Emerging and Re-emerging Infectious Diseases

Piroon Mootsikapun M.D.Boonsong Patjanasoonton M.D.

Emerging infectious diseases (EID)New infection occurred during 2 decades with tendency to cause more diseases and/or in new geographic area

Nipah virus, Avian Flu H5N1, SARS

Re-Emerging infectious diseases Pre-existing infections that cause new

epidemic or attacks or drug resistance

Dengue, TB, Malaria, Cholera

Examples of Viral EIDrecognized since 1973

Year Microbe Disease1973 Rotavirus Infantile diarrhea1977 Ebola virus Ebola hemorrhagic fever1977 Hantaan virus Pulmonary renal syndrome1980 HTLV-I T-cell leukemia1982 HTLV-II Hairy cell leukemia1983 HIV AIDS1988 Hepatitis-E Hepatitis1989 Hepatitis-C Hepatitis1994 Sabia virus Bazillian hemorrhagic fever1995 HHV-8 Kaposi sarcoma in AIDS2003 Coronavirus-urbani str. SARS

Examples of Bacterial EIDrecognized since 1973

Year Microbe Disease1977 Legionella Legionnaires’ disease1981 St. aureus(toxic strain) Toxic shock syndrome1982 E coli 0157:H7 Hemolytic uremic syndrome1982 Borrelia burgdorferi Lymes disease1983 H pylori Peptic ulcer1992 Vibrio cholera 0139 Cholera-new strain1992 Bartonella henselae Cat-scratch disease

Examples of Parasitic EIDrecognized since 1973

Year Microbe Disease1976 Cryptosporidium Acute & chronic diarrhea1985 Enterocytozoon bieneusi Persistent diarrhea1986 Cyclospora cayetanensis Persistent diarrhea1991 Encephalitozoon hellem Conjunctivitis1991 Babesia (new species) Atypical babesiosis1993 Encephalitozoon cuniculi Disseminated disease

Factors Contributing to Emergence or Re-emergence

ปจจยัจากเชื้อกอโรคNew agentAgent adapt from animal host to humanRare disease become commonMild disease become severePathogen gain resistance to antimicrobial therapy

Factors Contributing to Emergence or Re-emergence

การเปลี่ยนแปลงวิถีชีวิตFast-food: HUSWorking parents: Day care center: HFMDSuper-absorbing tampon: TSS Sexual practice: HIVDrug abuse: HIVCamping—ecotour: malaria, DHFInternational travelling: SARS

Factors Contributing to Emergence or Re-emergence

การเปลี่ยนแปลงระบบนิเวศนFlood and droughtWarTrans-border migrationNatural catastrophy: Tsunami, earthquakeDeforestation and re-forestationGlobal warming

Factors Contributing to Emergence or Re-emergence

ความกาวหนาทางเทคโนโลยีCancer chemotherapyOrgan transplantationImmunosuppressive therapyInvasive Dx and Rx proceduresNew devicesWidespread- and mis-use of antibiotics

Factors Contributing to Emergence or Re-emergence

การเพิ่มผลผลิตทางการเกษตร/อุตสาหกรรมอาหาร

Globalization of food supplyLarge farm production: JE, Nipah virusAnimal Feeding: BSE & variant CJDAnimal transportFood chain franchise: HUSWild animal market: SARS

Factors Contributing to Emergence or Re-emergence

การคาสากล/การคาเสรีMonkey shipments: Marburge & EbolaPet animals trafficking: West Niles, monkey-pox, avian influenzaUsed-tyres trading: dissemination of Aedesaegyptietc

Factors Contributing to Emergence or Re-emergence

ปจจยัจากเชื้อกอโรคNew agentAgent adapt from animal host to humanRare disease become commonMild disease become severePathogen gain resistance to antimicrobial therapy

Emerging Infectious Diseases-nearly all are zoonotic or species jumping agents

-HIV-Influenza-Hepatitis C and E

-E. coli 0157:H7-Cryptosporidium-Ebola-Hantavirus-Lyme disease-nvCJD-Trypanosomiasis-West Nile Virus

Species Jumping

Zoonoses

Zoonoses: Routes of pathogen exchange

Route of exchange PathogenAnimal bite Monkeypox

Fecal-oral Poliovirus

Hunting, food-prep., eating Ebola

Respiratory droplet, aerosalized Co-SARS, TB, M. leprae

Vector borne Malaria, Filaria

Water-mediated Dracunculiasis, Schistosomiasis

Animals Involved in Species Jumping

Arthropods (e.g. ticks and mosquitoes)

Wild animals (e.g. chimps and rodents)

Domestic animals (e.g. dogs and cats)-draught (e.g. horses)-food (e.g. poultry and cattle)

Emerging infectionsRespiratory syndrome

SARS, Avian flu

Neurological syndrome

West Nile virus, Nipah virus

Hemorrhagic syndrome

Ebola virus

Gastrointestinal syndrome

Cholera, E. coli O157H7

Severe Acute Respiratory Syndrome(SARS)

Increased Understanding of Transmission

A Novel coronavirus is associated with SARS

SARS Coronavirus (Urbani strain)SARS-CoV (Urbani strain)*

Previously unrecognized coronavirusGenomic sequence from viral RNA ~ 29,727 nucleotides in lengthComposed of spike protein (S), small membrane protein (E),

membrane protein (M), and nucleocapsid protein (N)

Virus entry

ACE-2 is a receptor for SARS CoVLi et al. Nature 2003; 426: 450-454Wang et al. BBRC 2004; 315: 439-444

ACE-2 is found on pneumocytes and enterocytes

Hammling et al. J Pathol. 2004; 203: 631-637

C type Lectin receptors DC-SIGN and L-SIGN bind virus. But entry via these does not lead to complete virus replication

Yang et al J. Virol. 2004; 78: 5642-5650

Jeffers SA et al. PNAS 2004; 101: 15748-53.

Pathogenesis:Pneumocytes infected with SARS CoVSwollen pneumocytes Viral antigen CD68 positive cells

in pneumocyte Macrophages

Nicholls et al Lancet 2003

Presenting clinical features of SARSA composite of multiple reports: Based on 752 patients, Summarised in Peiris et al NEJM Dec 18; 2003

Fever – 100% Myalgia – 68%Malaise – 59%Cough – 66%Chills / rigors – 52%Dyspnoea – 46%Headache – 39%Dizziness – 27%Diarrhoea – 20%(profuse, watery)

Rhinorrhoea – 14%Sore throat – 17%Chest pain / pleurisy – 20%Tachypnoea – 39%Chest rales – 28%

Leucopenia – 24%Lymphopenia – 66%Thrombocytopenia – 30%Elevated ALT – 44%Elevated LDH – 46%

Diagnosis of SARS

ผูปวยในขายตองสงสัยเปน SARS(Suspected SARS)WHO & CDC Surveillance definition

1. ไข > 38 * C2. อาการระบบการหายใจ3. ประวัตกิารเดนิทางไปในทีท่ีม่กีารระบาดในชมุชนภายใน 10 วนั หรอื

ประวัติสมัผัสใกลชิดกบัผูปวยหรอืดแูลผูปวย suspected or probable SARS

ผูปวยนาจะเปน SARS(Probable SARS)

Suspected SARS

1. CXR พบมีปอดอักเสบหรือ

2. มีอาการหายใจลําบากหรือ

(3.พบพยาธิสภาพเขาไดกับARDSโดยไมทราบสาเหตุจากการตรวจศพ)

ผูปวยSARSแนนอน(Definite or lab.-confirmed SARS)

Probable or Suspected SARS

Confirmation Test of Definite Pathogen1. Antigenic Testing

1.1 electron microscopy1.2 PCR Technique

2. Antibody Testing ( 4 fold rising of Ab titer in pair serum) 2.1 IFA2.2 ELISA

Asymptomatic and mild infections?

Severe

Mild or

Asymptomatic

Most respiratoryviruses

SARS

Close contacts of confirmed SARS

3 of 1068 (0.3%) asymptomatic contactsare seropositive

Asymptomatic infection is uncommon

Leung et al EID 2004; 10: 1653-6

Viral load is lower in first 5 days of illness.

SARSFlu

Predicts thatTransmission is less likely early in illness?Supported by epidemiological dataLipsitch et al 2003; Science 300: 1966-70If patients can be detected and isolated early, transmission can be interrupted

Factors associated with adverse clinical outcome

Age

Co-morbidity

Viral load at early stage of illness (in

nasopharyngeal aspirate and serum)

Chu et al. CMAJ 2004; 171: 1349-52

Ng et al. Clin Chem 2004; 49: 1976-80

Treatment

No effective antiviral agents

Prevention/Prophylaxis

Active and passive immunization candidates

Active immunizationInactivated vaccine protects from challengeSpike protein is sufficient for protection

DNA vaccines, Vectored vaccines (adenovirus, vaccinia, parainfluenza type 3)

Passive immunizationHuman monoclonal antibodies to spike protein

Where did SARS CoV come from?

Epidemiological link in early cases of SARSin Guangdong in Nov – Dec 2002Xu et al. EID 2004; 1030-7

Re-emergence of community acquired SARS in Guangdong

4 patients

Dec 16, 2003

Dec 26, 2003

Dec 30, 2003

Jan 8, 2004Liang et al EID 2004; 10: 1774-81

Influenza virusFamily Orthomyxoviridae: RNA virusSpherical shape with spikesFilamentous form- infectious Envelope + spikes -> Hemagglutinin (HA), Nuraminidase (NA)Cell membrane with M ion channelCore protein – typing A, B, CMultiple RNA 7-8 segments

Influenza RNA segment and protein

RNA Protein Size Fn activitysegment

1 PB2 759 Cap binding, endonuclease2 PB1 757 RNA polymerase3 PA 716 RNA polymelase4 HA 560 R attachment5 NP 498 RNP component6 NA 450 release of virus7 M1 252 structural protein

M2 96 ion channel 8 NS1 230 IFN antagonist

NS2 121 nuclear export factor

Influenza virus

Influenza A พบใน คน สัตวปก มา หมู แมวน้ํา

Influenza B พบเฉพาะในคน

Influenza C พบในคน หมู สุนัข

Influenza virus

Influenza A แบงเปนชนิดยอยตาม glycoprotein ที่ยื่นออกมา

Hemagglutinin (HA) – 15 subtypes (H1-H15)

Nuraminidase (NA) – 9 subtypes (N1-N9)

All subtypes found in birds = natural reservoir

of influenza A

Influenza virus

การเรียกชื่อสายพันธุ

Strain- types, host origin, geographic

isolates, serial number, year of

isolation, HA and NA subtypes

Influenza A/chicken/HK/258/97/H5N1

การกลายพนัธุ (Mutation)

Antigenic drift – เกิดการเปลี่ยนแปลงเล็กนอยที่ gene (gene mutation)

Antigenic shift – เกิดการแลกเปลี่ยน RNA

ของไวรัส (gene reassortment) ระหวางสายพันธุหรือชนิดยอย มักเกดิระหวางที่มีการติดเชื้อ 2 สายพันธุในเวลาเดียวกัน ทําใหเกดิการระบาดใหญ

Influenza A epidemicปพ.ศ. ระยะเวลา สายพันธุ ชื่อ อัตราตาย2432 28 H3N? สูง

2461 39 H1N1 spanish flu 548000

2500 11 H2N2 asian flu 860002511 ปจจุบนั H3N2 Hong Kong flu 34000

2519 <1 H1N1 swine flu 12520 ปจจุบนั H1N1 Russian flu nil

2540 <1 H5N1 bird flu 6 in HK

Avian influenza virus

แยกเชื้อไวรัสไดจากนกปาและนกบานมากมายหลายชนิด โดยเฉพาะนกทีช่อบน้ําหงส หาน เปด นกนางนวล นกเปดน้ํานกกระทา (qail), ไก Turkeys, นกกระสา นกกระยาง

Avian influenza virus

Virus replicate in GI tract - >

excrete feces of wild aquatic birds

Most asymptomatic but vary with

species

Avian influenza virus

สามารถถายทอดระหวางสัตวปกดวยกันได เชน จาก นกเปดน้ํา นกปา ไปยังไก เปด ทําใหเกดิอาการไดตั้งแตไมรุนแรงจนถึงรุนแรง ตายอาการที่พบ ไดแก หงอย เขียว มีน้ํามูกไหล ปอดบวม ทองเสีย

Avian influenza virusบางครั้งสามารถถายทอดไปยังสัตวเลี้ยงลูกดวยนมได เขน คน มา หมู ปลาวาฬ แมวน้ําเชื่อวา influenza A ในคนนั้นแทจรงิมีตนกําเนิดมาจากเชื้อไขหวัดนกที่เคยติดมายังคนในสมัยโบราณ

Birds -> Pigs < - Human

แตโดยทั่วไป avian flu ไมกอโรคในคนโดยตรงเนื่องจากมีความแตกตางกนัของการจับกับตัวรบั(receptor)Human flu prefer attach to sialic acid with alpha –(2,6) linkage that are predominant in human respiratory tract epithelium, avian flu prefer alpha –(2,3) linkage

Birds -> Pigs < - Human

หมมูี receptor ทั้ง 2 ชนิดในหลอดลม จึงสมารถเปนตัวกลางในการเกิดการแลกเปลี่ยน gene ระหวาง avian flu และ human flu ในสถานที่มีการอยูรวมกัน

How human to human transmission may occur

Migratory water birds

Domestic birds

Migratory water birds

Domestic birds

H5N1 bird flu

Genetic reassortment between H5N1 in

goose and H6N1 in duck or H9N2 in

quail

highly pathogenic to chicken, human

Infect human directly

Pathogenicity of avian flu

H5 in avian flu have extra basic amino acid in HA cleavage site -> easy to activation by cellular protease in tissue -> systemic replicationavian flu in HK virulence related to HA and PB

Pathogenicity of avian flu H5N1

Disseminated infection

Lymphocyte depletion

Deficient cytokine response

Lack of increase in transform beta

growth factor

H5N1 avian flu

First detect in human in 1997 in a

child with pneumonia -> death

Human infect 18 cases/ 6 deaths

Chicken slaught 1.6 million in 2

days

Confirmed Human Avian Influenza A /(H5N1)

12/2003-03/2004

Cases/deaths

07/2004-10/2004

Cases/deaths

12/2004-10/2005

Cases/deaths

TotalCases/deaths

Vietnam 23/16 4/4 64/21 91/41Thailand 12/8 5/4 0/0 17/12Cambodia 0/0 0/0 4/4 4/4Indonesia 0/0 0/0 5/3 5/3Total 35/24 9/8 69/25 117/60

Mortality rate = 51.2%

source WHO 10 Oct 2005

Area affected by H5N1 in poultry

JapanLaosMalaysiaSouth KoreaMongoliaRussiaKazakhstan

ThailandCambodiaVietnamIndonesiaChinaHong Kong

Diagnosis of avian flu

Cell culture in canine kidney cell lines,

LLCMK cells

Easily detect cytopathic effect in 4-5 days

Identification

- RT-PCR

- Immunostaining with H5-specific monoAb

Diagnosis of avian flu

Direct detection from nasopharyngeal

swab, endotracheal aspirate with IFA by

H5-monoAb

Direct detection by RT-PCR

Centrifugation of 2 day shell vial culture

from respiratory samples followed by

immunostaining

Management of influenza

Supportive treatment

Antiviral

Amantadine, rimantadine

Ostelmizavir, Zanamivir

Vaccination

Amantadine and rimantadine

Inhibit human A H1/N1, H2N2, H3N2Inhibit M2 channel –> inhibit uncoatingNon human subtypes also sensitiveNo activity to influenza BResistance can occurIn healthy adult, < 48 hr onset -> reduce viral replication, duration of symptoms in 1-2 daysUncertain benefit in flu pneumonia

Amantadine and rimantadine

Dose 100 mg BIDDuration 5 daysIndicationTreatment of influenza during outbreakPrevention during flu seasonPost exposure prophylaxis in householdsSide effect: CNS- dizziness, insomniaGI – nausea, vomitting

Nuraminidase inhibitor

Inhibit both influenza A and B

Potent activity in vitro to H5N1, H9N2

Reduce duration of illness 1-1.5 days

Reduce antibiotic prescription 30-40%

Nuraminidase inhibitor

Zanamivir inhaled 10 mg BID for 5 days

Oseltamivir oral 75 mg BID for 5 days

Side effect: nausea, vomitting with

oseltamivir

Prevention

Vaccination

Current influenza vaccine –

A/H1N1,A/H3N2 and influenza B, no

activity to avian flu

Avian flu vaccine in progress

Avian Flu vaccine trial now started

Now in Phase I trial in USA in 3 universities

Use H5N1 strain in Asia 2004

Produced by Sanofi-Pasteur

Test in 450 healthy volunteers 18-64 yrs for safety and immune response

Prevention

Risk of transmission from poultry to human

Associated with heavy exposure

No association was found with eating chicken

meat

Prevention

H5N1 and eggs from infected poultry

H5N1 cause viremia and damage other

tissues and seed in eggs

Eggs should be boiled or heated above 50 C

But no evidence of GI tract as entry of

infection

Prevention

Virus inactivated by pH>9 or < 5,

temperature > 50 C

Destroy by detergent and organic

solvents

Stable in low temperature 4C for months

Drying inactivate virus in <12 hours

ขอเปรียบเทียบ ซารส หวัดนกสาเหตุ Corona virus

(Urbani strain)Influenza A (H5N1,H9N2,H7N7)

การติดตอ สัตวสูคน

คนสูคน

สัตวปกสูคน

การระบาดในคน โอกาสมากกวา วงจํากดั

ระยะฟกตัว 3-10 วัน 1-3 วัน

อาการรุนแรง/ เสียชีวิต

20-25% / ~10%

~ 50 % / ~30%

Bioterrorism(Bioweaponization)

Recognized Agents (CAT. A) AnthraxBotulismPlagueSmallpoxTularemia Viral hemorrhagic fever

Features that should alert HCWsof

Outbreak & Bioterrorism-related

Clusters of patients from single locale

Rapidly & unusually increasing

“disease incidence” or people seeking

care of the same symptoms

Bioterrorism(Bioweaponization)Potential Agents (CAT. B)

BrucellosisQ-feverViral encephalitisMeliodosisPsittacosisStaphylococcus enterotoxin BVibrio cholerae ETC

Bioterrorism(Bioweaponization)

Emerging Agents (CAT. C)Nipah virus

Hunta virus

MDR-TB

Tick borne encephalitis

Controlling disease

SurveillanceResponse (& Research: Dx

& Prevention) Control & Connections Prevent & Prepare

Emerging Diseases: Networking Facilities

Global Regional National Cluster and provincialInstitutional Community

Emerging Diseases: Networking Facilities

Cluster and provincialSurveillanceResponseControlPrepare & preventionแผนรองรับสถานการณตามขนาดของปญหา/จํานวนผูปวย

PulseNet: The National Molecular SubtypingNetwork for FoodborneDisease Surveillance

Introduction and Spread of West Nile Virus in the United States

USA Today Apr 3, 2000

Human Cases of WNV in the United States1999—2003

Lancet Infectious Diseases 2004;4:547-556.

The 2002 WNV EpidemicLargest number of WNV severe neuro-invasive disease ever documented (4,156)New clinical syndromesFive novel modes of transmission

Transplanted organsTransfused bloodBreast milkTransplacental transmission Percutaneous, occupational exposure

Blood Donor Screening

• In 2003, screening of blood supply using pooled NAAT initiated

• ~6.2 million units screened July – Dec• >1,000 “viremic” donors identified• 6 transfusion-associated WNV infections occurred from components not detected by screening

In 2004, 192 presumptively viremicdonors to date

1 documented “breakthrough” case

2004 West Nile Virus Activity in the US, reported to CDC as of Nov. 16, 2004

2313 cases; 79 deaths

The Washington Post, June 9, 2003

MonkeypoxOrthopox virus First identified in non-human primates, but reservoir is rodents1st human illness seen in 1970 in Congo Clinical features similar to smallpoxLower mortality (<10%); less efficient person-to-person transmissionAll previous disease in West and Central AfricaUnderstudied; smallpox vaccine appears cross-protective

IL-1

Imported Lassa Fever, New Jersey, 2004

Lassa Fever

•Caused by an arenavirus•Discovered in Nigeria in 1969•Endemic in portions of West Africa•Estimated 300,000 – 500,000 infections per year•Incubation period: 5 – 21 days•Case-fatality rate of hospitalized patients: 15%-20%•Person-to-person transmission in healthcare

settings•Transmitted from rodents to humans