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بسم الله الرحمن الرحيمبسم الله الرحمن الرحيمBIODEFENSEBIODEFENSE

Epidemiology of Tularemia

Shahid Beheshti University of medical sciences, April 2005

By: Hatami H. MD. MPH

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الف ـ مقدمه و معرفي الف ـ مقدمه و معرفي بيماريبيماري

- تعريف و اهميت بهداشتي- تعريف و اهميت بهداشتي11

– عامل يا عوامل اتيولوژيك – عامل يا عوامل اتيولوژيك22

ب ـ اپيدميولوژي توصيفي و ب ـ اپيدميولوژي توصيفي و ((OCCURRENCEOCCURRENCE))وقوعوقوع

ج ـ پيشگيري و كنترلج ـ پيشگيري و كنترل

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Case definition of TularemiaCase definition of Tularemia•An illness characterized by several distinct forms, An illness characterized by several distinct forms, including the following:including the following:

· · UlceroglandularUlceroglandular (cutaneous ulcer with regional (cutaneous ulcer with regional lymphadenopathy)lymphadenopathy)

· · GlandularGlandular (regional lymphadenopathy with no ulcer) (regional lymphadenopathy with no ulcer)

· · Oculoglandular Oculoglandular (conjunctivitis with preauricular (conjunctivitis with preauricular lymphadenopathy)lymphadenopathy)

· · Oropharyngeal Oropharyngeal (stomatitis or pharyngitis or tonsillitis and (stomatitis or pharyngitis or tonsillitis and cervical lymphadenopathy)cervical lymphadenopathy)

· · PneumonicPneumonic (primary pleuropulmonary disease) (primary pleuropulmonary disease)

· · TyphoidalTyphoidal (febrile illness without early localizing signs (febrile illness without early localizing signs and symptoms)and symptoms)

- تعريف و اهميت بهداشتي- تعريف و اهميت بهداشتي11

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–Francisella tularensis

–Named for Sir Edward Frances (did original work on disease) and Tulare, CA (where disease agent was first isolated)

• Other names of human disease:–rabbit fever

–deer-fly fever

- عامل يا عوامل اتيولوژيك- عامل يا عوامل اتيولوژيك11

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– Gram-negative, coccobacillusGram-negative, coccobacillus

– non-motile, unencapsulatednon-motile, unencapsulated

– Two subtypes differ based on virulenceTwo subtypes differ based on virulence

• Type A (biogroup Type A (biogroup tularensistularensis))– highly virulent for humans and rabbitshighly virulent for humans and rabbits– found in North Americafound in North America

• Type B (biogroup Type B (biogroup palearcticapalearctica))– less virulent for humans, found in less virulent for humans, found in

aqauticaqautic animals animals– found in Asia and Europefound in Asia and Europe

Microbiological featuresMicrobiological features

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–No growth on routine media (requires cysteine or cystine)

–Special culture media - thioglycolate, glucose-cysteine blood agar, chocolate agar

–Addition of CO2 may enhance growth

Microbiological featuresMicrobiological features

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Francisella tularensisFrancisella tularensis

• Gram stainGram stain–Poorly staining, tiny Poorly staining, tiny Gram-negative Gram-negative coccobacillicoccobacilli

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–Hardy (weeks to 3-4 months) in cold (even frozen) and moist conditions, weeks in water, carcasses, soil, hay, frozen rabbit meat

–Killed by heat (55 C x 10 min)

–In aerosol, likely short lifespan

Environmental Survival

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–Intracellular growthIntracellular growth

–Infectious doseInfectious dose depends on depends on site of entrysite of entry•Few organisms (10-50) Few organisms (10-50) required for required for intradermalintradermal ‘‘Injection’Injection’ or inhalation or inhalation

• large number (10large number (1088) if ) if ingestedingested

PathogenesisPathogenesis

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–Growth at inoculation site–Lymphatic spread to regional nodes–May disseminate hematogenously,

especially untreated•Reticuloendothelial organs, lungs,

kidneys, skin, meninges• Bacteremia common early in course but

not usually detected

–Suppurative necrosis

PathogenesisPathogenesis

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Bioweapon PotentialBioweapon Potential• One of top 6 agents listed by CDCOne of top 6 agents listed by CDC• Weaponized in 1950s and 60s by Weaponized in 1950s and 60s by U.S.U.S.• Former Former Soviet UnionSoviet Union weaponizing in weaponizing in

1990s1990s• Antibiotic and vaccine resistant strains Antibiotic and vaccine resistant strains

developeddeveloped

• Used on prisoners 1932-45 by Used on prisoners 1932-45 by JapanJapan

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Bioweapon PotentialBioweapon Potential

• Estimated EffectEstimated Effect– 50kg F. tularensis over a city of 5 50kg F. tularensis over a city of 5

millionmillion• 250,000 incapacitated250,000 incapacitated

• 19,000 dead19,000 dead

• Incapacitation occurring within 1 to Incapacitation occurring within 1 to 2 days2 days

• Incapacitation lasts for days –weeksIncapacitation lasts for days –weeks

• Untreated disease is persistent and Untreated disease is persistent and relapsingrelapsing

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Bioweapon PotentialBioweapon Potential

Delivery MechanismDelivery Mechanism• AerosolAerosol would be most likely would be most likely

mechanismmechanism

• Could be weaponized Could be weaponized wet or drywet or dry

• PneumonicPneumonic form would be most form would be most likelylikely

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Bioweapon PotentialBioweapon Potential

• Delivery particle sizeDelivery particle size–Dictates severity and form of Dictates severity and form of

diseasedisease

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Bioweapon PotentialBioweapon Potential

• Factors suggesting aerosol Factors suggesting aerosol bioterrorism attackbioterrorism attack• Large number, Large number, previously healthypreviously healthy, with , with

sudden constitutional symptoms (fever, sudden constitutional symptoms (fever, myalgias, myalgias, flu-likeflu-like))

• Many then develop Many then develop coughcough and and dyspneadyspnea• At first difficult to differentiate from At first difficult to differentiate from

community acquired pneumoniacommunity acquired pneumonia, , influenzainfluenza• Rapid worsening to critical illness in high Rapid worsening to critical illness in high

percentage of patientspercentage of patients

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Bioweapon PotentialBioweapon Potential• Factors suggesting aerosol releaseFactors suggesting aerosol release–Point or line source outbreak Point or line source outbreak

patternpattern

–Acute constitutional signs and Acute constitutional signs and symptoms:symptoms:• PharyngitisPharyngitis

• BronchiolitisBronchiolitis

• PleuropneumonitisPleuropneumonitis

• Hilar lymphadenitisHilar lymphadenitis

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ب ـ اپيدميولوژي توصيفي و ب ـ اپيدميولوژي توصيفي و وقوع توالرميوقوع توالرمي

((Incubation periodIncubation period)) – دوره نهفتگي – دوره نهفتگي11( ( Natural courseNatural course)) – سير طبيعي – سير طبيعي22 Geographical Geographical)) – انتشار جغرافيائي – انتشار جغرافيائي33

distributiondistribution ) )((Timeline trendTimeline trend)) – روند زماني – روند زماني44 – تاثير سن، جنس، شغل و موقعيت – تاثير سن، جنس، شغل و موقعيت 55

اجتماعياجتماعي Predisposing Predisposing)) – تاثير عوامل مساعد كننده – تاثير عوامل مساعد كننده66

factorsfactors ) ) & Susceptibility & Susceptibility)) – حساسيت و مقاومت – حساسيت و مقاومت77

ResistanceResistance ) ) Secondary attack Secondary attack)) – ميزان حمله هاي ثانويه – ميزان حمله هاي ثانويه88

raterate ) ) – نحوه انتقال و دوره قابليت سرايت – نحوه انتقال و دوره قابليت سرايت99((Mode of transmission & period of communicabilityMode of transmission & period of communicability))

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ـ دوره نهفتگي ـ دوره نهفتگي11

•< 24 hours experimentally < 24 hours experimentally aerosolaerosol infected monkeysinfected monkeys

•Typically Typically 2-52-5 days days

•Range 1-21 daysRange 1-21 days

•Dependent on Dependent on inoculation doseinoculation dose, , typetype//virulencevirulence

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• Symptoms based on six classic forms Symptoms based on six classic forms of diseaseof disease

• ((Depends on route of infection, dose, strain, virulenceDepends on route of infection, dose, strain, virulence))– ulceroglandularulceroglandular

– glandularglandular

– oculoglandularoculoglandular

– oropharyngealoropharyngeal

– typhoidaltyphoidal

– pneumonicpneumonic

ـ سير طبيعيـ سير طبيعي 2 2

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• UlceroglandularUlceroglandular–Regional lymphadenopathyRegional lymphadenopathy – proximal – proximal

to inoculationto inoculation–LocationsLocations• Hand lesions – axillary (65%) > Hand lesions – axillary (65%) >

epitrochlear (8%), epitrochlear (8%), animal exposuresanimal exposures• Leg lesions – femoral/inguinal nodes, most Leg lesions – femoral/inguinal nodes, most

common for common for arthropod bitesarthropod bites

– Slow resolutionSlow resolution• Even with treatmentEven with treatment

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UlceroglandularUlceroglandular

45-85% of all cases45-85% of all cases

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Lymphoglandular lesion - ulcerLymphoglandular lesion - ulcer

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• TyphoidalTyphoidal–Fever, weight loss, prostration, Fever, weight loss, prostration,

deliriumdelirium–No ulcer, adenopathy, or other No ulcer, adenopathy, or other

localizing signslocalizing signs–Often with abdominal painOften with abdominal pain–Most likely form to be severeMost likely form to be severe–Often DIC, ARDS, sepsis, multiorgan Often DIC, ARDS, sepsis, multiorgan

failure, shockfailure, shock– Should not use this term if evidence of Should not use this term if evidence of

pleuropulmonary diseasepleuropulmonary disease

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• PneumonicPneumonic–PrimaryPrimary• Inhalational exposureInhalational exposure

– SecondarySecondary• Hematogenous spread generally Hematogenous spread generally

coincident with UGcoincident with UG

• 30% 30% UGUG cases develop pneumonia cases develop pneumonia

• 80% 80% typhoidaltyphoidal cases develop cases develop pneumoniapneumonia

–Unable to differentiate by Unable to differentiate by pathologic findingspathologic findings

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PneumonicPneumonic

• IncubationIncubation: 3 to 5 days : 3 to 5 days (range 1-21 days)(range 1-21 days)

• Abrupt onsetAbrupt onset fever, chills, fever, chills, headaches, myalgia, non-headaches, myalgia, non-productive coughproductive cough

• SegmentalSegmental/lobar infiltrates, /lobar infiltrates, hilar adenopathy, effusionshilar adenopathy, effusions

• MortalityMortality 30% if 30% if untreated; < 10% if untreated; < 10% if treatedtreated

pneumonic tularemiapneumonic tularemia

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Laboratory FeaturesLaboratory Features–Leukocytosis up to 22KLeukocytosis up to 22K

–Reversible hepatitis/mildly elevated Reversible hepatitis/mildly elevated LFTs (trans, Aphos, LDH)LFTs (trans, Aphos, LDH)

– Infrequent rhabdo (elevated Cr, Infrequent rhabdo (elevated Cr, CK, MYO)CK, MYO)

– Sterile pyuria – 32%Sterile pyuria – 32%– Focal necrosis leading to Focal necrosis leading to granulomatagranulomata in in

reticuloendothelial organs, lungs, kidneysreticuloendothelial organs, lungs, kidneys– Granulomata, initially PMNs, then caseating Granulomata, initially PMNs, then caseating

like TBlike TB

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–RadiographicRadiographic•Classic – Classic – patchy infiltratespatchy infiltrates (74%), (74%), often multiple, bilateraloften multiple, bilateral•Earliest abnormality – Earliest abnormality – peribronchial infiltratesperibronchial infiltrates•EffusionEffusion common (60-80%), common (60-80%), exudative, lymphocytic, sometimes exudative, lymphocytic, sometimes empyema or bronchopleural fistulaempyema or bronchopleural fistula•Hillar Hillar adenopathyadenopathy•AbscessAbscess – infrequent – infrequent

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Pneumonic Tularemia: Pneumonic Tularemia: Differential DiagnosesDifferential Diagnoses

• Community acquired pneumonia Community acquired pneumonia –Atypical CAPAtypical CAP (Legionella, Mycoplasma) (Legionella, Mycoplasma)

– Streptococcal pneumonia, Influenza, Streptococcal pneumonia, Influenza,

H. influenzaH. influenza

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•Oculoglandular–Conjunctivitis• Unilateral, painful, purulent• Ulcers +/- palpebral nodules with,

vasculitis, periorbital edema

–Ocular pain, excessive lacrimation, photophobia

– Local lymphadenopathy – preauricular, cervical

–Complications – rarely blindness

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–Antibody appearance• Begin to appear in approximately 1

week

•Usually not to diagnostic levels until 2 weeks

• Peak in 3-4 weeks

•Remains at high levels for 6 months

• Levels do not correspond with form or severity of disease

ImmunityImmunity

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–Antibody disappearance• Persisted 11 years at titre 80 in

•Agglutinin titres dropped from 160 to 40 in 51/53 cases infected 25 years previously

•Negative serology does not rule out past infection or lack of cell mediated immunity

ImmunityImmunity

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- Cell mediated immunity most important

–Reinfection unlikely but possible, > 12 reported

Cell mediated immunityCell mediated immunity

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• Generally Generally not fatalnot fatal

• Generally Generally very incapacitatingvery incapacitating for 2-3 for 2-3 months without treatment, occasionally not months without treatment, occasionally not back to normal after 1 yearback to normal after 1 year

• If recover, generally no If recover, generally no long-term sequelaelong-term sequelae• Prognostic indicatorsPrognostic indicators– Form of disease-typhoidal/pneumonicForm of disease-typhoidal/pneumonic– Type A or BType A or B– Immune status, ageImmune status, age– Inoculation doseInoculation dose– Time to presentation, diagnosis, antibioticsTime to presentation, diagnosis, antibiotics– Treatment with drug other than Treatment with drug other than

aminoglycosideaminoglycoside

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• Prognostic indicatorsPrognostic indicators– Renal failureRenal failure reported in > half reported in > half

– Underlying illnessUnderlying illness – alcoholism, lung – alcoholism, lung disease disease

– BacteremiaBacteremia

– ImmunocompromisedImmunocompromised – ¾ reported have – ¾ reported have been bacteremic with Type Bbeen bacteremic with Type B

– Elevated CKElevated CK with or without rhabdo with or without rhabdo

– Presence of Presence of fluctuant nodefluctuant node may increase may increase risk relapserisk relapse

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• Untreated mortality–5-15% Type A strains

–1-3% Type B strains

–5% Ulceroglandular (UG) form

–30-60% typhoidal/pneumonic

–>70% fatal cases have pulmonary involvement

Mortality

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ـ سير طبيعي ـ سير طبيعي 22)مرور()مرور(

ميزان موارد بدون عالمت )ساب ميزان موارد بدون عالمت )ساب •كلينيكال(كلينيكال(

ميزان موارد حادميزان موارد حاد•ميزان موارد مزمن ميزان موارد مزمن •ميزان موارد بهبودي خودبخوديميزان موارد بهبودي خودبخودي•سير بعدي بيماري با درمان و بدون سير بعدي بيماري با درمان و بدون •

درماندرمانميزان مرتاليتي و مربيديتي ميزان مرتاليتي و مربيديتي •

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• Northern hemisphere only– North America, Europe, Russia, China, Japan,

Mexico

ـ انتشار ـ انتشار 3 3جغرافيائيجغرافيائي

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ـ روند زماني ـ روند زماني44

( ( PandemicsPandemics))پاندمي ها ؟پاندمي ها ؟• ( ( EpidemicsEpidemics)) اپيدمي ها ؟ اپيدمي ها ؟•( ( OutbreaksOutbreaks)) طغيان ها ؟ طغيان ها ؟ •( ( DurationDuration ) )تناوب زماني ؟تناوب زماني ؟•( ( SeasonalitySeasonality))الگوي فصلي ؟الگوي فصلي ؟•

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Seasonality

• Summer peak related to ticks–90% pediatric cases

• Winter peak related to trapping and hunting of rabbits

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ـ تاثير سن، جنس ، شغل و ـ تاثير سن، جنس ، شغل و 55موقعيت اجتماعيموقعيت اجتماعي

•Over 75% in men

•More common in >30 years of age

•Recent studies indicate pediatric population can represent up to 28% of cases in certain areas

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ـ تاثير عوامل مساعد كننده ـ تاثير عوامل مساعد كننده66

Handling infected animalsHunting, trapping, farming,

butcheringIngestion of contaminated meat,

water, soilBitten by arthropods in endemic

areasMicrobiology laboratory workers

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ـ حساسيت و مقاومت در مقابل ـ حساسيت و مقاومت در مقابل 77بيماريبيماري

مقاومت طبيعيمقاومت طبيعي•مصونيت اكتسابي بعد از ابتالءمصونيت اكتسابي بعد از ابتالء•مصونيت اكتسابي بعد از مصونيت اكتسابي بعد از •

واكسيناسيونواكسيناسيون

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ـ ميزان حمالت ثانويه ـ ميزان حمالت ثانويه88

• Low infectious dose Low infectious dose – 1 to 10 organisms by aerosol or 1 to 10 organisms by aerosol or

intradermal routeintradermal route

• No person-to-person transmissionNo person-to-person transmission

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ـ منابع و مخازن ، نحوه انتقال ـ منابع و مخازن ، نحوه انتقال 99 بيماري و دوره قابليت سرايتبيماري و دوره قابليت سرايت

توالرمي توالرمي –Tick-rabbit• Ticks maintain infection in reservoirs

of rabbits, voles

–Animal-animal•Aquatic rodents infect each other and

through environment (e.g. contaminated water)

–Humans• Infected when they get in the way of

natural cycles

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چرخه زندگي فرانسيسال چرخه زندگي فرانسيسال ) ) 99توالرنسيس )توالرنسيس )

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–Arthropod vector bites•May be true reservoirs as well as

vectors

•Causes 1/3 to ½ tularemia cases now

•Dog tick, wood tick

•Deer fly, horse fly

•Mosquito

Rout of TransmissionRout of Transmission

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–Inhalation of aerosols/dustsInhalation of aerosols/dusts•Most humans exposed to aerosol Most humans exposed to aerosol

become infected, become infected, only 25-50%only 25-50% of those of those will get will get radiographic evidenceradiographic evidence of of pulmonary involvementpulmonary involvement•Handling contaminated Handling contaminated hayhay•Contaminated Contaminated water sprayswater sprays•DustDust from contaminated from contaminated soilsoil •Handling or in vicinity of Handling or in vicinity of dead rabbitsdead rabbits

Rout of TransmissionRout of Transmission

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Rout of TransmissionRout of Transmission

–Infectious doseInfectious dose

•1-10 organisms by 1-10 organisms by inhalation/intradermalinhalation/intradermal

•101088 organisms orally organisms orally

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–Many mammals, ticks, and Many mammals, ticks, and some birdssome birds

–Ticks and rabbitsTicks and rabbits most most importantimportant

–Rodent-mosquitoRodent-mosquito cycle in cycle in Russia, SwedenRussia, Sweden

ReservoirsReservoirs

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ج ـ پيشگيري و كنترل ج ـ پيشگيري و كنترل توالرميتوالرمي

• Primary Prevention:Primary Prevention: Prevention of disease in “well” Prevention of disease in “well”

individualsindividuals• Secondary Prevention:Secondary Prevention:

Identification and intervention in Identification and intervention in early stages of diseaseearly stages of disease

Tertiary Prevention:Tertiary Prevention: Prevention of further deterioration, Prevention of further deterioration,

reduction in complicationsreduction in complications

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ـ پيشگيري سطح اوtل ـ پيشگيري سطح اوtل 11

• EducationEducation

• Evoid Evoid exposureexposure

• Proper Proper handlinghandling during skinning, during skinning, processing; protective processing; protective glovesgloves, , eye weareye wear

• ArthropodArthropod control control

• Proper Proper cookingcooking of meat of meat

• Live attenuated Live attenuated vaccinesvaccines for certain for certain occupationsoccupations

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Prevention Prevention

• Avoid ticks in endemic areasAvoid ticks in endemic areas–Tuck in clothesTuck in clothes–Diethyltoluamide to skinDiethyltoluamide to skin–Permethrin to clothingPermethrin to clothing–Frequent exams and prompt removalFrequent exams and prompt removal

• Avoid contact with sick/dead Avoid contact with sick/dead animalsanimals–Wear gloves when handling carcassesWear gloves when handling carcasses

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Infection ControlInfection Control

• Precautions – standard onlyPrecautions – standard only

• Laboratory safetyLaboratory safety–Must alert lab if suspectMust alert lab if suspect

–BSL-2 needed for routine BSL-2 needed for routine proceduresprocedures

–BSL-3 for higher risk and BSL-3 for higher risk and animal studiesanimal studies

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DecontaminationDecontamination

• EnvironmentEnvironment–Likely Likely short half-lifeshort half-life if aerosol if aerosol

disperseddispersed

–Very unlikely Very unlikely secondarysecondary aerosolizationaerosolization

–Covert releaseCovert release likely not detected likely not detected for several daysfor several days

–Not recommendedNot recommended for large areas for large areas after releaseafter release

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Decontamination

• Clothing exposed to known aerosol or powder– Soap and water on body and clothing

• Corpses– Standard precautions only– Avoid aerosol-generating procedures at

autopsy

• Patient rooms– Clothing, linens disinfect via standard

protocols

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Post-Exposure ProphylaxisPost-Exposure Prophylaxis

• AntibioticsAntibiotics•Potentially exposed to same Potentially exposed to same aerosol as casesaerosol as cases•Goal- treat Goal- treat during incubationduring incubation period to prevent diseaseperiod to prevent disease•Lab personnelLab personnel with high-risk with high-risk exposureexposure

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Post-Exposure Prophylaxis–Who not to provide PEP•Contacts of index patient• Potentially exposed, who are

asymptomatic in covert release where cases identified later–Fever watch–Start full treatment if fever or flu-like

illness within 14 days of probably exposure

• Potentially exposed to natural infection• Lab personnel with low risk exposure

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Post-Exposure ProphylaxisPost-Exposure Prophylaxis

• AntibioticsAntibiotics–Same as for mass casualtiesSame as for mass casualties

–Duration – 14 days all groupsDuration – 14 days all groups

•Doxycycline 100 po bidDoxycycline 100 po bid

•Ciprofloxacin 500 po bid Ciprofloxacin 500 po bid

•Tetracycline 500 po qidTetracycline 500 po qid

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ـ پيشگيري سطح دوtم ـ پيشگيري سطح دوtم 22

ـ تشخيص زودرس1 ـ درمان به موقع2ــه 3 ــان ب ــه درم ــه ب ـ توج

عنــوان پيشــگيري ســطح اوtل و دوtم

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Diagnosis

• High index of suspicion vital

• No commercially available rapid diagnostic test

• Serology often available in labs, but does not detect acute infection

• Culture

Routine culture drawbacks– Dangerous to techs– Takes several days– Low sensitivity

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DiagnosisDiagnosis• BloodBlood

• Aids in rapid and confirmatory Aids in rapid and confirmatory diagnosisdiagnosis–CulturesCultures–SusceptibilitySusceptibility testing testing–Serology – Serology – microagglutinationmicroagglutination–+/- +/- PCRPCR, , antigenantigen detection – rapid detection – rapid–VirulenceVirulence testing and testing and molecularmolecular

geneticsgenetics

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DiagnosisDiagnosis

Samples :Samples :• BloodBlood

• Respiratory Respiratory secretionssecretions

• BiopsyBiopsy materials (if available), materials (if available), e.g. skin ulcerse.g. skin ulcers

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Diagnosis

• Presumptive Diagnosis–Typical presentation

(signs/symptoms or exposure history)• Sudden onset Febrile illness

• LAD

• Tick bite/wild animal exposure

• Endemic area or travel

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DiagnosisDiagnosis

Direct fluorescent antibody (DFA)Direct fluorescent antibody (DFA)• Use for Use for secretionssecretions, , biopsiesbiopsies

• Rapid (hours after received)Rapid (hours after received)

• Not widely availableNot widely available

– Indirect FAIndirect FA• Used as Used as confirmatoryconfirmatory test in one test in one

seriesseries

• Used on Used on tissuetissue samples samples

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DiagnosisDiagnosis• PCRPCR– RapidRapid-several hours-several hours– Very Very sensitivesensitive– ProblemsProblems with tissue samples with tissue samples– Less riskLess risk to lab personnel to lab personnel – Not affectedNot affected by prior antibiotics, by prior antibiotics,– Detects DNA so Detects DNA so viabilityviability not required not required– Very Very smallsmall quantities needed quantities needed – Can be used on Can be used on non-clinical samplesnon-clinical samples– 100% 100% specificspecific in animal study in animal study– Not widely availableNot widely available

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DiagnosisDiagnosis• Skin testSkin test–Injecting killed organisms Injecting killed organisms

intradermallyintradermally

–DTHDTH reaction reaction

–AdverseAdverse reactions reactions•Only in positivesOnly in positives

•¼ pruritis, 1/5 tenderness, rare ¼ pruritis, 1/5 tenderness, rare feverfever

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DiagnosisDiagnosis

• Skin testSkin test• Sensitivity 98.5% Sensitivity 98.5% • PositivesPositives usually >6 mm, negative < 4 mm usually >6 mm, negative < 4 mm• Good Good sensitivitysensitivity 1 (29%) to 2 (95%) weeks after 1 (29%) to 2 (95%) weeks after

infectioninfection• SpecificitySpecificity > 98% > 98%• Also effective at determining Also effective at determining vaccinationvaccination status status• No No correlationcorrelation of induration with severity or Ab of induration with severity or Ab

titerstiters

– Doesn’t usually cause rise in Antibody titreDoesn’t usually cause rise in Antibody titre

– Remains positive > 40 yearsRemains positive > 40 years

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DiagnosisDiagnosis

• Skin testSkin test– AdvantagesAdvantages• Turns positive Turns positive fasterfaster than agglutination than agglutination• StaysStays positive longer positive longer

– DisadvantagesDisadvantages• Read after Read after 4848 hours hours• Not easily Not easily availableavailable• Can’t distinguishCan’t distinguish between vaccinated and between vaccinated and

diseasedisease

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Diagnosis

• Serology–Has been the gold standard

–Generally only of epidemiological use, not acute infection unless diagnosis delayed

–Takes at least 2 weeks to reliably get positive titre (1:160)

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Diagnosis

• Confirmatory Diagnosis– Serology• Serum agglutins (combined IgM and IgG)– Tube agglutination – standard, more common–Microagglutination – available in reference

labs, more sensitive, can detect 10 days after illness onset

• Single 1:160 (tube) 1:128 (micro) in unvaccinated, presumptive of past or current infection• 4-fold rise acute/convalescent

•Not affected by antibiotic treatment

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DiagnosisDiagnosis–False negativesFalse negatives

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DiagnosisDiagnosis

–False positivesFalse positives•Cross reacts with Cross reacts with BrucellaBrucella and and

ProteusProteus OX-19 and OX-19 and YersiniaYersinia

• Prior vaccinationPrior vaccination–Usually convalescent titres Usually convalescent titres are < are <

12801280

–May lose abnormality May lose abnormality 28 months28 months after vaccinationafter vaccination

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DiagnosisDiagnosis–ELISAELISA• IgM, IgG,or IgA levels detectedIgM, IgG,or IgA levels detected

•Detects LPSDetects LPS

•Now more Now more preferredpreferred–Better sensitivity (95.7%) specificity Better sensitivity (95.7%) specificity

(96%)(96%)

–Less cross-reaction with Brucella, Less cross-reaction with Brucella, YersiniaYersinia

–Becomes positive a little earlier than Becomes positive a little earlier than agglutininsagglutinins

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DiagnosisDiagnosis

• MicrobiologicMicrobiologic–Growth from blood, sputum, Growth from blood, sputum,

wound, aspirate, pleural fluid, wound, aspirate, pleural fluid, exudatesexudates• On On cysteinecysteine-enriched media-enriched media

• In In inoculatedinoculated laboratory mice laboratory mice

–AttentionAttention • Hi-risk transmission to lab workersHi-risk transmission to lab workers

•Must notify labMust notify lab

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Diagnosis

• Microbiologic– Gram stain rarely helpful, usually negative– Difficult to differentiate from other gram

negatives by biotyping

Low sensitivityLow sensitivity

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Differential diagnosis

–Ulceroglandular/glandular• Bubonic plague, cutaneous anthrax,

lymphocutaneous syndromes, cat scratch disease, rat-bite fever, lymphogranuloma venereum, strep lymphadenitis, toxo, chancroid, atypical myocobacteria

– Typhoidal• Septicemic plague, typhoid fever,

brucellosis, listeriosis, malaria, rickettsial diseases, any cause of sepsis

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–OropharyngealOropharyngeal• Strep pharyngitis, EBV, other causes Strep pharyngitis, EBV, other causes

stomatitis and cervical adenitis, stomatitis and cervical adenitis, diphtheriadiphtheria

–OculoglandularOculoglandular• Lymphogranuloma venereum, adult Lymphogranuloma venereum, adult

inclusion conjunctivitis, zoster inclusion conjunctivitis, zoster conjunctivitis, listeriosisconjunctivitis, listeriosis

Differential diagnosis

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–PneumonicPneumonic• Pneumonic Pneumonic plagueplague, inhalational , inhalational

anthraxanthrax, , Q feverQ fever, , legionellosislegionellosis, , histohisto, , TB, CAP, TB, CAP, mycoplasmamycoplasma, , influenzainfluenza, , malignancymalignancy, other zoonotic , other zoonotic pneumoniaspneumonias

Differential diagnosis

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Case definition of TularemiaCase definition of Tularemia

Clinical diagnosis is supported by evidence or history of:

tick or deerfly bite,

Exposure to:Exposure to: tissues of a mammalian host of

Francisella tularensis, potentially contaminated water.

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Laboratory criteria for diagnosis

Presumptive

• · Elevated serum antibody titer(s) to F. tularensis antigen (without documented fourfold or greater change) in a patient with no history

of tularemia vaccination

or

• · Detection of F. tularensis in a clinical specimen by fluorescent assay

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Laboratory criteria for Laboratory criteria for diagnosisdiagnosis

• ConfirmatoryConfirmatory

• · Isolation of F. tularensis in a clinical · Isolation of F. tularensis in a clinical specimen orspecimen or

• · Fourfold or greater change in serum · Fourfold or greater change in serum antibody titer to F. tularensis antigenantibody titer to F. tularensis antigen

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TreatmentTreatment–Adults – 1Adults – 1stst choices choices• StreptomycinStreptomycin–Dose 500-1000 mg IM q 12 hrDose 500-1000 mg IM q 12 hr–Cure – 97%Cure – 97%–Up to 7% relapseUp to 7% relapse– Severe Jarisch-Herxheimer-like reaction Severe Jarisch-Herxheimer-like reaction

reportedreported

–MICMIC5050 – 2-4 – 2-4 g/ml, MICg/ml, MIC9090 - 4 - 4 g/mlg/ml

– FDA approvedFDA approved

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TreatmentTreatment–Adults – 1Adults – 1stst choices choices• GentamicinGentamicin – acceptable alternative – acceptable alternative–Dose 3-6 mg/kg/day divided q8hr, follow Dose 3-6 mg/kg/day divided q8hr, follow

levels or levels or – 5 mg/kg iv/im qd5 mg/kg iv/im qd

• CureCure – 86% – 86%–Has been successful after tetra/chlor failuresHas been successful after tetra/chlor failures

• FailureFailure – 8% – 8%– Some due to insufficient duration of therapy, Some due to insufficient duration of therapy,

severe illness severe illness

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TreatmentTreatment

–AlternativesAlternatives• DoxycyclineDoxycycline–Dose 100 mg iv q 12 hrDose 100 mg iv q 12 hr–Higher risk relapse, may be only Higher risk relapse, may be only

inhibitory at available MICsinhibitory at available MICs–Can switch to poCan switch to po– FDA approvedFDA approved

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TreatmentTreatment– AlternativesAlternatives• TetracyclineTetracycline– Doses equivalent to doxycyclineDoses equivalent to doxycycline– Cure – 88%Cure – 88%– Relapse 12%Relapse 12%– Slower defervescence than aminoglycosidesSlower defervescence than aminoglycosides– MICMIC5050 – 0.2-0.5 – 0.2-0.5 g/mlg/ml– DisadvantagesDisadvantages» Higher relapseHigher relapse» Bacteriostatic, not cidalBacteriostatic, not cidal» Longer course neededLonger course needed» Levels significantly lower if taken with foodLevels significantly lower if taken with food

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TreatmentTreatment–AlternativesAlternatives• ChloramphenicolChloramphenicol–Dose – 15 mg/kg iv q 6 hrDose – 15 mg/kg iv q 6 hr–Higher risk relapse, may be only inhibitory Higher risk relapse, may be only inhibitory

at available MICsat available MICs–Cure – 77%Cure – 77%– Failure – 2%Failure – 2%–Relapse – 21%Relapse – 21%– Slower defervescence than amioglycosidesSlower defervescence than amioglycosides

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TreatmentTreatment– AlternativesAlternatives• ChloramphenicolChloramphenicol– May be best if meningitis; success for meningitis that May be best if meningitis; success for meningitis that

occurred after gentamicin therapyoccurred after gentamicin therapy» Best agent for crossing blood brain barrierBest agent for crossing blood brain barrier» Normal meninges get 21-50% of serum levelsNormal meninges get 21-50% of serum levels» Inflamed meninges get 45-89%Inflamed meninges get 45-89%

– MICMIC5050 – 0.2-1 – 0.2-1 g/mlg/ml– DisadvantagesDisadvantages» Highest relapse ratesHighest relapse rates» Longer course requiredLonger course required

– Not FDA approved for tularemiaNot FDA approved for tularemia

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TreatmentTreatment–AlternativesAlternatives• CiprofloxacinCiprofloxacin–Dose 400 mg iv q 12 hrDose 400 mg iv q 12 hr–Multiple anecdotal successes including Multiple anecdotal successes including

outpatient pediatric type B bacteremic outpatient pediatric type B bacteremic pneumonics treated with levofloxacinpneumonics treated with levofloxacin–No reported failuresNo reported failures–One relapse after 7 daysOne relapse after 7 days–Has intracellular activityHas intracellular activity–Achieves high serum levelsAchieves high serum levels

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TreatmentTreatment– AlternativesAlternatives• CiprofloxacinCiprofloxacin– BactericidalBactericidal– Stable in acidic environmentStable in acidic environment– Excellent in vitro activityExcellent in vitro activity– Can switch to poCan switch to po– Norfloxacin may be equivalentNorfloxacin may be equivalent– DisadvantagesDisadvantages» Not a good pneumonia drug so would not Not a good pneumonia drug so would not

use alone if pneumonia not certainly use alone if pneumonia not certainly attributed to tularemiaattributed to tularemia

– Not FDA approvedNot FDA approved

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TreatmentTreatment

– Special populationsSpecial populations• ChildrenChildren – essentially same as adults – essentially same as adults– StreptomycinStreptomycin 15 mg/kg IM q 12 hr 15 mg/kg IM q 12 hr

(max 2 g/d) 1(max 2 g/d) 1stst choice choice–GentamicinGentamicin 2.5 mg/dg IM/IV q 8 hr 2.5 mg/dg IM/IV q 8 hr–AlternativesAlternatives»DoxycyclineDoxycycline 2.2 mg/kg IV q 12 hr if 2.2 mg/kg IV q 12 hr if

< 45 kg, o/w 100 mg iv q 12 hr< 45 kg, o/w 100 mg iv q 12 hr»ChloramphenicolChloramphenicol 15 mg/kg iv q 6 hr 15 mg/kg iv q 6 hr»CiprofloxacinCiprofloxacin 15 mg/kg iv q 12 hr 15 mg/kg iv q 12 hr

(max 1 g/day)(max 1 g/day)

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TreatmentTreatment

– Special populationsSpecial populations• ChildrenChildren–No chloramphenicol for < 2 years of ageNo chloramphenicol for < 2 years of age–Ciprofloxacin theoretical cartilage risk and Ciprofloxacin theoretical cartilage risk and

not FDA approved for use in children, but not FDA approved for use in children, but benefit may outweigh theoretical riskbenefit may outweigh theoretical risk–Avoid tetracycline for children < 8 years of Avoid tetracycline for children < 8 years of

ageage– Same duration as adultsSame duration as adults

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Treatment

–Special populations• Pregnant women–1st choice, gentamicin, same adult dose»Minimal fetal risk (renal toxicity)

–2nd choice streptomycin, same adult dose»Slightly higher fetal risk

–3rd choice doxycycline or ciprofloxacin, same adult dose–Same duration as adults

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Treatment

–Special populationsSpecial populations•Breastfeeding womenBreastfeeding women–Same recommendations as pregnant Same recommendations as pregnant

womenwomen

• ImmunosuppressedImmunosuppressed–Higher risk relapseHigher risk relapse

–Always use aminoglycoside if possibleAlways use aminoglycoside if possible

–Consider longer durationConsider longer duration

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Treatment–DurationDuration• 10 days for aminoglycosides, 10 days for aminoglycosides,

ciprofloxacin 10-14 daysciprofloxacin 10-14 days

• 14-21 days for doxycycline 14-21 days for doxycycline /chloramphenicol to prevent /chloramphenicol to prevent relapserelapse

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Treatment

–Switch to poSwitch to po•When improvedWhen improved

•Able to tolerate poAble to tolerate po

• If oral equivalent availableIf oral equivalent available

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Treatment• Insufficient IV resourcesInsufficient IV resources–AdultsAdults•Doxycycline 100 po bidDoxycycline 100 po bid

•Ciprofloxacin 500- 750 po bid Ciprofloxacin 500- 750 po bid – not FDA approved– not FDA approved

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Treatment Treatment • Insufficient IV resourcesInsufficient IV resources

• ChildrenChildren–Doxycycline same po dose as iv aboveDoxycycline same po dose as iv above–Ciprofloxacin same po dose as iv aboveCiprofloxacin same po dose as iv above–Benefits of short courses of these Benefits of short courses of these

probably outweigh small risksprobably outweigh small risks

• Pregnant womenPregnant women–Ciprofloxacin 500 po bidCiprofloxacin 500 po bid–Doxycycline 100 po bidDoxycycline 100 po bid

• Duration – 14 days for all groupsDuration – 14 days for all groups

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TreatmentTreatment

• Generally ineffective – Not Generally ineffective – Not RecommendedRecommended– Beta lactamsBeta lactams

–MacrolidesMacrolides

• Usual responseUsual response–Most afebrile within 24-72 hoursMost afebrile within 24-72 hours

– Pharyngitis, LAD improved in 24-72 Pharyngitis, LAD improved in 24-72 hourshours

99

Treatment

• Resistance / susceptibility–No known naturally-occurring

resistance to aminoglycosides

–Engineered resistance to streptomycin, chloramphenicol, tetracycline have been produced

–Susceptibility testing should be done and treatment modified accordingly

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كنترل توالرميكنترل توالرمي

ـ مـبارزه ـبا مـنابع و 1مخازن

ــيره 2 ــ ــع زنج ــ ـ قطانتقال

ـ حفظ افراد سالم3

101

كنترل توالرميكنترل توالرمي

ـ مبارزه با مخازن1شناســــــــائي بيمــــــــاران و •

؟؟ ناقلينايزوله كردن بيماران ؟؟•تجويز آنتي توكسين ؟؟•تـجويز آـنتي بيوتـيك ـبه بيـماران • درمان حالت ناقلي ؟؟•

حيوانات بيمار و ناقل •منابع محيطي ؟؟•

102

كنترل توالرميكنترل توالرمي

ـ قطع زنجيره انتقال2ــتقيم و • ــاي مسـ تماس هـ

غيرمستقيمآب، غذا و . . . •پوست، مخاط، هوا، . . .•

103

كنترل توالرميكنترل توالرمي

ـ حفظ افراد سالم3مصونسازي اكتيو•مصونسازي پاسيو•كموپروفيالكسي•