Download - emerging and reemerging viral infectious diseases · PDF fileEmerging and Reemerging Viral Infectious Diseases Joseph Becker, MD Michele Barry, MD FACP Yale University School of Medicine

Emerging and Reemerging Viral Infectious Diseases

Joseph Becker, MD

Michele Barry, MD FACP

Yale University School of Medicine

January, 2009

Prepared as part of an education project of the Global Health Education Consortium

and collaborating partners

Learning Objectives

1. Ecology of Emerging & Re-emerging Diseases

2. Public Health Relevance

3. Relevant host-vector-pathogen interactions

4. Ecological, Epidemiological, and Clinical

Characteristics

5. Current Approaches to Surveillance

Emerging Infectious Diseases: Historical Context

• 1340: Bubonic Plague “Black

Death”: 75 million deaths

- 30-60% of European

population killed

• 1500s: Smallpox to the

Americas: 10-15 million deaths

- End of Aztec civilization

• 20th Century: HIV/AIDS:

>50 million deaths

Fig 1: Illustration from the Toggenburg

Bible of those afflicted by the Bubonic

Plague

Page 3

Why Emerging Infectious Disease? 1*

• Multiple explanations for the emergence and

reemergence of infectious diseases:

- Climate change

- Injudicious and widespread use of

antimicrobials

- Bioterrorism (‘weaponization’ of

pathogens)

- Mobile human populations

- Environmental modification (Legionnaires

disease)

*Superscript references can be found at the end of this module

Page 4

Why Emerging Infectious Disease?

Continued:

- Human population encroachment on

wilderness (vector populations)

- Concentration of human populations

- Dispersal of vectors (and pathogens)

through trade, transport, migration

- Immuno-compromised populations

Page 5

The State of Emerging

Infectious Diseases

• Analysis of 335 “EID Events”: 1940 to 2004

• Control for geographic and historical reporting bias

• EIDs dominated by zoonoses (60% of EIDs)

- 71.8% of zoonoses arise in wildlife

• Viral EIDs: 25% of all EIDs

• Vector borne EIDs: 23% of EIDs: significant recent rise

• Threat of EIDs is increasing

• Non-random geographic distribution of EIDs

Jones K, Patel G, Levy M, et al. Global trends in emerging infectious diseases.

Nature 2008. 451:21; 990-994.

Page 6

The State of Emerging Infectious Diseases Continued.

• Antimicrobial resistant EIDs: 20.9% of EIDs

- attributable to increase in antimicrobial use

• Zoonotic EID events correlate with geographic wildlife diversity

- No correlation with population growth

• Zoonotic non wildlife EIDs: predicted by human population

density/growth

• Vector borne EIDs: No correlation with rainfall, human

population or wildlife diversity

• Human population density independent predictor of EID events

Jones K, Patel G, Levy M, et al. Global trends in emerging infectious diseases.

Nature 2008. 451:21; 990-994.

Page 7

Geographic Distribution of Detection of EIDS (1940-2004)

Fig 2: Geographic Distribution of EIDs 1940-2006: Jones et al.

Page 8

This graphic demonstrates the geographic distribution of detected EIDs portraying the trend that EIDs are

largely detected once they have reached Europe and the US, while their geographic origins are shown in the

following slide. The size of each circle is proportional to the number of EID events.

Global EID Risk Distribution

Fig 3: Global EID Risk Distribution: a) zoonoses from wildlife, b) zoonoses from non-wildlife, c) drug resistant

pathogens, d) vector borne pathogens. Jones et al.

Page 9

This slide demonstrates the regions at most risk for the development of EIDs based on the historical sample in this

study. The upper left box (a) shows zoonotic pathogens from wildlife. Box b (upper right) zoonotic pathogens from non-

wildlife. Box c (lower left box) drug resistant pathogens, and lastly box d (lower right hand box) demonstrating vector

borne pathogens.

Selected Emerging Viruses of Public Health Significance

• SIV/HIV

• Viral Hemorrhagic Fevers

- Filoviruses

- Arenaviruses

- Bunyaviridae

• Flaviviruses (Yellow Fever, Dengue, West Nile)

• Emerging Respiratory Pathogens

- SARS

- Avian Flu

Page 10

Lentiviruses: SIV and HIV 4

• SIV/HIV: retroviruses (RNA viral genome converted to DNA via enzyme

reverse transcriptase)

• Simian Immunodeficiency Viruses (SIVs) are the origin of Human

Immunodeficiency Viruses (HIV 1,2)

• Origin of HIV 1: SIVcpz (Chimpanzee: Pan troglodytes troglodytes)

• Origin of HIV 2: SIVsm (Sooty Mangabee: Cercocebus atys)

• SIVcpz/SIVsm cause no discernable disease in their hosts

• SIVcpz and SIVsm have existed for millennia

Page 11

HIV-1 and HIV-2 are direct descendants from SIVcpz (Chimpanzee) (Cameroon, Gabon, DRC, central Africa)

and SIVsm (Sootey Mangabey) (Sierra Leone, Liberia). SIVcpz and SIVsm have existed for thousands of

years and no longer cause discernable disease in their hosts. However, these same viruses cause lethal

immunodeficiency in other primates, particularly Asian Macaques. It is likely that humans have had contact

with these viruses for an extensive period of time. However, HIV is likely a fairly new pathogen as HIV was

not carried to the New World with the estimated 10 million slaves that were forcibly transported to the

Americas. Evidence suggests that HIV developed within the past 100 years. It is unknown what behavioral,

societal or biological factors contributed to the emergence of these cross species transmission events in the

last century. It is as well unknown if these factors are still in existence and could therefore contribute to the

emergence of further epidemic or pandemic subtypes of HIV.

Lentiviruses: SIV and HIV 4,5

• Human contact with SIVs is likely longstanding (> 1000 years) through

hunting and butchering of Non-Human Primates (NHPs) for food

• Despite longstanding human SIV exposure: epidemic HIV only emerges

only in last 60 years

• No HIV brought to the New World with >10 million African slaves

• Unclear mechanism of cross species transmission and origin of

epidemic HIVs

• 11 individual cross species transmission events documented (HIV-1

subgroups M,N,O and HIV-2 subgroups A-G) in mid twentieth century

Page 12

SIV and HIV :

• Cross species transmission events may

be ongoing

• 33 species of Non-Human Primates

(NHPs) harbor their own SIV species

• Hunting and butchering of NHPs for food

common in central Africa

• SIVs isolated from bushmeat prepared for

human consumption

• Ancestral strains of HIV-1 persist in wild

chimps

• Precedent of laboratory worker acquired

SIV infection

• 12 of 16 SIVs capable of infecting human

lymphocytes in vitro Fig 4: Bushmeat: Source:

www.bonoboincongo.com

Page 13

http://www.bonoboincongo.com/

http://www.flickr.com/photos/ashleyvosper/1325039916/

SIV and HIV: Human SIV Exposure 6

• Cameroonians (HIV 1 & 2 -) with reported history of high, medium and

low levels of exposure to NHPs and bushmeat tested for presence of

SIV antibodies

• Findings:

- 17.1% reactive in high exposure group

- 7.8% exposure in low exposure

- 2.3% in the general population

• Conclusion: Humans are exposed and possibly infected with SIVs

• Implications: blood supply safety, further emerging zoonotic lentiviral

epidemics/pandemics Kalish M, Wolfe N, Ndongmo C, et al. Central African Hunters Exposed to Simian

Immunodeficiency Virus. Emerging Infectious Diseases 2005. 11(12) 1928-1931.

Page 14

Although a significant portion of the general population is positive for SIV antibodies, no SIV viral nucleic

acid has been isolated from human blood. This may indicate that the SIVs that have produced antibody

responses in humans, are non productive or at least not capable of producing chronic infection.

Viral Hemorrhagic Fevers (VHFs)

• Enveloped RNA viruses of diverse families

• May be arthropod borne with multiple, different animal

reservoirs

• Symptoms and disease severity vary widely

• Precedent of international travel transporting viruses

into non-endemic countries

• Precedent for nosocomial outbreaks involving

healthcare workers and laboratory personnel

Page 15

Distinct VHF Families

• Filoviridae

- Ebola

- Marburg

• Arenaviridae

- Lassa Hemorrhagic Fever

- South American Hemorrhagic Fevers

• Bunyaviridae

- Rift Valley Fever

- Crimean Congo Fever

Page 16

VHFs: Clinical Factors

• Initial symptoms nonspecific - incubation period of 2-14 days

• Severe sore throat, abdominal pain, progressive fever, vomiting

and diarrhea (bloody), easy bruising and bleeding

• Conjunctival injection and non-pruritic torso rash

• Multi-organ hemorrhage and failure with widespread necrosis

and microvascular thrombosis

• Uncontrolled activation of systemic inflammatory and

coagulation pathways

• Ebola and Marburg: most severe with mortality 25-100%

Page 17

VHFs: Filoviridae: Ebola 7,8

• Ebola (5 species)

- Sudan

- Zaire

- Ivory Coast

- Reston Agent

- Uganda

• First appearance in 1976

• Sporadic outbreaks

Fig 5: Electron micrograph of Ebola virus:

Photo Source: Dr. F.A. Murphy

Page 18

VHFs: Ebola: Documented Outbreaks 9

• Zaire sp.: 9 outbreaks

- Mortality: 57-88%

• Sudan virus: 4 outbreaks

- 50% case fatality rate

• Ivory Coast: two individuals (one survived)

• Uganda: 1 outbreak (2005)

- different symptom profile: 31% case fatality rate

• Reston Agent: No documented epidemics in humans

(epidemic in captive laboratory primates)

Page 19

VHFs: Filoviridae: Marburg 9,10

• All isolates considered single

species

• Varying pathogenicity (mortality

ranging from 21-80%)

• Responsible for 1967 outbreak

in Europe

• Outbreaks in 2000 in

Democratic Republic of the

Congo and 2005 in Angola

Figure 2: Electron micrograph of Marburg Virus. Photo Source: Centers for Disease Control and Prevention

Page 20

VHFs: Ebola and Marburg: Epidemiology 9-11-12

• Disease burden in comparison to HIV/Malaria/Tb is small

• Total number of identified cases <3000

• Increasing frequency of outbreaks in sub-Saharan Africa

• Significant ongoing outbreaks in wild (endangered) non human primate

species (chimpanzees)

• Unknown natural reservoir: primates likely secondarily infected (bats

suspected to be reservoir)

• Diagnosis: Currently ELISA viral antigen or PCR based field techniques

(antibody response can be muted)

Page 21

Viral hemorrhagic fevers, including Ebola and Marburg have been implicated in several epidemics amongst endangered non-

human primate species including gorillas and chimpanzees. Surveillance for primate illness has been suggested as a method

for detecting emerging VHF epidemics prior to significant human infections.

ELISA: Enzyme Linked Immunosorbency Assay is a method for detecting antigens and antibodies specific to particular

pathogens in blood or other body fluids. PCR: Polymerase Chain Reaction is a laboratory method for amplifying potentially

minute amounts of viral nucleic acid from body fluids.

VHFs: Ebola and Marburg: Transmission 9,13,14

• Person-person spread: contact with infected fluids

• Corpse preparation a risk factor for exposure

• Sexual transmission: documented but likely rare

• Droplet infection via mouth or eyes

• Aerosol spread documented in animals (likely minimal role of respiratory spread in epidemics)

• No evidence for mosquito or arthropod spread

• Animal to human transmission: dead primates butchered and eaten

Page 22

VHFs: Ebola and Marburg: Transmission

• Nosocomial Transmission:

- Syringe reuse/contaminated blood products

- Explosive and exponential outbreaks

- Exposure during procedures and care giving

- Exposure during preparation of bodies for burial

- Extremely variable rates of health care worker infection

• Epidemic “burnout”:

- Short incubation period

- Precipitous progression of disease and death

- Extreme clinical manifestation and symptoms

- Limited means of transmission

Page 23

VHFs: Ebola and Marburg: The Reservoir Hunt 13,14

• Traditionally infectious disease causes mild or no disease in reservoir

species

• Primates succumb to HF after infection

• No definite reservoir or vector identified

• Epidemic and vector control hampered by lack of clear reservoir animal

• Evidence for fruit bats as possible reservoirs (asymptomatic hosts)

- Experimentally infectable

- Bats strongly present in epidemic environments

- ~5% of 3 species of fruit bat have Ebola IgG in epidemic and

non-epidemic areas

Page 24

VHFs: Ebola and Marburg: Infection Control

• CDC Documents: 2005: Interim guidance for managing patients with

suspected viral hemorrhagic fever in US hospitals/Infection Control for

viral hemorrhagic fevers in the African Healthcare Setting

www.cdc.gov/ncidod/dhqp/bp_vhf_interimGuidance.html

www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual.htm

• Universal precautions are sufficient to prevent transmission –

- N-95 masks or respirators

- Gowns, face shield, rubber boots, double glove

- Triton X decontamination of all medical, laboratory

equipment and surfaces

• Private rooms with negative pressure for patients (if available)

• Restrict access to infected or exposed patients

Page 25

http://www.cdc.gov/ncidod/dhqp/bp_vhf_interimGuidance.html

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual.htm

VHFs: Ebola and Marburg: Infection Control

• Low Resource Isolation:

- limit access to suspected cases

- separate from

general patient population

- isolate early

- limit staff in isolation area

- isolated toilet

- changing room

- adequate ventilation

- screened windows

• Low Resource Waste Disposal

- 1/10 and 1/100 bleach solutions

after cleaning with soap solution for

reusable equipment

- liquid waste, laboratory samples,

and used disinfectants: discard in

isolated latrine

- solid waste, disposable medical

equipment: burned (diesel fuel)

- cleaning and waste disposal staff:

personal protective equipment

Page 26

VHFs: Vaccine Development 15

• Pan-filovirus vaccine under development

• Live attenuated viruses risk possibility of reversion to pathogenicity

• Adenovirus vector expressing multiple filoviral antigens

• Inoculation of nonhuman primates at 1,000 times lethal dose

• 100% protection against infection by 2 species of Ebola virus and 3

Marburg virus subtypes

• Utility for biodefense and epidemic preparation: early epidemics

typically undifferentiated

Dana L. Swenson, Danher Wang, Min Luo, Kelly L. et al. Vaccine To Confer to Nonhuman Primates

Complete Protection against Multistrain Ebola and Marburg Virus Infections. Clin Vaccine Immunol.

2008 March; 15(3): 460–467.

Page 27

VHFs: Ebola and Marburg: Treatment 12

• Treatment:

- Supportive care

- Respiratory support

- Reversal of coagulopathy

- Limited role for convalescent sera

- No role for ribavirin

- Post-exposure prophylaxis for exposed patients:

Research underway

- Interferons: Research underway

Page 28

Ribavirin is an anti-viral medication useful in treating some viral infections (Lassa) it has not

been shown to be useful in Ebola Marburg or HIV infections. Interferon is a man-made

molecule (cytokine) that plays a central role in the immune response to viral infection.

VHFs: Reston Agent 16

• Considered an Ebola species

• Possible animal reservoir-

Philippine Islands

• Outbreak amongst non-human

primates in quarantine facilities in

US leading to widely fatal

hemorrhagic fever in captive

primates

• Unclear human pathogenicity

• Unclear role of airborne or droplet

spread in primate outbreaks

Page 29

http://www.campusi.com/load.pl?cat=book&script=prod&op=buy&ean=9780385495226&pqcs=QUlF3vHjx0hsvqhTKjBhdw

VHFs: Filoviridae: Marburg and Ebola-Summary Points

• Potential for global spread via transportation networks

• Limited large scale epidemic potential given short incubation

period, severity of illness and limited transmission patterns

• Likely bat reservoir species

• Potential for impact on non-human primate populations

• Concerning for severe illness in returned travelers from central

Africa (and the Philippine Islands?)

• Limited treatment options

• Concern for development as bioterrorism agents

Page 30

VHFs: Arenaviruses

• Enveloped RNA viruses

• Hemorrhagic disease is typical

• Generally rodent transmitted disease

• Rodents have no apparent illness

• Incidental human infection via contact with infected

rodent urine or feces

• Contact with infected material typically from agricultural

work or rodent infestation of homes or other buildings

• Documented nosocomial and person to person spread

Page 31

VHFs: Arenaviruses

• Hemorrhagic febrile syndrome

• Variable case infection and

mortality rates

• Old World Arenavirus:

- Lassa Fever (West

Africa)

• New World Arenaviruses:

- South American

Hemorrhagic Fevers Fig. 5: New World Arenavirus particles

budding out of an infected cell: Source CDC

Page 32

Arenaviruses: Lassa Fever 17-18-19

• Localized to West Africa although travel has resulted in cases in

Europe and North America

• Discovered in 1969

• Likely asymptomatic/mild disease in ~80% of infected

• Can manifest outbreaks with case fatality rates of 50%

• Estimated 100-300,000 cases/year in West Africa

• Significant contribution to population mortality in selected communities

in Nigeria, Sierra Leone

• Diagnosis: ELISA for Lassa IgM or Lassa Antigen, PCR

- substantial population with prior exposure (IgG)

Page 33

IgM and IgG are two types of antibodies produced by B cells to combat infection. IgM (Immunoglobulin M) is typically

produced early in infection and as the infection progresses the antibody response shifts and IgG (Immunoglobulin G)

antibodies become prominent. IgG responses are typically more specific to the pathogen antigens than IgM responses. The

IgG response may be lifelong and as such IgG positivity may reflect prior exposure, rather than acute infection, which is

typically suggested by the presence of IgM. Acute and convalescent sera is another means for detecting acute infection.

Serum is drawn at the onset of illness and antibody response and then is measured again after several days. An interval

increase in the IgM or IgG response during this time is suggestive of acute infection.

Arenaviruses: Lassa Fever: Transmission

• Vector: Rodents: Mastomys

genus

• Transmission occurs with

human contact or inhalation of

infected rodent urine and feces

• Mastomys sometimes

consumed as food source

• Nosocomial transmission via

contact with infected medical

equipment Fig 6.: Lassa virions (arenavirus).

Source : CDC

Page 34

Arenaviruses: Lassa Fever: Clinical Notes

• Incubation period lasts 1-3 weeks

• Symptoms:

- High Fever - Conjunctivitis

- Retrosternal Pain - Vomiting

- Neurologic Deficits - Hemorrhage

- Liver inflammation - Sore throat

• Complications: Deafness (may occur with mild or serious

infection)

• Prognosis: Mortality: 15-20% of symptomatic cases but only

~1% of overall cases

Page 35

Lassa Fever: Prevention and Treatment

Prevention:

• Safe food storage

• Rodent control

• Wet down surfaces prior to

sweeping

• Lassa vaccine (?)

Treatment:

• Ribavirin (early treatment

improves survival)

• Supportive care

• Correction of coagulation

abnormalities, resuscitation Fig.: 7 African Countries endemic

for Lassa Fever

Page 36

Ribavirin for Lassa Fever 20

• Sierra Leone, 1986

• Study of therapy/prognostic factors in Lassa Fever

• Findings:

- Elevated aspartate aminotransferase (AST) > 150 IU/L

at admission associated with 55% mortality rate

- Viremia > 10(3.6) TCID50 per milliliter on admission

associated with a case-fatality rate of 76%

• Intravenous ribavirin within first 6-7 days of fever associated with

reduced mortality (5-9% vs 55-76%)

Lassa Fever: Effective therapy with ribavirin. McCormick JB, King IJ, Webb PA.

N Engl J Med. 1986 Jan 2;314(1):20-6.

Page 37

Arenaviruses: South American Hemorrhagic Fevers (HFs)

• Viruses:

- Machupo (Bolivia HF)

- Junin (Argentine HF)

- Guanarito (Venezuelan HF)

- Sabia (Brazilian HF)

• As with other arenaviruses:

- rodents serve as vector

- significant hemorrhage

- rural populations and

farmers frequently infected

- documented nosocomial &

occupational spread

(Machupo/Sabia)

Fig 6: Victim of Bolivian Hemorrhagic Fever.

Photo Source: www.medicineworld.org

Page 38

http://www.medicineworld.org/

Arenaviruses: South American HFs 21,22

• Case infection rate of 50% of exposed (overall)

• Mortality: 15-30% of those infected (overall)

• Symptoms similar to Lassa Fever with significant

neurologic manifestations

• Live, attenuated Junin virus vaccination in Argentina:

reduced incidence to less than 100 cases per year

• Significant success with vector control efforts

Page 39

VHFs: Bunyaviruses

• Enveloped RNA viruses

• Largest family of viruses with >200 species

• Diagnosis: Antigen detection and serological tests

available although virus isolation and PCR useful

• Most bunyaviruses require an arthropod vector

(exception: Hanta)

• Humans are usually dead end hosts

Page 40

VHFs: Bunyaviruses 23

• Crimean Congo Hemorrhagic Fever

- Bulgaria, Yugoslavia, former Soviet Union, China,

Middle East, Pakistan, and sub Saharan Africa

- Infection rate: 20-100% with case fatality rate: 15-30%

- Most severe bleeding and ecchymoses of VHFs

- Transmitted via tick bite (Hyalomma genus) or

exposure to aerosols or fomites of slaughtered livestock

- Nosocomial outbreaks documented

- Human vaccine available

- Vector control efforts of primary importance

Page 41

VHFs: Bunyaviruses 24

• Rift Valley Fever

- South Africa, Kenya, Uganda, Sudan, Egypt, Mauritania

- Appears as epizootics in sheep, cattle, camels, goats

-1% infection rate of exposed with mortality rate of 50%

- Retinal vasculitis that may cause blindness

- Transmission: mosquito or contact with infected

livestock blood

- No interhuman transmission documented

- Animal (sheep and cattle) vaccine available to break

transmission cycle

Page 42

Flaviviridae

• Wide range of clinical symptoms (including

hemorrhagic fever)

• RNA viruses

• Insect borne (arthropod borne)

• Main human pathogens:

- Yellow Fever

- Dengue

- West Nile Virus

- Encephalitic Viruses (Japanese, St Louis, Tick

Borne Encephalitis)

Page 43

Flaviviridae - Transmission

• Human to human

transmission noted for

Dengue, Yellow Fever, and

West Nile

• Humans are typically dead

end hosts

• Animal infection as well,

but likely dead end (NHP)

• Tick and mosquito vectors Fig 6: Aedes sp mosquito taking a

blood meal. Photo Source:

www.aedesmosquito.com

Page 44

http://images.google.com/imgres?imgurl=http://www.similima.com/images/phil_aedes_albopictus.jpg&imgrefurl=http://www.similima.com/chikungunya.html&h=351&w=480&sz=19&hl=en&start=1&tbnid=84DzLDmlzxf3HM:&tbnh=94&tbnw=129&prev=/images?q=yellow+fever,+mosquito&gbv=2&hl=en&sa=G

http://www.aedesmosquito.com/

Flaviviruses: Yellow Fever 25,26,27

• Single serotype RNA virus

• Yearly incidence: 200,000 cases (90% in Africa) with

30,000 deaths

• Distribution: Sub-Saharan Africa, South America,

Central America, Caribbean

• Possible differences in mortality and epidemic incidence

between African and South American Yellow Fever

• Aedes sp. mosquitoes infect primates & humans

Page 45

Yellow Fever: Distribution

Fig 7: Yellow Fever distribution in South America and Africa (red areas).

Photo Source: www.geo.arc.nasa.gov

Page 46

http://www.geo.arc.nasa.gov/

http://www.geo.arc.nasa.gov/

Yellow Fever Transmission Cycles

• African Yellow Fever (Old

World)

- Jungle -virus circulation

between NHPs (no effect) and

humans (dead end hosts)

- Intermediate- Small

simultaneous epidemics

in many small villages

- Urban Yellow Fever: Human-

human transmission can occur

in populated / urban areas

(mosquito transmission)

• South American Yellow Fever

(New World)

- Introduction of virus from

Africa within 500 years

- Haemagogus and Sabethes

species of mosquito

- S. American monkeys

die following infection

- Similar jungle and urban

transmission cycles to that of

African YF (no intermediate

cycle)

Page 47

Yellow Fever: Clinical Points

• Symptoms range from asymptomatic to life threatening

shock, liver/kidney failure and hemorrhage

• Highest disease severity in elderly

• 3 distinct clinical phases:

- Period of Infection: viremia, fever, acute illness (3-4

days), relative neutropenia

- Period of Remission: potential recovery and clinical

improvement (2 days)

- Period of Intoxication: 15% progress to intoxication

with hemorrhage, multi-organ failure (20% mortality)

Page 48

Yellow Fever: Diagnosis and Treatment

• Diagnosis:

- Can be confused clinically with Dengue, other

VHFs, viral hepatitis, severe malaria

- ELISA for IgM (acute and convalescent sera) cross

reactivity with other flaviviruses confuses diagnosis

- Viral isolation: PCR, viral culture (special cases only)

• Treatment:

- Supportive and symptomatic care

- Unclear role for hyperimmune globulin

- Animal evidence: ribavirin or interleukins

Page 49

Yellow Fever Vaccination

• Effective attenuated vaccine

available since 1936

• 95% vaccine seroconversion

rate

• Recommended for travelers

or residents of endemic

areas (required for entry to

some nations)

• Few adverse effects (two

serious clinical syndromes) Fig 7: Yellow Fever vaccination.

Photo Source: Author

Page 50

Yellow Fever Vaccine Adverse Effects 27

• YEL-AND: YF Vaccine Associated Neurotropic Disease

- Viral presence in CSF after vaccination

- Historically in children < 9 months but can affect adults

- Symptoms consistent with viral encephalitis

- Incidence: 1.8-5.1/million

• YEL-AVD: YF Vaccine Associated Viscerotropic Disease

- Symptoms consistent with wild type Yellow Fever

Infection with identical mortality

- 2.2/million but higher in elderly

- No viral mutations identified, likely determined by host

susceptibility factors, immunodeficiency, thymus

removal (primary vaccination, >65 years old)

Page 51

Flaviviridae: Dengue Fever 25,28

• Most prevalent mosquito (Aedes sp.) borne viral disease

• Greater than 100 million dengue infections yearly

• Wide range of clinical symptoms (mild to severe)

• 4 separate viruses (DEN 1-4)

• Weak cross reactivity between subtype antibodies allows

multiple infections with different subtypes

• Range of symptoms from mild to severe

Page 52

Dengue Fever: Clinical Points #1 28,29,30

• Symptoms: Asymptomatic to life threatening shock and

hemorrhage

• Severity may be inversely proportional to age

• Incubation period of 4-7 days

• Laboratory: transaminitis (elevations in liver function tests),

leucopenia, thrombocytopenia

• Symptoms:

- Fever

- Retro-orbital pain

- Headache

- Muscle and join pain (“Break Bone Fever”)

- Rash - may be late

Page 53

Dengue Fever: Clinical Points #2

• Diagnosis: clinical diagnosis or IgM ELISA with paired

acute and convalescent sera

• Treatment: Supportive care, avoid NSAIDs (Reyes

Syndrome), fluid replacement

• Prevention: Mosquito control, tetravalent Dengue vaccine

(in development)

• Dengue Hemorrhagic Fever (DHF)

- Severe manifestation of Dengue infection

- Secondary exposure to different Dengue subtypes

- Circulatory failure, hemorrhage and shock

Page 54

Dengue Fever: 2 Transmission Patterns

Epidemic Dengue

• Introduction of single viral

subtype as isolated event

• Large susceptible populations:

explosive transmission (25-50%

incidence during epidemic)

• Predominant in small islands

• Low infection risk for travelers,

except in epidemics

• DHF frequency low

Hyperendemic Dengue

• Continuous transmission of

multiple subtypes in same area

• Year round presence of

susceptibles and mosquitoes

• Majority of Dengue infections

• 5-10% of the susceptibles are

afflicted annually

• Seasonal variation

• DHF frequency higher

Page 55

Flaviviridae: West Nile Virus 31,32,33

• First isolated in West Nile Province of Uganda in 1937

• 1999: 62 cases of encephalitis and 7 deaths

• WN Virus now detected across North America, Caribbean and

South America

• Nearly all human infections due to mosquitoes (Culex)

• Virus maintained/amplified in bird-mosquito-bird cycle

• Birds usually asymptomatic, with exceptions of native bird

deaths in North America (crows) and elsewhere

• Transmission documented from infected blood products and

organ transplantation (screening now in place)

Page 56

West Nile Virus: Clinical Points 32,34,35

• Symptoms

- 80% infections asymptomatic

- Immunity after infection thought to be life long

- Peak in late summer/early fall (mosquito cycles)

• West Nile Fever

- Self-limited febrile illness (fatigue, fever, headache, rash)

- Indistinguishable clinically from other viral illnesses

- Symptoms can last up to 30 days

• Neuroinvasive Disease

- Only 1 in 150 infections (2-12% case fatality rate)

- Encephalitis, meningitis, flaccid paralysis, cranial nerve palsies

- Associated with old age, diabetes and alcohol abuse

Page 57

West Nile Virus: Diagnosis & Treatment

• Diagnosis

- ELISA for IgM antibody (plasma or CSF)

- IgM may appear after 8 days of infection and may

persist for 6 months

- Viral isolation: Viral culture, PCR (not routine)

• Treatment

- Supportive care

- In vitro and animal evidence for interferon alfa efficacy

- Ribavirin: not proven and possibly detrimental in

animal models

- Possible role for IV immunoglobulin (unstudied)

Page 58

Emerging Respiratory Pathogens: SARS 36,37,38

• Severe Acute Respiratory Syndrome

• 2003: Severe, progressive respiratory infection in Hong

Kong, China, Viet Nam, Singapore, Taiwan, Canada

• First ever WHO travel advisories: Guangdong Province

China, Hong Kong, Taiwan, Hanoi, Singapore

• Contagion identified as a new Coronavirus

• Significant number of health care worker infections

• 9 cases due to viral research: National Institute of Virology,

Beijing

Page 59

SARS: WHO Case Definitions

• Suspected Case

- Fever >38 deg C plus

- Cough or respiratory distress plus

- Contact with a SARS patient, travel/residence in

affected area

• Probable Case

- Suspected Case + x-ray evidence: pneumonia, or ARDS

- Suspected Case with positive SARS diagnostic testing

- Fatal respiratory illness with evidence of ARDS

without other etiology

Page 60

SARS - Epidemiology

• First cases in Guangdong Province China

• Most cases in adults with higher mortality in elderly (43% case

fatality > 60 years old)

• Likely milder disease in children with no fatal pediatric cases

documented

• 2003 outbreak: 8422 cases with 916 deaths (case fatality rate

of 11%)

• Reservoir: Horseshoe bats harbor viruses with identical

sequence to SARS/Molecular similarity to civets (cat-like

animal) coronavirus

• Transmission likely via droplet (high rate of nosocomial

spread) and possibly airborne

Page 61

SARS: Clinical Points

• Prodromal Phase: fever, myalgias, malaise

• Respiratory Phase: 3-7 days: non productive cough, respiratory failure

• Poor Prognostic Factors

- Diabetes - Older age

- Acute Renal failure - Comorbid conditions

- Elevated serum LDH

• Diagnosis:

- Serology: ELISA (acute and convalescent sera)

- Viral isolation: PCR

• Treatment: Supportive care (critical care and ventilatory support)

- No proven anti-viral therapy

- Interferon alfa may decrease symptom length (animal model)

Page 62

SARS: Prevention

• Avoidance of exposure and infection control for suspected

cases and contacts

• Infection control difficult as not all patients require

hospitalization

• Voluntary measures to avoid exposing others

• Closing of facilities (e.g., schools, hospitals, clubs) and

quarantines, travel advisories

• Strict adherence to infection control practices in hospitals

(droplet and airborne precautions)

• Avoid respiratory procedures

Page 63

Emerging Respiratory Pathogens: Avian Flu

• Avian Influenza H5N1 endemic among bird and poultry in

Asia

• Spread via migratory birds

• Sporadic transmission to humans

• Concern for exchange of genetic material with co-infecting

human influenza viruses-new epidemics

• For further information please see the GHEC Module

entitled: Emerging Infectious Disease: Focus on

Avian Influenza

Page 64

Summary: Emerging and Reemerging Viral Infectious Diseases

• Multiple biological, behavioral, ecological factors contributing

to the emergence and reemergence of viral infectious

diseases

• Multiple EID hotspots exist globally

• SIV/HIV

• Viral Hemorrhagic Fevers

- Filoviruses

- Arenaviruses

- Bunyaviridae

Summary

• Flaviviruses

- Yellow Fever

- Dengue

- West Nile

• Emerging Respiratory Pathogens

- SARS

- Avian Flu H5N1

• Other viral pathogens not covered in this module:

- Hanta virus - Viral Encephalitidies

- Hepatitis C - Resistant pathogens (HIV)

Page 66

References

1.Morens D, Folkers G, Fauci A. The challenge of emerging and re-

emerging infectious diseases. Nature 2004. Vol 430. p. 242-249.

2.Jones K, Patel G, Levy M, et al. Global trends in emerging infectious

diseases. Nature 2008. 451:21; 990-994.

3.Woolhouse M. Emerging diseases go global. Nature 2008, vol 451/21.

898-99.

4.Apetrei C, Marx P, Smith S. The evolution of HIV and its consequences.

Infect Dis Clin Am 2004. vol 18. p 369-394.

5.Van Heuverswyn F, Peeters M. The origins of HIV and implications for the

global epidemic. Curr Infect Dis Rep. 2007 Jul;9(4): 338-346.

6.Kallish M, Wolfe N, Ndongmo C, McNicholl J et al. Central African

hunters exposed to Simian Immunodeficiency Virus. Emerging Infectious

Diseases 2005. vol 11:12. p 1928-1930.

7.Bray M. FIloviridae. Clinical Virology, Richman D, Whitley R, ASM Press,

Washington DC 2002. p 875.

8.Pourrut X, Kumulungui B, Wittman T, et al. The natural history of ebola

virus in Africa. Microbes Infect 2005; 7:1005.

References

9. Bray M. Epidemiology, pathogenesis, and clinical manifestations of Ebola and

Marburg hemorrhagic fever. Up to Date online serial. http://www.uptodate.com.

Accessed July, 2008.

10.Martini G. Marburg agent disease: in man. Trans R Soc Trop Med Hyg 1969;

63:295.

11.Bray M, Murphy F. Filovirus research: knowledge expands to meet a growing

threat. J Infect Dis 2007; 196 suppl 2: S438.

12.Bray M. Diagnosis and treatment of Ebola and Marburg hemorrhagic fever. Up to

Date online serial. http://www.uptodate.com. Accessed July, 2008.

13.Groseth A, Feldman H, Strong J. The ecology of Ebola virus. Trends in

Microbiology 2007. 15:9. 408-415.

14.Peterson A, Bauer J, Mills J. Ecologic and geographic distribution of filovirus

disease. Emerging Infectious Disease 2004. 10:1. 40-47.

15.Swenson D, Wang D, Luo M, Kelly L. et al. Vaccine To Confer to Nonhuman

Primates Complete Protection against Multistrain Ebola and Marburg Virus

Infections. Clin Vaccine Immunol. 2008 March; 15(3): 460–467.

16.Preston R. The hot zone. Random House, New York 1994.

http://www.uptodate.com/


References

17.Richmond J, Baglole D. Lassa fever: epidemiology, clinical features, and social

consequences. BMJ. 2003 Nov 29;327(7426):1271-5.

18.Lassa Fever. Centers for Disease Control and Prevention: Special Pathogens

Branch. http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lassaf.htm.

Accessed August, 2008.

19.McCormick J, Fisher-Hoch S. Lassa fever. Curr Top Microbiol Immunol.

2002;262:75-109.

20.McCormick J, King I, Webb P. Lassa Fever: Effective therapy with ribavirin. N

Engl J Med. 1986 Jan 2;314(1):20-6.

21.Arenaviruses. Centers for Disease Control and Prevention: Special Pathogens

Branch. http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/arena.htm.

Accessed August, 2008.

22.Gonzalez JP, Emonet S, de Lamballerie X, Charrel R. Arenaviruses. Curr Top

Microbiol Immunol. 2007;315:253-88.

23.Ergönül O. Crimean-Congo haemorrhagic fever. Lancet Infect Dis. 2006

Apr;6(4):203-14.

24.Flick R, Bouloy M. Rift Valley fever virus. Curr Mol Med. 2005 Dec;5(8):827-34.

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lassaf.htm

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/arena.htm

References

25. Gould E, Solomon T. Pathogenic Flaviviruses. The Lancet 2008. vol

371. 500-509.

26. Barnett, E. Yellow Fever: epidemiology and prevention. Clin Infect Dis

2007; 44;850.

27. Monath T. Yellow Fever. Up to Date online serial.

http://www.uptodate.com. Accessed September, 2008.

28. Halstead S. Dengue. Lancet. 2007 Nov 10;370(9599):1644-52.

29. Gubler D. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev

1998; 11: 480.

30. Rothman A. Clinical presentation and diagnosis of dengue virus

infections. Up to Date online serial. http://www.uptodate.com.

Accessed September, 2008.

31. West Nile Virus Activity- United States, 2001. MMWR Morb Mortal Wkly

Rep-2001;51:497.

32. Petersen L Roehring J. West Nile Virus: a reemerging global pathogen.

Emerg Infect dis 2001; 7:611.



References

33. Petersen, L. Epidemiology and pathogenesis of West Nile virus infection.

Up to Date online serial. www.uptodate.com. Accessed September,

2008.

34. Watson J, Pertel P, Jones R et al. Clinical characteristics and functional

outcomes of West Nile Fever. Ann Intern Med 2004; 141:360.

35. Petersen L, Marfin A. West Nile virus: A primer for the clinician. Ann

Intern Med 2002; 137:173.

36. Cheng V, Lau S, Woo P, Yuen K. Severe acute respiratory syndrome

coronavirus as an agent of emerging and reemerging infection. Clin

Microbiol Rev. 2007 Oct;20(4):660-94.

37. Severe Acute Respiratory Syndrome. Centers for Disease Control and

Prevention. http://www.cdc.gov/ncidod/sars/. Accessed September,

2008.

38. Christian, MD, Poutanen, SM, Loutfy, MR, et al. Severe acute respiratory

syndrome. Clin Infect Dis 2004; 38:1420.


http://www.cdc.gov/ncidod/sars/

http://www.uptodate.com/online/content/abstract.do?topicKey=viral_in/23539&refNum=1









Credits

• Joseph U. Becker, MD:

– Chief Resident Yale University, Division of Emergency

Medicine, Department of Surgery

• Michele Barry, MD FACP:

– In 2009: Professor of Medicine and Global Health.

Director, Office of International Health, Yale University

– In 2013: Professor of Medicine, Senior Associate Dean

for Global Health, Director of Global Health Programs in

Medicine, Stanford University

Sponsors The Global Health Education Consortium gratefully acknowledges the support provided for developing these teaching modules from:

Margaret Kendrick Blodgett Foundation

The Josiah Macy, Jr. Foundation

Arnold P. Gold Foundation

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0

United States License.

http://creativecommons.org/licenses/by-nc-nd/3.0/us/





