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BSIM 12th Annual Congres 2007

Emerging and Re-emerging Infectious Diseases

W. PeetermansInternal Medicine – Infectious Diseases

UZ Leuven

Emerging and Re-emerging Infectious Diseases

Clinical syndromes or pathogens never recognised before :HIV, Bartonella henselae, Helicobacter pylori, SARS, etc.

Emerging

Re-emerging

Clinical syndromes or pathogens that are or have been endemic in some parts of the world and come back in a different form or different location :West Nile in USA, severe dengue fever in the Americas, CA-MRSA, Clostridium difficile 027, etc.

Fauci AS. Acad Med 2005;80:1079-1085

King DA et al. Science 2006; 313:1392-1393

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Emerging and Re-emerging Infectious Diseases

• Dis-Balance between human and microbial species1. Genetic and biologic factors : high replication and mutation rate2. Physical environmental factors3. Ecologic factors4. Social, political or economic factors

• Mostly zoonotic : animal reservoir

• Rapid spread (travel, migration, trade)

• Prepare for deliberately emerging ID : Bioterrorism

Fauci AS. Acad Med 2005;80:1079-1085

King DA et al. Science 2006; 313:1392-1393

Beyond the scope of this presentation

• Aids; Malaria; Tuberculosis including MDR-TB and XDR-TB

• SARS (2003); Ebola (2005)

• New species (Bartonella bacilliformis, NEJM 2007) or

new serotypes (non-vaccine IPD, JAMA 2007) or

new patient populations (aspergillosis in ICU, CID 2007)

• Non-events : Chlamydophila pneumoniae and atherosclerosis (721 hits in pub med, JCM 2005)

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N. meningitidis infections in Belgium

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N. meningitidis infections in Belgium

Within the scope of this presentation

• CA-MRSA

• Clostridium difficile 027

• Syphilis and FQ-resistant gonorrhea

• Chikungunya and Dengue fever

• Avian influenza

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Community-acquired MRSA

• Differs from HC-associated MRSA microbiologicallyand clinically

• Clonal epidemics in children, MSM, prisoners, football players, beauty clinics, etc.

• Nosocomial spread less prevalent but reported

• Still rare in Belgium

Zetola N et al. Lancet Infect Dis 2005;5:275-286

N Engl J Med 2005; 352: 468-475.

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Community-acquired MRSA : microbiology

• Type IV SCC mec cassette andPanton-Valentine gene for Leucocidin positive

• High producer of multiple toxins

• Susceptible to clindamycin (80%), gentamicin, cotrimoxazole, glycopeptides and linezolid

Zetola N et al. Lancet Infect Dis 2005;5:275-286

Community-acquired MRSA : clinical

• Young healthy people

• Severe skin and soft tissue infections

• Necrotising pneumonia

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7537SSTI (%)

1576Underlyingdisease (%)

2368Age (yr)

CA-MRSAHC-Associated MRSA

Naimi TS et al. JAMA 2003;290:2976-2984

MRSA in pig and cattle Farmers

• Scc mec cassette type III-IV-V;PVL-negative; non-typable by Sma1 PFGE;new clonal complex ST398 by MLST

Kluytmans J. EID 2007 dec.

• Belgian survey in pig farms44% of pigs were carrier (all ST398)68% of farms had at least 1 carrier pig38% of farmers were carrier

3% in MRSA-free farms50% in MRSA-pos farms

Struelens M. BVIKM 16/11/2007

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Clostridium difficile

Clostridium difficile associated diarrhea : Classical

• Mild to moderate disease : diarrhea and pseudomembranous colitis

• Well-known risk factors

• Metronidazole first-choice (VRE threat)

• High recurrence rate (20%) associated with poorantibody response

Bartlett JG. Ann Intern Med 2006;145:758-764

Aslam S et al. Lancet Infect Dis 2005;5:549-557

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Clostridium difficile associated diarrhea : New

• Incidence increased 4-fold

• Severe disease : toxic megacolon; septic shock; perforation or bleeding; death (15%)

• Refractory to metronidazole; oral vancomycin superior

• (frail) elderly

• Very high recurrence rate (>50%)

→ New epidemic strain : PCR ribotype 027, PFGE-NAP1Bartlett JG. Ann Intern Med 2006;145:758-764

Pepin J et al. Clin Infect Dis 2005;40:1591-1597

Zar FA et al. Clin Infect Dis 2007;45:302-307

Clostridium difficile NAP1 – Ribotype 027

• Resistant to fluoroquinoles : independent risk factor

• Hyperproducer of toxin A and toxin B (toxinotype III)

• Deletion of tcdC in pathogenicity locus

• Producer of a binary toxin

• Clonal spread

Bartlett JG. Ann Intern Med 2006;145:758-764

Mc Donald LC et al. N Eng J Med 2005;353:2433-2441

Loo VG et al. N Engl J Med 2005;353:2442-2449

Warny M et al. Lancet 2005;366:1079-1084

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Clostridium difficile associated disease : Treatment

• Discontinue implicated antibiotic

• Hydration and electrolyte replacement

• Avoid antiperistaltics

• oral vancomycin 4 x 125-250 mg daily for 10 days

• Initiate infection control measures

• Surgical consultation if severe CDAD

• Retreat if recurrence

Bartlett JG. Ann Intern Med 2006;145:758-764

Kuijper EJ et al. Curr Op Infect Dis 2007;20:376-383

Clostridium difficile associated disease : Prevention

• Restrictive use of antibiotics

• Early identification of new cases (toxin EIA)

• Isolation precautions and cleaning (spores!)

• Probiotics if recurrence (?)

• Prolonged vancomycin treatment if recurrence

• IVIG if multiple recurrences

• (experimental : active and passive immunisation)

Bartlett JG. Ann Intern Med 2006;145:758-764

Kuijper EJ et al. Curr Op Infect Dis 2007;20:376-383

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STD:

syphilisgonorrhoea

LGV

Syphilis

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Re-emergence of Syphilis

• 156 new registered cases in Flanders (jan - july 2007)

• Ongoing outbreaks, mainly MSM (50% HIV-pos.)

• Clinical diagnosis and serology

• Standard treatment: benzathine–Pen G (availability?)

Sasse A et al. Euro Surveillance 2004;9:6-8

Peterman TA et al. Curr Op Infect Dis 2007;20:54-59

0

5

10

15

20

25

30

35

Period 1 Period 2 Period 3 ¨Period 4 Period 5

Num

ber o

f syp

hilis

dia

gnos

es

MSMHetero MWomen

I P H - 2005

Syphilis cases per sex and sexual orientation, Sentinel Network of Clinicians, Belgium, Oct.-Jan. periods, 2000 - 2005

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Primary syphilis

Secundary syphilis

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Gonorrhoea

Gonorrhoea

• 4-fold increase over 10 years (MSM; sextravel)

• Transport medium or bed-side inoculation

• PPNG (>20%) and doxycycline resistance (>40%)

• Increasing resistance to fluoroquinolones→ 28% (2002-2003) → 47% (2004-2005)

• First-choice treatment :

ceftriaxone 250 mg IM or spectinomycin 2g IM

• Also treat for NGU

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Lymphogranuloma Venereum

• Chlamydia trachomatis LGV serovars L1-3

• Endemic in tropics – outbreaks in MSM

• Necrotising lymphadenitis – deep anorectal ulcers

• Clinical diagnosis and PCR (serology)

• Doxycycline 200 mg for weeks

Fever in returned travelers

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Fever in returned travelers

• Spectrum of diseases according to travel destination and time of presentation

• Tropical diseases (39%) and cosmopolitan infections (34%)

71%58%21%Pretravel advice

8%18%42%Hospitalisation

9%24%45%Malaria

18%29%52%Fever

TouristTraveler VFRImmigrant VFR

Bottieau E et al. Arch Intern Med 2006;166:1642-1648

Freedman DO et al. NEJM 2006;354:119-130

Leder K. et al. Clin Infect Dis 2006;43:1185-1193

Chikungunya

• Arbovirus transmitted by Aedes mosquitoes

• Endemic in Africa, South- and South-East Asia

• Outbreaks: India 2006-2007 and Réunion 2005-2007

260000 cases in 775000 population

• Acute febrile syndrome with rash and incapacitatingarthralgia

• Severe disease : MODS – encephalitis – death

• PCR (Pasteur, Paris) and serology

• Symptomatic treatment

Pialoux G et al. Lancet Infect Dis 2007;7:319-327

Seneviratne SL et al. J Travel Med 2007;14:320-325

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Chikungunya and Dengue

Dengue

• Arbovirus (4 sterotypes) transmitted by Aedesmosquitoes

• Asia, Latin-America, Subsaharan Africa

• 2 clinical syndromes (WHO)• Classic Dengue Fever• Dengue Haemorrhagic Fever and Dengue Shock Syndrome :

capillary leakage

• Rapid Ag-test and serology

• Symptomatic treatment

Halstead SB. Lancet 2007;370:1644-1652

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Dengue : Geographical Distribution

Avian Influenza

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Influenza : The Pandemic Threat

• Influenza A and B winter epidemicsHA and NA mutations : Ag drift

• Influenza A pandemicsHA and NA reassortment : Ag shift

• Stable lineage• No immunity in population• Human to human transmission• Pathogenicity virulence in humans

Origin of antigenic shift and pandemic influenza

Lancet 2003; 362: 1733-1745.

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The Influenza Pandemics of the 20th century

• 1918-19: Spanish flu (H1N1; swine or water fowl)20-50 million deaths worldwide (500.000 in USA)nearly half of deaths were young healthy adults

• 1957-58: Asian flu (H2N2; re-assortment with avian type)70.000 deaths in USA

• 1968-69: Hong-Kong flu (H3N2; re-assortment with avian type)34.000 deaths in USA

• 1977-78: Russian flu-swine flu(H1N1; similar to virus that circulated up to 1950’s)low death rate

H5N1 Avian Influenza

• Ongoing spread since 2004 (clade 1 – clade 2)

• Human cases due to direct exposion to poultry

• (extremely) high death rate

• Resistant to adamantanes (clade 1) and sporadic resistance to oseltamivir reported

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NEJM 2006;355:2174-2177.

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Cumulative number of confirmed cases of Avian Influenza A / H5N1 (WHO 25-07-2007)

192319Total

154

3812

EgyptTurkey

1725Thailand4295Vietnam81102Indonesia

DeathsCasesCountry

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H5N1 Influenza : Virulence• Pro inflammatory cytokine responses induced by influenza A H5N1

viruses in primary alveolar and brocheal epithelial cellsChan MCW et al. Respir Res 2005;6:135

• Fatal outcome of human H5N1 influenza A is associated with high viral load and hypercytokinemia

de Jong MD et al. Nature Med 2006;12:1203-1207

• Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection

Salomon et al. PNAS 2007;104:12479-12481

• A single mutation in the PB1-F2 of H5N1 and 1918 influenza A viruses contributes to increased virulence

Conenello GM et al. PLoS pathogens 2007;3:e141

• Aberrant immune response in lethal infection of macaques with the 1918 influenza virus

Kobasa D et al. Natrure 2007;445:319-323

Pandemic Preparedness Plan

• Surveillance and virological research

• Pandemic vaccine(s) development

• Risk management1. Contain impact on morbidity and mortality

– Vaccination– Antiviral drugs– Reduction of transmission

2. Sustain good management of cases

3. Contain impact on social disruption

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Emerging and Re-emerging Infectious Diseases

• Don’t forget the lesson of the sixties“… anticipate that within some measurable time allmajor infections will have disappeared”“Close the book on Infectious Diseases”

US Surgeon General 1968

• Invest in– Knowledge of broad range of I.D.– Surveillance systems to detect new evolutions– Research in new modalities of diagnosis, treatment

and prevention

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R. KochNobelprice 1905

R. Warren en B. MarshalNobelprice 2005

Emerging and Re-emergingInfectious Diseases