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Pathophysiology and Diagnosis of Pathophysiology and Diagnosis of Thyphoid FeverThyphoid Fever

Iskandar Zulkarnain

Division of Tropical Medicine and Infectious DiseasesDepartement of Internal Medicine

Faculty of Medicine, University of IndonesiaDr. Cipto Mangunkusumo General Hospital

Jakarta

Typhoid FeverTyphoid Fever

l Typhoid fever is an acute systemic infection caused by Salmonella entericaserotype typhi or paratyphi, characterized by constitutional and gastrointestinal symptoms

Epidemiologic Distribution of Typhoid Fever

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OrganismOrganism

l Salmonella typhi, a Gram-negative bacteria.

l Similar but often less severe disease is caused by Salmonella serotype paratyphi A & B.

l Contains 3 important antigens:1. O antigen: a lipopolysaccharide part of the cell wall. It is an

important pathogenic factor and is common for typhi and paratyphi species (group-specific)

2. H or flagellar antigen: strain specific; important in diagnosis

3. Polysaccharide capsule Vi: present in about 90% of all freshly isolated S. typhi and has a protective effect against the bactericidal action of the serum of infected patients.

S. typhiS. typhi

TransmissionTransmission

l Reservoir is chronic carriers: Organisms may live for months or years in the Gall Bladders of carriers and are passed intermittently in stool and less frequently in urine.

l Infection occurs by fecal-oral route. Common sources are infected water supply and polluted vegetables and food. Direct contact and insects as flies play a minor role.

l Occurrence of clinical disease depends on the amount of infecting organism.

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Some example of commonlyOccuring Salmonella serotypes and groups

Group SerotypeA S. paratyphi AB S. paratyphi B

S. stanleyS. saintpaulS. agonaS. typhimurium

C S. paratyphi CS. choleraesuisS. virchowS. thompson

D S. typhiS. enteritidisS. dublinS. gallinarium

PathogenesisContaminated food of drinks Gastric acid

Bowel lumen

Mucosal defence

ColonizationAdhesion to mucose

Invasion to Peyer Patch

Regional Lymphadenitis Thoracic duct

1st systemic bacteriemia

PathogenesisInfection of RE system

Liver, Spleen2nd Bacteriemia

Gall bladder Lung, MyocardKidney, etc

Reinfection in bowel mucose Systemic manifestation

Hyperplasia Peyer Patch Inflammation, erosion

Feces

Bleeding, perforation

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Pathology of typhoid feverPathology of typhoid fever

Clinical features: symptomsClinical features: symptomsClassic disease passes into 3 stages each lasting one week:

First week- Fever : Temp rises gradually in a stepladder

manner.- Headache, malaise, myalgia, drowsiness- Abdominal pain and distension, constipation

(pea-soup diarrhea and vomiting in children)- Cough, sore throat

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Clinical features: symptomsClinical features: symptomsl Second week

Patient is more ill, prostrated with continuous high fever. Abdominal symptoms are more severe with jaundice in some cases. Others may have delerium or stupor.

l Third week Cure or Complications ?Untreated, patients may improve gradually or toxaemia increases and pass into coma (typhoid state). This is rare now and the course is modified by the early use of antibiotics.

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Fever pattern in Typhoid Fever

High feverHeadacheAbdominal discomfortDiarrhea or constipationRelative bradicardia

LeucopeniaMild thrombocytopeniaRelative neutrofiliaAneosinofilia

Fever pattern : typhoid feverTyphus Inversus Pattern

Lowest early in the morning Highest about 5.30 to 6.30 pmCan be found in typhoid fever, TB

Pulse Temperature dissosiationIn normal temperature 37oC (99oF) pulse 80 beats/minIncreased 8 beats/min every 1o CRelative bradicardia can be found in

enteric/typhoid fever, mycoplasma, malaria falciparum

Devervescence à 3-7 days after treatmentusually on 2nd or 3rd weeks

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Female 31 yo, fever since 2 weeks agoHb 9.3 L 1600 Ht 28 Tr 107.000Diff -/1/4/62/31/2 ESR 60 CRP 68Widal ty O 1/160 H >1/640 ty B H 1/160Treatment : Ceftriaxone 3g/dayGall culture - PCR S typhi +

Clinical features: signsClinical features: signsl Relative bradycardia (pulse-temp dissociation)

l Fine rose-spot rash on the trunk appearing on the 4th – 5th day of fever, more in whites. Rash fades on pressure and disappears in 3-4 days.

l Coated tongue

l Diffuse abdominal distension and tenderness. Rigidity and rebound tenderness suggest intestinal perforation.

l Mild splenomegaly is detectable by the end of first week. Hepatmegaly and jaudice are uncommon.

l Delerium, stupor. Sign of meningism are occasional.

l Leucopenia is typical. Leucocytosis (and tachycardia) suggest a complication as intestinal bleeding or perforation.

Typhoid rashTyphoid rash

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Clinical Presentation of Typhoid FeverClinical Presentation of Typhoid Fever

Headache 94.9Epigastric pain 94.7Nausea 90.7Anorexia 90.2Fever (>37.2) 89.8Muscular pain 78.6Rigor 78.4Coated tongue 41.8Vomiting 57.7Cough 46.2Relative bradicardia 34.2Diarrhea 32.1Constipation 33.9Hepatomegaly 12.3Splenomegaly 0.8

Clinical sign and symptom (n=119) %

Pohan HT, Indones J Int Med 2004;36(2)

Clinical scoring scale for typhoid feverClinical scoring scale for typhoid fever

Fever < 1 wk 1Headache 1 Weakness 1Nausea 1 Anorexia 1Abdominal pain 1Vomiting 1Disturb GI motility 1

Insomnia 1Hepatomegaly 1Spelenomegaly 1Fever > 1 wk 2Relative bradicardia 2Typhoid tongue 2Melena stools 2Impaired consciousness 2

Clinical typhoid fever if score > 13 of maximal 20

Adapted from : Nelwan RHH. Conns Current Traatment 2003

Laboratory Examination : DiagnosisLaboratory Examination : DiagnosisPeripheral blood count Leucopenia, leucocytosis

normal WBC countmild anemia thrombocytopeniaincreased ESR

Serum transaminase increased ALT and AST

Albumin Hypoalbuminemia

Serology Increased titer ofaglutinin O, H and Vi

Blood culture Salmonela typhi

PCR Positive

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Laboratory diagnosis : CultureLaboratory diagnosis : Culture

l Culture: is essential for diagnosis. – Blood culture is positive in >70% in the first week and rate

of positivity declines thereafter. – Bone marrow aspirate culture gives the highest yield all

through the disease and should be performed in presence of a negative blood culture.

– Urine culture is positive in 10% temporarily in the first week. – Stool culture is positive in 30% in the 2nd and 3rd weeks but

is difficult and unreliable due to presence of other Salmonellae in stool.

Laboratory Diagnosis: Widal testAgglutination test that detects antibodies against S. typhi and paratyphi

in the patient’s serum. Involves reaction against 5 antigens : O antigen and H antigens of typhi

and paratyphi A, B & C; O antibodies appear on days 6-8 and H antibodies on days 10-12.

The role of Widal test in diagnosis of typhoid vever is complicated by:1. False negative results in up to 30% of culture-proven cases of typhoid

fever2. False positive results: S. typhi shares O and H antigens with other

Salmonella serotypes and has cross-reacting epitopes with other Enterobacteriacae

3. Results should be interpreted with care in accordance with appropriate local cut-off values for the determination of positivity which depends on endemicity of infection and application of vaccination.

Cut off titres à depends on local data

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Diagnostic criteriaDiagnostic criteria

l Definite- Positive gall culture or PCR Salmonella typhi - Widal serology agglutinin O titer > 1/640 or H titer >1/1280 - Increased of O titer twice or more

l ProbableWidal serology agglutinin O titer 1/320 or H titer 1/640.

TreatmentTreatmentl Non Pharmacologic : Bed Rest, Nutrition

l Pharmacologic : 1. Symptomatic & Supportive Treatment

2. AntibioticAmpicillin/Amoxicillin 2x750 or 3x500 mgCotrimoxasazole2 x 960 mgChloramphenicol 4 x 500mg / Tiamphenicol 4 x 500 mgCephalosporin : Ceftriaxone 3-4 g/daysFluoroquinolones : Ciprofloxaxin 2 x 500 mg

Levofloxacin 1 x 500mgOfloxacin 2 x 400 mg

Azithromycin 1 x 500 mg

ComplicationsIntestinal Complication

Intestinal perforationGastrointestinal hemorrhageHepatiitis, pancreatitis, paralytic ileus

Extraintestinal ComplicationCardiovascular : shock, myocarditisNeuropsychiatric : encephalopaty, delirium

psychosisTOXIC TYPHOID

Respiratory : bronchitis, pneumonia, pleuritisHematology : anemia, DICKidney : glemerulonephritis, pyelonephritisOthers : osteomyelitis, focal abscess

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Intestinal ComplicationsBasic pathogenesis :Plaque peyeri lesions Mild Bleeding Perforations --> Severe bleeding

Clinical Diagnosis :Physical signs of acute peritonitisLeucocytosis; neutrophils shift to the leftAbdominal x-ray

Treatment :Maintain adequate blood pressureBlood tranfusion (if indicated)Broad spectrum AntibioticsSurgical procedure

Extraintestinal ComplicationsHematologic complicationsDIC

Hepatitis typhosaEnlargement of livers in 50% of cases

Pancreatitis typhosaVery rare complication

Myocarditis typhosaOccur in 1-5% of all cases ECG abnormality occur in 10-15% of casesMay cause sudden death due to acute cardiac failure

The Role of Steroids :Indicated only on severe typhoid complications :

1. Toxic Typhoid2. Typhoid with Shock

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Carrier State

• Exist. of S. typhi in feces or urine withoutclinical manifestation 1 year after recovery fromtyphoid fever

S. typhi still be found in feces of urine 2 or 3 months after recovery in 16% patients

• Impairment of host defence mechanism,gall and kidney stone, chronic gall andkidney infection contribute in pathogenesis of carrier state

Carrier State• Diagnosis of carrier state :Feces and urine culture

• Treatment : Without gall stone :

Ampicillin, Amoxicillin, Cotrimoxazole

With gall stone :Cholecystectomi and treatment withCiprofloxacin or Norfloxacin

With Schistosomiasis :Eradication of schistosomiasis before treatment of carier state

Prevention

• Avoid risky food or drinks• Hand washing• Vaccination• Detection of carrier state in food handler

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Clinical Trials of Typhoid FeverClinical Trials of Typhoid Fever

Amoxicillin in Typhoid fever study with twice Amoxicillin in Typhoid fever study with twice daily dosagedaily dosageHendarwanto, Nelwan RHH, Zulkarnain I, et alHendarwanto, Nelwan RHH, Zulkarnain I, et al

Drugs : Amoxicillin loading dose 2250mg then 2x750vs 3x 1000 oral for 14 days

Design : Open randomized controlledSubject : 25 vs 23 uncomplicated typhoid feverResults : Clinical efficacy 100%

Microbiological efficacy 88 vs 91% on day 3rd

100% in day 10th

Devervescens 6.8 vs 7.2 days

CLASSIFICATION OF FLUOROQUINOLONEGEN. NAME ANTIBACT. ACTIVITY

Gen I Nalidixic acid predominantly for enterobacteriaceae

Gen II Ciprofloxacin predominantly for gramPefloxacin negative bacteria & limitedOfloxacin gram positive bacteria

Gen III Levofloxacin ‘Broad spectrum’ activeSparfloxacin gram neg & pos,atypical

Gen IV Gatifloxacin 3rd generation plusMoxifloxacin anaerobesGemifloxacin

Clin Inf. Dis, 2000; 31:47- 82

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Clinical Trials of Fluoroquinolones Clinical Trials of Fluoroquinolones in Typhoid feverin Typhoid fever

Invest Year Medication Treatment number Clinical BacterialIgator duration cases efficacy efficacy

Arnold 1993 FLX 14 35 100 96Nelwan 1993 PEF 7 20 100 100Hien 1994 FLX 7 16 100 100Nelwan 1994 OFL 7 12 100 100Nelwan 1995 CIP 6 31 100 100Duong 1995 FLX 5 41 97.5 94Duong 1995 FLX 3 22 100 100Nelwan 1997 FLX 3 4 100 100

COMPARISON OF DEFERVESCENCE IN TYPHOID FEVER

Name of Drug Dosage Duration Fever Clearance

Ciprofloxacine(5) 500 BID 6 days 3,60 days

Ofloxacine(6) 600 mg OD 7 days 3,40 days

Pefloxacine(7) 400 mg OD 7 days 3,10 days

Fleroxacine(8) 400 mg OD 5 days 3,4 days

Fluoroquinolones for treating typhoid and paratyphoid fever (Cochrane Review)

Thaver D, Zaidi AK, Critchley J, Madni SA, Bhutta ZA

Main results:Compared with chloramphenicol, fluoroquinolones were not statistically

significantly different Compared with co-trimoxazole, we detected no statistically significant

difference Among adults, fluoroquinolones reduced clinical failure compared with

ceftriaxone but showed no difference for microbiological failure or relapse.

We detected no statistically significant difference between fluoroquinolones and cefixime orazithromycin

In trials of hospitalized children, fluoroquinolones were not statistically significantly different from ceftriaxone or cefixime

Authors' conclusions: Many trials were small, and methodological quality varied widely. Although enteric fever most commonly affects children, trials in this group were particularly sparse. Insufficient data in all comparisons preclude any firm conclusions to be made regarding superiority of fluoroquinolones over first-line antibiotics in children and adults.

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Open Study of Efficacy and Safety 500 mg Once Daily Open Study of Efficacy and Safety 500 mg Once Daily Levofloxacin in Treatment of Uncomplicated Typhoid Levofloxacin in Treatment of Uncomplicated Typhoid FeverFever

R H H. Nelwan, Khie Chen, Nafrialdi

Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine, Medical Faculty

University of Indonesia/Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia.

Primary endpoint: Primary endpoint: efficacy and day of defervesecenceefficacy and day of defervesecenceSecondary endopoint :Secondary endopoint :SafetySafety

Design : Open StudyLocation : Dr. Cipto Mangunkusumo and Affiliated

Hospital in JakartaPeriod : October 2003 – April 2004 Subject : Uncomplicated Typhoid feverLevofloxacin (Daichi) 500 mg od (oral or iv) for 7 days.

Aims

Methods

Diagnostic criteriaDiagnostic criteria

l Definite :Positive gall culture or PCR Salmonella typhi Widal serology agglutinin O titer > 1/640

or H titer >1/1280 Increased of O titer twice or more

l Probable :Widal serology agglutinin O titer 1/320

or H titer 1/640.

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ResultsResultsEnrolled : 52 subjects

47 pt received therapy severe, pregnant, fever decr 5 pt exc

44 pt continue 3 pt withdrawal

Definite 20 4 excl other diagnosisProbable 9 AnalyzedClinical 11

Definite (n= 21 ) 70Positive Microbiological Blood Culture 4Positive Salmonella typhi PCR 8Positive S.typhi PCR & Blood Culture 1Widal agglutinin O titer 1/640 1Widal agglutinin H titer 1/1280 1Increasing Widal agglutinin O titer > 2 times 6

Probable (n=9) 30Widal agglutinin O titer 1 /320 7Widal agglutinin H titer 1/640 2

DISTRIBUTION OF SUBJECTS ACCORDING TO DIAGNOSTIC CRITERIA

Diagnostic criteria n %

CLINICAL RESULTS OF TREATMENT

Treatment results Definite cases Probable casesn % n %

Clinical efficacyResponse 21 100 9 100Failure 0 0

Defervescence on:1st day after treatment 4 19.0 1 11.12nd day after treatment 6 28.6 6 66.73rd day after treatment 10 47.6 1 11.14th day after treatment 0 1 11.15th day after treatment 1 4.8 0Mean (days) 2.43 2.22

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MildNausea * 4 8.3Vomit * 1 2.1Insomia * 1 2.1Rash /Pururitis ** 2 4.2

ModerateMeteorism *** 1 2.1

Severe None

ADVERSE EVENTS EXPERIENCED (N=48)

* probably related **definitely related *** unlikely related

Adverse events n %

Results of Preliminary study of Levofloxacin Results of Preliminary study of Levofloxacin for uncomplicated typhoid feverfor uncomplicated typhoid fever

A preliminary open study of levofloxacin in treatment of uncomplicated typhoid fever showed that this drug was effective and relatively safe. The day of defervescence also quite short (mean 2.4 days).

ConclusionsConclusionsl Typhoid fever is an acute systemic infection caused by

Salmonella enterica serotype typhi or paratyphil Clinical manifestation include local symptoms in GI tract,

systemic manifestation and/or complicationsl Treatment include supportive and antimicrobialsl Antibiotics include :

Amoxicillin, Cotrimoxazole, Chloramphenicol, Ceftriaxone and fluoroquinolones (Cipro, Oflo, Flero,Peflo) are effective.

l Some complications possible include severe toxic, intestinal bleeding and perforation should be anticipated.

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ConclusionsConclusions

l Typhoid fever is an acute systemic infection caused by Salmonella enterica serotype typhi or paratyphi

l Clinical manifestation include local symptoms in GI tract, systemic manifestation and/or complications

l Diagnosis of Typhoid fever is essentially be made through clinical judgement and wise implementation of laboratory results.