Emerging and Re-emerging Infectious DiseasesEmerging infectious diseases (EID) New infection...
Transcript of Emerging and Re-emerging Infectious DiseasesEmerging infectious diseases (EID) New infection...
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