Lassa and Ebola), Mehedi et al. 2011 (for Marburg)

Year Ebola Sub-type Country Number of Cases Percentage of deaths Situation

1976 Ebola-Zaire Zaire (DRC) 318 88% Spread by close personal contact and needles and syringes in hospitals/clinics. First recognition

1976 Ebola-Sudan Sudan 284 53% Disease spread through close personal contact within hospitals.

1976 Ebola-Sudan England 1 0% Laboratory infection by accidental stick of contaminated needle.

1977 Ebola-Zaire Zaire 1 100% Noted retrospectively in the village of Tandala.

1979 Ebola-Sudan Sudan 34 65% Occurred in Nzara. Recurrent outbreak at the same site as the 1976 Sudan epidemic.

1989 Ebola-Reston USA 0 0% Ebola-Reston virus in quarantine facilities in VA, TX, and PA by monkeys imported from the Philippines.

1990 Ebola-Reston USA 0 0% Ebola-Reston virus was introduced once again into quarantine facilities by monkeys from the Philippines.

1992 Ebola-Reston Italy 0 0% Ebola-Reston virus was introduced into quarantine facilities in Sienna

1994 Ebola-Zaire Gabon 49 59% Occurred in Mékouka and other gold-mining camps deep in the rain forest.

1994Ebola-Ivory

CoastIvory Coast 1 0% Contracted after conducting an autopsy on a wild chimpanzee in the Tai Forest.

1995 Ebola-Zaire DRC 315 81% Index case worked in forest. Epidemic spread through families and hospitals.

1996 Ebola-Zaire Gabon 31 68%Chimpanzee found dead in the forest was eaten. 19 involved in the butchery of the animal became ill;

other cases occurred in family members.

1996 Ebola-Zaire Gabon 60 75% Index case was a hunter. Disease spread by close contact with infected persons

1996 Ebola-Zaire South Africa 2 50% HCW from Gabon to South Africa, having treated Ebola patients. A nurse became infected and died.

1996 Ebola-Reston USA 0 0% Ebola-Reston virus was introduced into a quarantine facility in Texas

1996 Ebola-Reston Philippines 0 0% Ebola-Reston virus was identified in a monkey export facility in the Philippines.

2000-2001 Ebola-Sudan Uganda 425 53% Risks were funerals; contact with patients in family, and medical care without adequate protection.

2001-2002 Ebola-Zaire Gabon and DRC 122 79% Outbreak occurred over the border of Gabon and DRC.

Prior Ebola Outbreaks

Year Ebola Sub-type Country Number of Cases Percentage of deaths Situation

2002 Ebola-Zaire Congo 143 89% Hunters with wildlife contact that was killed or found dead. Direct contact with infected persons.

2003 Ebola-Zaire Congo 35 83% Limited due to early mobilization

2004Ebola-Zaire

Russia 1 100% Laboratory infection by accidental stick of contaminated needle.

2004 Ebola-Sudan Sudan 17 41% Limited data

2005 Ebola-Zaire Congo 12 83% Hunters and caretakers

2007Bundibugyo ebolavirus

Uganda 131 32% New strain with lower mortality

2007 Ebola-Zaire DRC 264 71% Ebola-Reston virus was introduced once again into quarantine facilities by monkeys from the Philippines.

2008 Ebola-Zaire DRC 32 47% International response

2011 Ebola-Sudan Uganda 11 36% Limited outbreak

2012 Ebola-Sudan Uganda 1 0% Contracted after conducting an autopsy on a wild chimpanzee in the Tai Forest.

2012Bundibugyo ebolavirus

DRC 36 36% Separate from Ugandan outbreak which was simultaneous

2012 Ebola-Sudan Uganda 11 36% Early recognition

2014 Ebola-Zaire DRC 69 71% Not related to West Africa outbreak

2014 Ebola-ZaireGuinea, Liberia,

Sierra Leone28,610 39% Largest outbreak ever. Many initial errors and urban spread

2014Ebola-Zaire

USA 0 0% Ebola-Reston virus was introduced into a quarantine facility in Texas

2014 Ebola-Reston Philippines 0 0% Ebola-Reston virus was identified in a monkey export facility in the Philippines.

2017 Ebola-Zaire DRC 8 50% Remote area

2018 Ebola-Zaire DRC Ongoing ? Control limited by logistics, war

Prior Ebola Outbreaks

Where does Ebola hide?

• 2002- Fruit Bats - do not show any symptoms

• Best candidate to be the reservoir

• Antibodies against Ebola

• Primate outbreaks often precede Human outbreaks

• Ebola Gene sequences in liver and spleen and many other mammals

Ebola Virus- Risk Factors

• Hunting and butchering wild animals, especially non-human

primates

• Healthcare workers and family

Photo courtesy of Nathan Wolfe Photo courtesy of the CDC PHIL

Transmission• Direct contact with the blood, secretions, organs or

semen of infected persons: • Risk factors among 27 surviving members in Kikwit

• Direct contact during late hospital phase were at very high risk.

• Those with no physical contact with infected remained uninfected.

• Transmission through semen occurs up to 80 d.• Recent report 14 cases - funeral preparations.

• Handling dead infected people or chimps.

• Neonatal

• Droplets or small filovirus particle aerosols confirmed in alveoli of monkeys during Reston outbreak and BT evaluations