Global Epidemiology of H5N1 in Humans Tim Uyeki MD, MPH, MPP - - PowerPoint PPT Presentation

Global Epidemiology of H5N1 in Humans

Tim Uyeki MD, MPH, MPP Influenza Division, National Center for Immunization and Respiratory Diseases Coordinating Center for Infectious Diseases, CDC August 9, 2006

Avian Influenza A Viruses H1 - H16 N1 - N9

H1 - H3 N1 - N2

Human Influenza A Viruses Natural reservoir for new human influenza A Natural reservoir for new human influenza A virus subtypes: virus subtypes: Wild waterfowl, aquatic ducks Wild waterfowl, aquatic ducks

Antigenic “shift”

Emergence of a new human influenza A virus subtype (new HA subtype) through:

• Genetic reassortment (human and animal

viruses)

• Direct animal (poultry) to human transmission

A pandemic can occur if:

• A novel influenza A subtype virus infects people
• The new influenza A subtype virus causes disease
• Efficient and sustained virus transmission occurs

among humans (sustained person-to-person spread)

Avian Influenza A Viruses Avian Influenza A Viruses

• Infect respiratory and gastrointestinal tracts of birds

Infect respiratory and gastrointestinal tracts of birds

• Natural reservoir is wild waterfowl

Natural reservoir is wild waterfowl -

• usually infections

usually infections do not cause disease (wild ducks and geese) do not cause disease (wild ducks and geese)

• Genetic re

Genetic re-

• assortment occurs

assortment occurs

• Viruses are present in respiratory secretions, excreted

Viruses are present in respiratory secretions, excreted in feces in feces

• Can survive at low temperatures and low humidity for

Can survive at low temperatures and low humidity for days to weeks days to weeks

• Can survive in water

Can survive in water

• Disinfection of the environment is needed

Disinfection of the environment is needed

Classification of Avian Influenza A Viruses Classification of Avian Influenza A Viruses

• Two classes

Two classes

• Low Pathogenic Avian Influenza viruses (LPAI)

Low Pathogenic Avian Influenza viruses (LPAI)

• Highly Pathogenic Avian Influenza viruses (HPAI)

Highly Pathogenic Avian Influenza viruses (HPAI)

• Determined by molecular and

Determined by molecular and pathogenicity pathogenicity criteria criteria

Any one of the following:

• Any avian influenza A virus that is lethal for four-

week old chickens

• 6, 7 or 8 of 8 four-week-old chickens within 10 days

following IV inoculation with 0.2ml of 1:10 dilution of infectious allantoic fluid.

• Any H5 or H7 virus that has a multi-basic amino

acid sequence at the hemagglutinin cleavage site compatible with HPAI.

• Any non H5 or H7 that kills 1-5 of 8 inoculated

chickens and grows in cell culture without trypsin

Avian Influenza A Viruses Avian Influenza A Viruses Criteria for High Pathogenicity Criteria for High Pathogenicity

Fulfillment of one or more of criteria would categorize the virus as an HPAI virus. United States Animal Health Association, 1994.

Pathogenicity Pathogenicity of AI in Poultry

• f AI in Poultry
• Low Pathogenic Avian Influenza viruses (LPAI)

Low Pathogenic Avian Influenza viruses (LPAI)

• Usually do not cause illness in wild birds

Usually do not cause illness in wild birds

• May cause mild illness in domestic poultry

May cause mild illness in domestic poultry

• Cause poultry outbreaks worldwide

Cause poultry outbreaks worldwide

• Can evolve into highly pathogenic viruses

Can evolve into highly pathogenic viruses

• Highly Pathogenic Avian Influenza viruses (HPAI)

Highly Pathogenic Avian Influenza viruses (HPAI)

• Usually do not cause illness in wild birds

Usually do not cause illness in wild birds

• Usually cause high mortality in domestic poultry

Usually cause high mortality in domestic poultry

• Subtypes: H5, H7

Subtypes: H5, H7

HA nucleotide

VietnamHN3040805

Phylogeny of H5N1 viruses from Asia

DkVietnamNCVD0105 CkVietnamNCVD1005 Vietnam120304 VietnamJPHN3032105 Hong Kong21303 CkIndonesia703 CkIndonesia1103 CkYunnan49305 CkGuangxi1204 CkYamaguchi704 CkKoreaES03 CkShantou423103 BarhdGooseQinghai1205 DkFujian173405 CkGuangdong19104 DkHunan19105 DkChinaE319203 CkGuangdong17804 CkShantou81005 GsShantou162105 CkVietnamNcvd803 tealChina2978102 Hong Kong15697 GsGuangdong196

0.005

Clade 1 1’ Clade 2

H5N1 Virus Binding

• H5N1 viruses bind to cells in the lower

respiratory tract: different than for human influenza A viruses

• Human influenza A viruses bind to receptor cells with

sialic acid linked to galactose by α-2,6 linkage

• Upper respiratory tract (epithelial cells in paranasal

sinuses, pharynx, trachea, bronchi)

• H5N1 viruses bind to receptor cells with sialic acid

linked to galactose by α-2,3 linkage

• Lower respiratory tract (Type II pneumocytes, non

ciliated epithelial cells in terminal and respiratory bronchioles, alveolar macrophages)

Van Riel D et al. Science Express March 26,2006; Shinya K et al. Nature 2006;440:435-436.

1997: H5N1 Emerges in Hong Kong

18 confirmed cases, 6 deaths

• Median age: 9.5 years (range 1-60 yrs.)
• 1 had active chronic illness (SLE)
• Admission findings:
• High fever, cough, sore throat, rhinorrhea, vomiting, diarrhea
• Clinical complications
• Severe pulmonary disease
• 11 (61%) pneumonia; 6/11 died; 3 had pleural effusions
• 6 (33%) had ARDS (5 fatal)
• Other complications:
• 5 (28%) had multi-organ dysfunction (all fatal)
• Reactive hemophagocytosis, renal failure, Reye syndrome
• None had evidence of bacterial pneumonia

Chan PKS. CID 2002;34(Suppl 2):S58-S64; Mounts A et al., JID 1999;180:505-508; Yuen KY et al. Lancet 1998;351:467-71.

H5N1 Re-emerges 2003

• Hong Kong, February 2003
• 2 confirmed cases (5-person family)
• Visited Fujian Province, China (Jan., Feb. 2003)
• 7-year old girl died of pneumonia in China (not tested)
• 33-year old man hospitalized in Hong Kong, died
• 9-year old boy hospitalized in Hong Kong, survived

(H5N1 virus isolated from both)

• Clinical findings:
• Fever, malaise, sore throat, cough
• Pneumonia (1 with respiratory failure)

Peiris J, et al. Lancet 2004;363:617-619

H5N1 Re-emerges 2003

• Beijing, China, November 2003
• 1 confirmed case
• 24-year old male (military) hospitalized for

pneumonia, suspected to have SARS.

• Died on December 3, 2003.
• H5N1 virus isolated from patient, reported in

2006

• Confirmed by Chinese CDC

Zhu QY et al., NEJM 2006;354:2731-2; WHO August 8, 2006

At least 52 countries with H5N1 in poultry (36) or wild birds (16)

Li KS, et al. Nature 2004; 430:209-13

Seasonality of H5N1 Among Domestic Poultry, China

Hanoi, Vietnam 2002

• T. Uyeki, CDC

• T. Uyeki, CDC

Hanoi, Vietnam 2002

Dead Market Poultry, Nigeria, February 2006

• D. Klaucke CDC

Recent H5N1 Issues in Animals

Role of migratory birds increasing?

Die offs of migratory birds in western China, Siberia,

Mongolia, introduction into Europe

Ducks may be infected without illness

Pigs can be infected (China, Vietnam, Indonesia)

Other animals

• Domestic cats; civet cats
• Tigers, leopards (Thailand, China)
• Tiger-to-tiger transmission (Thailand)

Li HY et al. Chinese Journal of Preventive Veterinary Medicine 2004;26:1-6; Kuiken T et al. Science 2004;306:241; Keawcharoen J et al EID 2004;10:189-91; Thanawongnuwech R et al. EID 2005;11:699-701. Choi et al. Virology 2005;79:10821-5.

H5N1 in poultry or wild birds in 2006

Human H5N1 cases, Nov. 2003-06*

• 235 confirmed H5N1 cases, 137 deaths
• Vietnam: 93 cases (42 deaths)
• Indonesia: 55 cases (43 deaths)
• Thailand: 24 cases (16 deaths)
• China:

20 cases (13 deaths)

• Egypt:

14 cases (6 deaths)

• Turkey: 12 cases (4 deaths)
• Cambodia: 6 cases (6 deaths)
• Iraq: 2 cases (2 deaths)
• Azerbaijan: 8 cases (5 deaths)
• Djibouti: 1 case (0 deaths)

Case fatality: 58.3%

*As of August 8, 2006: H5N1 cases reported to WHO

Human H5N1 cases, 2006*

• 90 confirmed H5N1 cases, 60 deaths
• Vietnam: 0 cases (0 deaths)
• Indonesia: 38 cases (32 deaths; 84%)
• Thailand: 2 cases (2 deaths)
• China:

11 cases (7 deaths)

• Egypt:

14 cases (6 deaths)

• Turkey: 12 cases (4 deaths)
• Cambodia: 2 cases (2 deaths)
• Iraq: 2 cases (2 deaths)
• Azerbaijan: 8 cases (5 deaths)
• Djibouti: 1 case (0 deaths)

Case fatality: 66.7%

*As of August 8, 2006: H5N1 cases reported to WHO

H5N1 human cases since 2003

H5N1 human cases in 2006

Epidemiology of Human H5N1 cases 2003-06

Infrequent, sporadic avian-to-human transmission

• Previously healthy children, young adults
• WHO review of 205 confirmed H5N1 cases:
• Median age: 20 years (range: 6 months - 75 years)
• 90% of cases <40 years old
• Median duration from illness onset to hospitalization:

4 days

• Mortality highest in cases aged 10-19 years (73%)
• Mortality lowest in cases aged ≥50 years (18%)
• Median duration from illness onset to death: 9 days

(range 2-31 days)

• Clustering of cases

No evidence of sustained person-to-person spread

• WHO. Weekly Epidemiological Record 2006;81:249-257.

H5N1 Transmission

• Avian-to-human
• Most H5N1 cases had direct contact with

sick or dead poultry prior to illness onset

• Significant risk factors: direct touching of

sick or dead poultry in Thailand

• A few cases ingested uncooked duck blood

in Vietnam

• Some cases de-feathered dead wild swans in

Azerbaijan

Areechokchai D et al. MMWR 2006;55(Suppl):3-6; WER 2006;81(18):183-8.); Gilsdorg A et al. Eurosurveillance 2006.

H5N1 Case Clustering

• Hong Kong 1997
• 2 confirmed pediatric cases were cousins
• Hong Kong 2003
• 2 confirmed cases in a father and son (1 family

member died of a pneumonia-like illness)

• 2004-06
• Family clusters: Vietnam, Thailand, Indonesia,

China, Turkey, Iraq, Azerbaijan, Egypt

• Possible interpretations
• Common exposures, different incubation periods?
• Different exposures?
• Genetic susceptibility?
• Limited person-to-person transmission?

Chan PKS. CID 2002;34(Suppl 2):S58-S64; Peiris J, et al. Lancet 2004;363:617-619; Olsen S et al. EID 2005;11:1799-1801

Probable Limited Non-Sustained Person-to- Person H5N1 Transmission

• 1997 (Hong Kong)
• 2 Health care workers exposed to H5N1 patients had mild

illness (no poultry exposure, serological evidence of H5N1)

• 2003-06
• Thailand 2004
• 11-year old girl cared for by mother and aunt in

hospital, died; mother and aunt confirmed with H5N1, mother died

• Vietnam 2005: Patient-to-nurse transmission in a hospital
• Indonesia 2006: Large family cluster in North Sumatra

Ungchusak K et al., NEJM 2005; 352(4):333-40; Bridges CB et al., JID 2000:181:344-8.

H5N1 Case Clustering: Indonesia

• At least 7 clusters of cases to date (2005-06)
• Limited human-to-human transmission likely in

some clusters

• Limited human-to-human-to-human transmission of H5N1

(Northern Sumatra, May 2006)

• 8 cases (7 confirmed H5N1) in blood-related family

members, 7 died

• Index case likely acquired H5N1 virus infection from

infected poultry

• Index case transmitted to 6 family members through

prolonged close contact before hospitalization

• One case transmitted to his father in the hospital
• H5N1 viruses isolated from 7 cases: no evidence of

reassortment, no evidence of greater transmissability

Timeline of suspect and confirmed H5N1 cases, Karo District, North Sumatra Province, Indonesia 24 April – 22 May 2006

Died Suspect Survived Confirmed H5N1

37/F 25/M 29/F 18/M 1.6/F 19/M 32/M

24 April 4 May 2 May 8 9 4 May 8 4 May 8 4 May 4 May 8 Onset B Onset *C Onset C *C Onset

son

Onset *C

Died Confirmed H5N1 Died Confirmed H5N1 Died Confirmed H5N1 Died Confirmed H5N1

8 *C Died 10 Died

10/M

2 May 9 Onset *C

Died Confirmed H5N1

index brother sister son niece

Onset

nephew

11 C

brother

Case 1 Case 5 Case 7 Case 6 Case 2 Case 4 Case 3 Case 8 A 2 Clinic 5 14 12 13 Died Died Died 29

Family Gathering

3 15 May Onset Died 22

Died Confirmed H5N1 Relation to index case

Died 10 B

A = admission to Kabanjahe Hospital B = admission to Saint Elizabeth Hospital C = admission to Adam Malik Hospital (*denotes seen at Klinik Mandala, Kabanjahe prior to admission)

Epidemic Curve, by Date of Onset of Confirmed and Suspect H5N1 Cases, Karo District, April-May 2006

death of index family gathering death of cases 2, 3, 4, 6, 7 7 6 3 5 1 2 4 8 22 23 24 25 26 27 28 29 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 April May survived died confirmed

H5N1 Case Cluster and Family Members, Karo District, April-May, 2006

Female B 29 A 29 A 25 E 36 J 55 L 6

Kubu Simbelang village Kabanjahe town

case Index case Male G (dead) D 32 C 10 H 32 J 25 I 37 P 37 R 39 R 19 B 18 A 10 R 10 A 6 B 1.5 P 3 P

5 months

B 3 P 19 I 15 P 10 S 9 S

4 months

Household 1 Household 2 Household 3 Household 4

Divorced Lives apart

Asymptomatic or Mild Illness

• Asymptomatic or mild H5N1 virus infection

documented in 1997 Hong Kong

• 10% of PWers+ for H5N1 antibodies (N = 1525) single serum

specimen (avian-to-human transmission)

• 3% of government poultry cullers+ for H5N1 antibodies, paired

sera; 1 seroconverted (N = 293)

• Most pediatric confirmed cases had clinically

mild disease in Hong Kong 1997

• 7 of 11 cases were clinically mild (uncomplicated influenza)
• 4 of 11 were severe: 2 deaths, 1 respiratory failure, 1

pneumonia

• H5N1 2004-06: very limited data
• Case-finding focused upon severe respiratory disease
• Some mild H5N1 cases, some asymptomatic cases

Sero-epidemiological investigations are needed

Bridges et al., JID 2002;1005-1010; CDC unpublished data Chan PKS, CID 2002:34 (Suppl 2):S58-64.

Atypical H5N1 Virus Infection Atypical H5N1 Virus Infection

• 2004 (Southern Vietnam)
• 4-year old male fatal case of encephalitis

(seizures, coma) with diarrhea in February 2004 – clinical specimens obtained as part of encephalitis surveillance

• November 2004, laboratory testing of specimens

completed

• H5N1 virus isolated from CSF, serum, throat and

rectal swab specimens

• 2004 (Southern Vietnam)
• 4-year old male fatal case of encephalitis

(seizures, coma) with diarrhea in February 2004 – clinical specimens obtained as part of encephalitis surveillance

• November 2004, laboratory testing of specimens

completed

• H5N1 virus isolated from CSF, serum, throat and

rectal swab specimens

de Jong MD et al. NEJM 2005;352:686-91

H5N1 Incubation Period

Difficult to estimate when infection occurred from poultry exposure (range: 2-8 days)

• Hong Kong 1997: Unknown, but probably <7 days
• Vietnam 2004: (N = 6 cases)
• Poultry exposure to illness onset range: 2-4 days
• Thailand 2004: (N = 12 cases)
• Median incubation period: 4 days, range (2-10)

Hien TT et al., New England J Med 2004;350:1179-1188; Chotpitayasunodh T et al. EID 2005;11:201-9; Beigel JH et al. NEJM 2005;353:1374-85.

H5N1 Virus Replication

Thailand 2004, 6-year old fatal male H5N1 case autopsy report:

• Diffuse alveolar damage, interstitial pneumonitis, focal

hemorrhage, bronchiolitis

• Type II pneumatocytes infected, but not columnar

epithelium, no antigen in trachea, or upper airway

• Viral RNA detected by RT-PCR in lung, small

and large intestine, spleen tissues

• Positive stranded mRNA detected in lung,

intestines (replicating)

• Negative stranded RNA detected in spleen
• No viral RNA in adrenals, brain, bone marrow,

kidneys, liver, pancreas

• TNF-α mRNA detected in lungs

Uiprasertkul M et al. EID 2005;11:1036-41

Duration of H5N1 Viral Shedding Duration of H5N1 Viral Shedding

• Unknown, but may be longer than with human

influenza A virus infection (up to 16 days)

• Hong Kong 1997: 7 cases: H5N1 viruses isolated at

Days 2-11

• 3 cases had virus isolated ≥Day #9.
• Day #9 tracheal aspirate, Day #9 BAL, Day #11

tracheal aspirate; PCR+ up to day #16

• Vietnam 2004: 10 cases RT-PCR+ at Days #5-12.
• Thailand 2004: viral culture + at Days #3-16

Depends upon specimen: throat and lower respiratory specimens are best

• Unknown, but may be longer than with human

influenza A virus infection (up to 16 days)

• Hong Kong 1997: 7 cases: H5N1 viruses isolated at

Days 2-11

• 3 cases had virus isolated ≥Day #9.
• Day #9 tracheal aspirate, Day #9 BAL, Day #11

tracheal aspirate; PCR+ up to day #16

• Vietnam 2004: 10 cases RT-PCR+ at Days #5-12.
• Thailand 2004: viral culture + at Days #3-16

Depends upon specimen: throat and lower respiratory specimens are best

Hien TT et al., New England J Med 2004;350:1179-1188; MMWR 1997;46:1204-6

• WHO. NEJM 2005;353:1374-85.

What are Risk Factors for H5N1?

• H5N1 (Hong Kong, 1997)
• 18 confirmed human cases, 6 deaths (all ages)
• Median age: 9.5 years (range 1-60 yrs.); 11

pneumonia cases

• Case-control study: (15 cases, 41 age, sex,

neighborhood-matched controls)

• Risk factor: exposure to to live poultry the week

before illness (OR = 4.5, p = 0.045)

Mounts A et al., JID 1999;180:505-508

What are Risk Factors for H5N1?

• Thailand 2004
• Case-control study
• Controls: matched by village and age, 4:1
• Most significant risk factor: directly touching sick
• r dead poultry (OR = 29; 95% CI 2.7-308)
• Other risk factors: cleaning poultry, de-feathering,

having sick or dead poultry around the home, within 1 meter of dead poultry

• Vietnam 2004 (preliminary, unpublished)
• Case-control study
• Controls: matched by village and age, 4:1
• Most significant risk factor: direct contact with sick or dead

poultry

Areechokchai D et al. MMWR 2006;55(Suppl):3-6.

How many people have been infected with H5N1 viruses?

• Avian-to-human transmission?
• Unknown, surveillance biased toward severely ill
• How many severely ill persons, deaths?
• How many mildly ill and asymptomatically ill?
• General population? (Urban versus rural)
• Persons with poultry exposure (markets, farms)
• Different age groups
• Limited human-to-human transmission?
• Persons exposed to confirmed cases, controlling for

poultry exposure (close contacts)

• Health care workers

What is the risk of H5N1 avian-to- human transmission?

Persons with poultry exposure

• H5N1 1997 Hong Kong (outbreak)
• 10% of PWers+ for H5N1 antibodies to A/HK/156/97 (N = 1525)

single serum specimen

• 3% of government cullers+ for H5N1 antibodies, paired sera;

1 seroconverted (N = 293)

• Risk factors: work in retail poultry, reporting mortality of >10%

poultry when working, butchering, feeding poultry

• H5N1 2001 Vietnam (no outbreak)
• 2 (1%) of PWers+ for antibodies to H5N1 isolated from a healthy

goose (N = 200) (A/Gs/VN/113/01); 0% of non poultry workers (N = 200)

• 6 (3%) of PWers+ to A/HK/156/97 or A/HK/213/03; compared to 2

(1%) of non poultry workers

• H5N1 2004-06: no published data

Bridges et al., JID 2002;1005-1010; CDC unpublished data

Risk of H5N1 for Health Care Workers?

Health care worker study, HK 1997

526 (217 exposed, 309 unexposed) to ≥1 H5N1 case, limited

PPE, Hong Kong

8 (3.7%) exposed, 2 (0.7%) unexposed seropositive 2 HCWs had seroconversion: 1 asymptomatic, 1 had mild

respiratory illness (no poultry exposure)

Health care worker studies, 2004 (N=3)

83 (79 exposed, 4 unexposed) to 4 H5N1 cases, PPE used,

Hanoi (all seronegative)

49 (25 exposed, 24 unexposed) to 1 H5N1 case, limited PPE

in first 48 hours, Bangkok (all seronegative)

60 exposed to 2 H5N1 cases, limited PPE, Ho Chi Minh City

(all seronegative)

Bridges CB et al. JID 2001;181:344-8; Liem NT et al. Emerg Infect Dis 2005;11:210-215; Apisarnthanarak A et al. Clin Infect Dis 2005;40:e16-8. Schultsz C et al. Emerg Infect Dis 2005;11:1158-9

H5N1 Serology

Detection of antibodies to H5N1 virus

Microneutralization assay using live H5N1 virus

in BSL3 enhanced lab conditions, confirm with Western Blot

Standard influenza HI antibody assay is not sensitive

• r specific; produces false results

Modified horse red blood cell HI assay is a screening

assay

H5N1 antibody titer is not detectable until after

10-14 days from illness onset or after 21 days

Collect acute serum and convalescent serum

specimens (1st week, and 2 weeks after the 1st specimen)

H5N1 in 2006

• Good news: No evidence of sustained human-

to-human transmission of H5N1 viruses

• 2006 Reality (Bad news):
• H5N1 viruses are circulating widely among poultry in

Asia, have spread to Eastern Europe, Africa, the Middle East - cannot be eradicated soon; H5N1 viruses continue to evolve

• Sporadic H5N1 human infections have caused severe

illness, high mortality (10 countries with human cases)

• Probable limited person-to-person transmission has
• ccurred: WHO Pandemic Alert Period: Phase 3

Key to reducing the public health threat of a global

pandemic is to control H5N1 viruses among poultry

• International assistance and coordination is critical
• Global, regional, national pandemic planning is needed