Enteric Fever

Enteric Fever

• Synonims :
• Typhoid Fever, Enteric Fever
• This Terms (Typhoid Fever And Enteric Fever), Are Now Used Interchangeably
  
• Definition :
• Systemic Disease Characterized By Fever, And Abdominal Pain And Caused By Salmonella Typhi Or Salmonella Paratyphi
• Epidemiology :
• Prevalence / Incidence
• Worldwide (Based On 2002 Data - Estimated 22 Million Cases, With 200.000 Deaths)
• United States
• 400 Cases Of Typhoid Fever Annually Over Tha Past 10 Years
• Incidence Among U.S Travelers - Estimated At 3 - 30 Cases Per 100.000
• In 2003 : 356 Cases Reported
• Develop Nations - RARE
• Because Of Food Handling And Water / Sewage Treatment Improvements Over The Pass 4 Decades
• Distribution
• Humans - THE ONLY HOST
• Worldwide Incidence
  
• SOUTH CENTRAL & SOUTHEAST ASIA - HIGHEST
• > 100 Cases Per 100.000 Population Per Year
• ASIA, AFRICA, LATIN AMERICA, And OCEANIA (Excluding Australia And New Zealand) - MEDIUM
• 10 - 100 Cases Per 100.000
  
• OTHER PARTS OF THE WORLD - LOW
• Correlates With POOR SANITATION And LACK Of ACCESS TO CLEAN DRINKING WATER
• Young Children & Adolescents - MORE COMMON
• Related To : RAPID POPULATION GROWTH, Increased URBANIZATION, Inadequate HUMAN WASTE TREATMENT, Limited WATER SUPPLY, Overburdened HEALTH CARE SYSTEMS, And ANTIBIOTIC RESISTANCE Among Salmonellae (Linked To Antibiotic Use In Livestock)
• Trend Toward Increase In MULTIDRUG RESISTANT (MDR) Salmonella In Developing Countries, Which Was Reflected By The Increased Proportion Of U.S Cases Caused By MDR Strains
• From 0.6 % In 1985 - 1989, To 12 % In 1990 - 1994
• 25 - 30 % Of Cases Reported In The US Are Domestically Acquired
• 80 % Are Sporadic
• 7 % Have Occured In Recognized Outbreaks Linked To Contaminated Food Products And Previously Unrecognized Chronic Carriers
  
• Age
• Children <> - MOST SUSCEPTIBLE To Initial Infection And TO Development Of Severe Disease
• Risk Factors :
• Exposure To Acutely Infected Persons Or To Chronic Carriers
• Exposure To Contaminated Food Or Water Accounts For More Disease Than Direct Person To Person Transmission Through The Fecal Oral Route
• Travel To Or Residence In A Developing Region, Especially The Indian Subcontinent, The Philippines, Latin America, Or Africa
• Employment As A Health Care Or Laboratory Worker With Exposure To Infected Patients And / Or Laboratory Specimens
• Conditions That Increase Susceptibility To Salmonella Infection
• Decreased Stomach Acidity - Age Of <>
• Decreased Intestinal Integrity - Inflammatory Bowel Disease, Prior GI Surgery, Alteration Of The Intestinal Flora By Antibiotic Administration
• Additional Risk Factors :
• Contaminated Water Or Ice,
• Flooding,
  
• Food And Drinks Purchased From Street Vendors
• Raw Fruits And Vegetables Grown In Fields Fertilized With Sewage
• Ill Houshold Contacts
• Lack Of Hand Washing And Toilet Access
• Evidence Of Prior Helicobacter Pylori Infection
• Probably Related To Chronically Reduced Gastric Acidity
• Etiology :
• Salmonella Typhi, Or Salmonella Paratyphi Serotypes A, B, And C
• Transmission
• Food Borne Or Waterborne Transmission From Fecal Contamination By Ill Or Asymptomatic Chronic Carriers - MOST COMMON
• Sexual Transmission Between Male Partners Has Been Described
• Health Care Workers - Occasional Acquisition After Exposure To Infected Patients Or During Processing Of Clinical Specimens And Cultures

• Diagnosis
• Signs And Symptoms :
• Incubation Period :
• Range : 3 - 21 Days
• Average : 10 - 14 Days
• Prodrome Of Non Specific (FLULIKE) Symptoms Preceding Fever
• Chills ( 35 - 40 % ), Headache ( 80 % ), Anorexia ( 55 % ), Cough ( 30 % ),
• Weakness, Sore Throat, Dizziness, Malaise
  
• Sweating ( 20 - 25 % ), Myalgias ( 20 % ), Arthralgia ( 2 - 4 % )
• Most Prominent Symptoms - PROLONGED FEVER
• Documented At Presentation In 75 % Of Cases
• Can Continue For Up To 4 Weeks If Untreated
• RELATIVE BRADYCARDIA - Classically Described But Not Diagnostically Useful In An Individual Patients
• Variable GI Symptoms
• Nausea ( 18 - 24 % ), Vomiting ( 18 % ), Diarrhea ( 22 - 28 % ) Or Constipation ( 13 - 16 % )
• Diarrhea - MOST COMMON Among Patients With AIDS And Among Children <>
• Abdominal Pain - In 30 To 40 % Of Patients On Presentation
• Physical Examination
  
• Early Physical FIndings :
• Rash ( ROSE SPOTS )
• Faint, Salmon Colored, Blanching Maculopapular Rash
• Primarily On TRUNK And CHEST
• Evident In Around 30 % Of Patients AT THE END OF THE FIRST WEEK
• Resolves Without A Trace After 2 - 5 Days
• Sometimes 2 Or 3 Crops Of Lesions
• Rash Color Sometimes Difficult To Detect In Highly Pigmented Patients
• Viable Organisms In Lesion

• Coated Tongue ( 51 - 56 % )
• Hepatosplenomegaly
• Splenomegaly ( Around 5 - 6 % )
• Abdominal Tenderness ( 4 - 5 % )
• Epistaxis
• Relative Bradycardia
• Neurologic Manivestation
• Meningitis - MENINGEAL SIGN
• Guillain Barre Syndrome
• Neuritis
• Neuropsychiatric Symptoms
• Muttering Delirium Or Coma Vigil
• With Picking At Bedclothes Or Imaginary Objects
• Late Complications ( 3 - 4 Weeks Into Infection ) - MOST COMMON In UNTREATED ADULTS
  
• Intestinal Perforation ( 1 - 3 % ) And / Or Gastrointestinal Bleeding ( 10 - 20 % )
• Can Develop Despite Clinical Improvement
• Presumably From Necrosis At Initial Site Of Salmonella Infiltration At Peyer Patches Of Small Intestine

• Laboratory :
• White Blood Cells - NORMAL, Despite High Fever
• Leukopenia And Neutropenia - In 15 - 25 % Of Cases
• Leukocytosis - During First 10 Days, And Later If Disease Course Is Complicated By Intestinal Perforation Or Secondary Infection
• Disseminated Intravascular Coagulation (DIC)
• Can Be Seen But Usually Is Not Clinically Significant
• Moderately Elevated Liver Function Test Results
• Aminotransferase, Alkaline Phosphatase, And Lactate Dehydrogenase
• Moderately Elevated Muscle Enzyme Levels
• Nonspecific ST And T Wave Abnormalities - On Electrocardiogram
• CULTURE POSTIVE For Salmonella Typhi Or Salmonella Paratyphi - GOLD STANDARD
• Blood Culture, Or Bone Marrow Culture, Or Gastric / Intestinal Secretions Culture, Or
  
• If Blood, Bone Marrow, And Gastric / Intestinal Secretions Are All Cultured, The Yield Of A Positive Culture Is > 90 %
• Blood Culture
• May Be As High As 90 % During The FIRST WEEK Of Infection And Decrease To 50 % By The Third Week
• Low Yield Is Related To Low Numbers Of Salmonella ( <>
• Centrifugation To Isolate And Culture The Buffy Coat, Which Contains Abundant Blood Mononuclear Cells Associated With The Bacteria, Decreases Time To Isolation, But Does Not Affect Culture Sensitivity
• Bone Marrow Culture
• Remain Highly Sensitive ( Around 90 % ), Despite <>
• Gastric / Intestinal Secretion Culture
• Best Obtained By A Non Invasive Duodenal String Test,
  
• Can Be Positive Despite A Negative Bone Marrow Culture
  
• Stool Culture, Or Urine Culture, Or Rose Spots Culture
• Stool Cultures
• Negative In 60 - 70 % Of Cases During The First Week But Can Become Positive During THIRD WEEK Of Infection In Untreated Patients
• Majority Of Patients ( 90 % ) Clear Bacteriaa From The Stool By The Eighth Week
• A Small Percentage Become Chronic Carriers And Continue To Have Positive Stool Cultures For At Least 1 Year
• Serologic Tests - Including The Classic WIDAL TEST For Febrile Agglutinins
  
• None Of These Tests Is Sufficiently Sensitive Or Specific To Replace Culture Based Methods For The Diagnosis Of Enteric Fever In Develop Countries
• Polymerase Chain Reaction ( PCR ) And DNA Probe Assays Are Being Develop

• Imaging :
• Abdominal Imaging
• To Rule Out Intestinal Perforation (Complication Of Typhoid Fever) - In Patients Whose Symptoms Are Severe Enough
• In Patients With Suspected Complications Of Visceral Abscesses
  
• Echocardiography
• In Patients With Prolonged Bacteremia For Evidence Of Endocarditis
• Diagnostic Procedures
• Bone Marrow Aspiration
• To Obtain Sample Of Bone Marrow And Culture
  
• Non Invasive Duodenal String Test
• To Obtain Sample Of Gastric / Intestinal Secretion And Culture
• Treatment :
• Chloramphenicol, Ampicillin, And Trimethoprim - Sulfamethoxazole Were Used Routinely (HISTORICALLY)
• But, These Drugs No Longer Constitute Reliable Treatment For Typhoid Fever In Many Areas Because Of High Level Resistance
• MDR Salmonella Typhi
• Emerged In 1989
• Resistant To Chloramphenicol, Ampicillin, Trimethoprim, Streptomycin, Sulfonamides, And Tetracycline
• Initial Choice Of Antibiotics :
• Depends On The Susceptibility Of The Salmonella Typhi And Salmonella Paratyphi Strains In The Area Of Residence Or Travel
• Drug Susceptibility Typhoid Fever
• Fluoroquinolones
• Most Effective Class Of Agents
• Cure Rates Of 98 %
• Relapse And Fecal Carriage Rates Of <>
• Nalidixic Acid Resistant (NAR) Salmonella Typhi
• Increased Incidence In Asia (Probably Related To The Widespread Availability Of Fluoroquinolone Over The Counter
• Treat With Ceftriaxone, Azithromycin, Or High Dose Ciprofloxacin
• However, High Dose Fluoroquinolone Therapy For NAR Enteric Fever Has Been Associated With Delayed Resolution Of Fever And High Rates Of Fecal Carriage During Convalescence
  
• In Endemic Areas, The Majority Of Patients Are Treated As Outpatients With Antibiotics And Bedrest
  
• In Severe Typhoid Fever, Dexamethasone Treatment Should Be Considered
• Indication For Hospitalization :
• Patients With Persistent Vomiting, Diarrhea, And / Or Abdominal Distension Should Be Hospitalized
• Antibiotics (A Parenteral Third Generation Cephalosporin Or Fluoroquinolone, Depending On The Susceptibility Profile), Fluid Administration, Nutritional Support, Electrolyte Repletion, And Close Monitoring For Life Threatening Complication Are Paramount
• Therapy Should Be Administered For At Least 10 Days Or For 5 Days After Fever Resolution
  
• Empirical Treatment :
• Ceftriaxone - Third Generation Cephalosporin
  
• Dose 1 - 2 Grams / Day (Intravenous)
• Duration : 7 - 14 Days
• Other Third Generation Cephalosporin
• Cefotaxime 2 Grams Q 8 Hours Intravenous, Or
• Cefixime 400 mg BID Per Orem
• Efficacy Of Ceftriaxone, Cefotaxime, Cefixime
• Fever Cleared In 1 Week
• Failure Rates Of 5 - 10 %
• Fecal Carriage Rates Of <>
• Relapse Rates Of 3 - 6 %
• Azithromycin
• Dose : 1 Gram / Day Per Orem
• Duration : 5 Days
• Efficacy :
• Defervescence In 4 - 6 Days
• Rates Of Relapse And Convalescent Stool Carriage Of Less Than 3 %
• Fully Susceptible :
• Ciprofloxacin - FIRST LINE
• Dose : 500 mg BID P.O Or 400 mg Q 12 Hours Intravenously
• Duration : 5 - 7 Days
• Ofloxacin :
• Dose : 400 mg BID P.O
• Duration : 2 - 5 Days
• Amoxicillin - SECOND LINE
• Dose : 1 Gram TID P.O, Or 2 Grams Q 6 Hours Intravenously
• Duration : 14 Days
• Chloramphenicol :
• Dose : 160 / 800 mg BID P.O
• Duration : 14 Days
• Multi Drug Resistant (MDR) :
  
• Ciprofloxacin
• Dose : 500 mg BID P.O Or 400 mg Q 12 Hours Intravenously
• Duration : 5 - 7 Days
• Ceftriaxone
• Dose 2 - 3 Grams / Day (Intravenous)
• Duration : 7 - 14 Days
• Azithromycin
  
• Dose : 1 Gram / Day Per Orem
• Duration : 5 Days
• Alternative :
• 1 Gram On Day 1 Followed By 500 mg / Day P.O For 6 Days
• Nalidixic Acid Resistant (NAR) :
• Ceftriaxone
• Dose : 1 - 2 Grams / Day IV
• Duration : 7 - 14 Days
  
• Azithromycin
• Dose : 1 Gram / Day P.O
• Duration : 5 Days
  
• High Dose Ciprofloxacin
• Dose : 750 mg BID P.O Or 400 mg Q 8 Hours IV
• Duration : 10 - 14 Days

• Dexamethasone :
• A Single Study Of Chloramphenicol Treated Patients In Jakarta In The 1980s Showed An Association Of Dexamethasone Treatment With Reduction In Mortality From 56 % To 10 % In Critically Ill Patients
• Implications Of These Findings For Non Chloramphenicol Treated Populations Are Unclear
• In Severe Typhoid Fever
• Characterized By Persistent Fever, Delirium, Stupor, Coma, Or Shock, And A Positive Culture For Salmonella Typhi Or Salmonella Paratyphi A, Dexamethasone ( A Single Dose Of 3 mg / kg, Given Every 6 Hours Should Be Considered)
• Chronic Carriage :
• 1 - 5 % Of Patients Can Develop Chronic Carriage Of Salmonella, Defined As Excretion Of The Organism In The Stool For > 12 Months After Acute Infection
• Extended Duration Treatment With Fluoroquinolones Leads To Eradication Rates Of 70-90%.
• Ciprofloxacin 500 - 750 mg By Mouth Twice Daily For 28 Days
• Ofloxacin 400 mg By Mouth Twice Daily For 28 Days
• Alternative To Fluoroquinolones
• Ampicillin Or Amoxicillin ( 4 - 6 Grams Per Day) For 3 Months
• Trimethoprim - Sulfamethoxazole 2 Tablets By Mouth Twice Daily For 3 Months
• In Cases Of Anatomical Abnormality, Such As : Biliary Or Kidney Stones, Then Eradication Of Infection Often May Require Surgical Correction
  

• Complication :
• Late Complications ( 10 - 15 % Of Patients )
• 3RD - 4TH Weeks Of Infection
• Life Threatening Complication :
• Intestinal Hemorrhage ( MOST COMMON ) Or Ileal Perforation
• Most Common In Untreated Adults
• Can Develop Despite Clinical Improvement, And Presumably Results From Necrosis At Initial Site Of Salmonella Infiltration At Peyer's Patches Of Small Intestine
• Require Immediate Medical And Surgical Interventions, With Broadened Antibiotic Coverage For Polymicrobial Peritonitis And Treatment Of Gastrointestinal Hemorrhages, Including Bowel Resection
• Typhoid Encephalopathy
• Also Associated With HIGH MORTALITY
• Rare Complication
• Incidence Are Reduced By Prompt Antibiotic Treatment
• Such As :
• Disseminated Intravascular Coagulation, Hemophagocytic Syndrome, Pancreatitis, Hepatic And Splenic Abscesses And Granuloma, Endocarditis, Pericarditis, Myocarditis, Orchitis, Hepatitis, Meningitis, Glomerulonephritis, Pyelonephritis, Hemolytic Uremic Syndrome, Severe Pneumonia, Arthritis, Osteomyelitis, Parotitis
• Relaps
  
• Around 10 % Rate in Immunocompetent Hosts Despite Prompt Antibiotic Treatment
  
• Prognosis :
• In The Preantibiotic Era, Mortality Rate From Typhoid Fever Was As High As 15 %
• Recently, The Mortality Rate Has Been Very Low For Uncomplicated Typhoid Infection
• Among Hospitalized Patients, Mortality May Be Much Higher In Some Areas Of The World
• Prompt Administration Of Appropriate Antibiotic Therapy Prevents Severe Complications Of Enteric Fever And Results In A Case Fatality Rate Of <>
• Despite Prompt Antibiotic Treatment, Relapse Rate Remains At 10 % Among Immunocompetent Hosts
• Up To 10 % Of Untreated Patients With Typhoid Fever Excrete Salmonella Typhi In The Feces Up To 3 Months
• 1 - 4 % Develop Chronic Asymptomatic Carriage
  
• Shedding Salmonella Typhi In Either Urine Or Stool For > 1 Year After Acute Infection
• The Incidence Of Chronic Carriage Is More Common Among : Women, Infants, Persons With Biliary Abnormalities (Such As : Gallstones, Carcinoma Of The Gallbladder) And Gastrointestinal Malignancy
• The Anatomical Abnormalities In Persons With Renal Stones Or Concurrent Bladder Infection With Schistosoma Haematobium Allow Prolonged Colonization
• Prevention :
• Avoidance Of Exposure
• Vaccination
• U.S Centers For Disease Control And Prevention (CDC) And The World Health Organization Recommend Typhoid Vaccination For Travelers To Typhoid Endemic Countries
• Analysis From The CDC Found That 16 % Of Travel Associated Cases Occured Among Persons Who Stayed At Their Travel Destination For Less Than Or Around 2 Weeks
• Thus, Vaccination Should Be Strongly Considered Even For Persons Planning Short Term Travel To High Risk Areas Such As The Indian Subcontinent
  
• Domestic Vaccination Is Recommended For People Who Have Intimate Or Household Contact With A Chronic Carrier And For Laboratory Personnel Who Frequently Work With Salmonella Typhi
• Two Vaccine Alternatives Have Similiar 3 Year Cumulative Efficacies ( 50 - 55 % ) And Side Effect (Fever) Rates ( 1 - 2 % )
• Ty21a, Live Attenuated Salmonella Typhi Vaccine ( 4 Oral Doses Given On Days 1, 3, 5, And 7, With A Booster Every 5 Years
• Minimum Age - 6 Years
• Duration Of Protection - 5 Years
• VICPS, Purified Vi Polysaccharide From The Bacterial Capsule ( 1 Parenteral Dose, With A Booster Every 2 Years)
• Minimum Age - 2 Years
• Duration Of Protection - 2 Years
• VICPS, Is Preferred For Vaccination Of Almost All Patients, Including Immunocompromised Hosts
• Acetone Killed Whole Cell Vaccine Is Available Only For Use By The U.S Military
• A New Vaccine, Vi - rEPA, Has Been Develop
• Vi Polysaccharide Is Bound To A Nontoxic Recombinant Protein That Is Identical To Pseudomonas Aeruginosa Exotoxin ; 2 Parenteral Doses Are Given
• In 2 - 4 Years Old, 2 Injections Of Vi - rEPA Induced Higher T - Cell Responses And Higher Levels Of Serum IgG Antibody To Vi Than Did ViCPS In 5 - 14 Years Old
• In A 2 Dose Trial In 2 - 5 Year Old Children In Vietnam, Vi - rEPA Provided 91 % Efficacy At 43 Months And Was Very Well Tolerated
• Similiar Results Were Obtained In A Trial In Cambodia
• This Vaccine Is Not Yet Commercially Available In The U.S
  
• At Least 3 New Live Vaccines Are In Clinical Development And May Prove More Efficacious And Longer Lasting Than Previous Live Vaccines
  
• Infection Control / Public Health Measures
• Enteric Fever Is A Reportable Disease In U.S
• Individual Health Departments Have Guidelines For Allowing Food Handlers Or Health Care Workers To Return To Work
• The Reporting System Enables Public Health Departments To Track Down Potential Source Patients And To Identify And Treat Chronic Carriers To Prevent Further Outbreaks