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Enteric fever

Generalized infection
of RE system and intestinal lymphoid tissue accompanied by sustained fever and bacteremia

Levine 1983

Causative organisms
Typhoid fever: global, more severe
Salmonella Typhi Rarely by other serovars

Paratyphoid fevers: regional, less severe


Salmonella Paratyphi A south and SE Asia, middle east, central and south America

Salmonella Paratyphi B (S. Schottmuelleri) Europe, north America


Salmonella Paratyphi C (S. Hirschfeldii)

Salmonellosis
Bacterial infections caused by species of Salmonella
ranges from mild to serious infections Types in humans: enteric fever (typhoid and paratyphoid) gastroenteritis (non-typhoidal)

Salmonella
rod-shaped, gram-negative,

facultative anaerobe in the family Enterobacteriaceae

Salmonella Taxonomy
Salmonella

S.enterica

S.bongori

enterica salamae arizonae diarizonae houtenae indica

Principal habitats in different types of Salmonella


Principal habitat : intestinal tracts and bloodstream of

humans, and in the intestinal tracts of a wide variety of animals.


The WHO groups Salmonella into 3 types:

- Typhoidal (enteric) Salmonella (example: S. typhi) causes typhoid and paratyphoid fever restricted to growth in human hosts principal habitat is in intestinal tracts and the bloodstream

- Nontyphoidal Salmonella (example: S. enteritidis, S. typhimurium) prevalent in gastrointestinal tracts of a broad range of animals, including mammals, reptiles, birds and insects. cause a whole range of diseases in animals and humans, mainly gastroenteritis. usually transferred animal-to-person, through certain food products: fresh meat, poultry, eggs and milk - fruits, vegetables, seafood house and exotic pets, contamination through contact with their feces

Salmonella mostly restricted to certain animals- cattles and

pigs, infrequently in humans, if these starin do cause disease in humans, it is often invasive and life threatening.

History of Salmonella
Cause of death of Alexander the Great is supposed to be due to salmonella 323 B.C William Jenner- payers patches and mesenteric lymph node William Budd- transmission by food, water and fomites Control by safe disposal of feaces

1850

1873

1880

Eberth observed S.typhi

Gaffky- isolated organism from spleen, feces & blood 1884 -86 Pfeiffer & Kalle- developed heat killed phenol preserved vaccine

1896

1896
192040

Widal Agglutinating Ab

Kauffman & White -Antigenic structure

1948

Theodore Woodward Chloramphenicol

Epidemiology
Agent: S.typhi & paratyphi
Host:
Age

SEX : M>F

15-25y in West 5-19y in India

Environment: Unsafe drinking water Inadequate sewage disposal Flooding

TIME

Time: Highest rates of typhoid are recorded during July to

October

BURDEN: Worldwide, typhoid fever affects about six million

people with more than 6,00,000 deaths a year in Africa and Latin America.

Almost 80% of cases and deaths occur in Asia, and most others Among Asian countries, India probably has a large number of

these cases.

Global Incidence of Typhoid Fever

Bull World Health Org 2004; 82: 351.

Incidence in Asian Countries

Bulletin of the World Health Organization Volume 86, Number 4, April 2008, 241-320

Burden In India
Typhoid fever is endemic in India
morbidity rate varying from 102 to 2219 per

1,00,000 population in different parts of the country ( Ministry of Health)


urban slum showed 1% of children up to 17 years of age suffer from typhoid fever every year.

Epidemiology: India
30 25 20 15 10 5 0 Under 5 5 to 19 19 to 40 Overall 1.1 11.7 27.3

9.8

Highest incidence at 3y: 51.6 per person year

Seasonal Maximum incidence: monsoon winter summer

18.8/p.y. 4.7/p.y. 5.4/p.y.


Sinha et al. Lancet 1999

Outbreaks in India
Year
2013 2010 2009 1998

Place
Kolkata AndraPradesh Manglore Delhi

Organism
Salmonella spp Paratyphoid S.enterica S.senftenberg

No. of cases
278 40 34 8

1997
1996 1996 1995 1995

Delhi
Delhi Maharastra Varanasi Delhi

S.barelly
Paratyphoid S.Paratyphi A S typhimurium S. typhimurium

36 33 21 8

1994 - 2013 GIDEON Informatics, Inc.

Carrier state
Some individuals have natural immunity to Salmonella. they contract only

mild or asymptomatic disease, but still carry the bacteria in their body for a long time

Typhoid Mary Mallon was the first famous carrier of typhoid fever in the

U.S.

Approximately 3% of persons infected with S. typhi and 0.1% of those

infected with non-typhoidal salmonellae become chronic carriers which may last for a few weeks to years.

Mary Mallon caused several typhoid outbreaks, moving from household to

household, always disappearing before an epidemic could be traced back to the particular household Mary was working in.
All together, over a period of 15 years, caused at least seven outbreaks affecting

over 200 persons.


She was finally overtaken by the authorities in 1907 and committed to an

isolation center on North Brother Island, NY. There she stayed until she was released in 1910, on the condition that she never accept employment involving food handling.
She was found to work as a cook and to cause typhoid outbreaks again. She was

admitted back to North Brother Island, where she lived until her death in 1938.

Pathogenesis

Virulence Factors
Genes for virulence factors cluster in pathogenicity islands

(PI)
Genes acquired through lateral transfer Bacteriophage and transposon insertion sequences flank PI Maybe vehicles for transfer of PI to Salmonella at one time Acquisition of PI enhances virulence of bacteria

Horizontal Transfer
Transformation
Uptake of naked DNA Mediates exchange of any part of DNA

Conjugation
F+ to F Requires cell to cell contact conjugation bridge

Transduction
Transfer of DNA by a phage New phage: viral coat with bacterial DNA

Salmonella Pathogenicity Islands


Salmonella Pathogenicity Island 1 (SPI-1)
entry into intestinal epithelium Enables pathogen to exploit host intestinal environment

Salmonella Pathogenicity Island 2 (SPI-2) intracellular bacterial replication and initiation of systemic infection Do not influence enteropathogenesis to any great extent

Membrane Ruffling
Cytoskeleton-associated proteins relocate to site of bacterial entry Bacterial effector proteins trigger cytoskeleton rearrangements Apical membrane surface undergoes structural changes, resembling ruffling This triggers endocytosis into vesicles Slightly different from receptor-mediated endocytosis

Type III Secretion System (TTSS)


Main way Salmonella delivers virulence factors to host Made up of 20 proteins
Assemble in step-wise order

PrgI is a needle structure extended by protein base, forms a channel to host

Salmonella-host Interaction
Two forms of TTSS One encoded on SPI-1, other on SPI-2
SPI-1 TTSS probably causes initial interaction Starts bacteria-mediated endocytosis Entry activates SPI-2 TTSS to cause thorough infection

SPI-1 Effector Proteins


SipA Binds actin and stabilizes filaments Allows actin to polymerize more easily Maximizes efficiency of Salmonella invasion

SipC
Aides in entry of other SPI-1 effector proteins Activtes G-actin to form F-actin, then polymerize Aides in cytoskeleton rearrangements in membrane ruffling

SPI-2 TTSS
Activated once bacteria enters cell
Necessary for systemic infection SPI-2 TTSS secretes effector proteins from phagosome

into cytosol
Interfere with maturation of phagosome

No fusion with lysosome How Salmonella avoids degredation in cell

SopB
Main virulence factor
Encoded by SPI-5 An enterotoxin associated with SPI-1 TTSS Induces an increase in concentration of cellular inositol

polyphosphate Increased chloride secretion into lumen Na+ follows to balance charge Water follow to balance osmolarity diarrhea

Immune Response
White blood cells recognize trigger T cells, B cells
Two types of B cells: one to attack now, one for

memory Macrophages and neutrophils attack bacteria, secrete interleukins, causing cell-mediated response by T-cells Antibodies from B cells attach to bacteria, allowing cytotoxic T cells, macrophages, and neutrophils to kill the organism

Inside Macrophages
SPI-2 TTSS works in macrophages as well Bacterium produces enzymes that inactivte toxic

macrophage compounds Homocysteine (Nitric Oxide antagonist) Superoxide dismutase (inactivates reactive peroxides) Salmonella must produce additional factors to survive limited nutrient base
Allows bacteria to travel throughout body, causing systemic

infection (only in S. typhi)

Salmonella Containing Vesicle


After ingestion, Salmonella enters a SCV through

bacteria-mediated endocytosis Lives and multiplies in SCV Very little known about SCV or how bacteria exist inside A method to avoid host immune response Phagosome: maturing SCV

Schematic representation of the pathogenesis of Salmonella-induced enteritis, with the most significant events described from A through H.

R.L. Santos et al, Braz J Med Biol Res 2003

R.L. Santos et al, Braz J Med Biol Res 2003

Clinical presentation
Incubation period: 5-21days
Onset: insidious (90%), abrupt(10%) Ingestion to onset of fever: 3 50 days( 2 weeks ) early symptoms are vague Dull continuous head ache Abdominal tenderness discomfort may present with

constipation. May progress and present with step ladder pattern temperature Temperature fall by crisis in 3 4th week

Events in a Typical typhoid Fever

Clinical presentation (cont.)


Complications:
Int. perforation: 0.5-10%,, 3-4wk, most dreaded
Int. hemorrhage- 10-20% in untreated, rare now Hematologic- leukopenia (leucocytosis in children),

anemia, thrombocytopenia Others- hepatitis, liver abscess, OM, pyemia, polyneuritis Reactive arthritis - among 16.8% of cases Inflammatory Bowel Disease -risk for development among cases increase

Clinical presentation (cont.)


Carrier state:

Age: >1y in 1-4% Sex: F>M, Risk factors: biliary disease, bladder schistos.

Relapse- 10-20% after 8-9d (1-70), shorter,

milder
Mortality Preantibiotic: 15%, Presently 10-30% in Asia & Africa.

Laboratory Diagnosis
Based on three principles Isolation of organism Detection of microbial antigen Titration of antibody against causative organism
Week Blood Faeces Urine 1 +++ 2 ++ ++ 3 + + + 4 + +

Isolation of organism: Culture


Culture specimens: blood, stool, urine, rose spots, the

blood mononuclear cell platelet fraction, bone marrow, and gastric or intestinal secretions
Sensitivity: positive culture for S typhi or S paratyphi Blood culture : 50 to 70% Bone marrow culture : 90% If blood, bone marrow and intestinal secretions all are performed: more than 90% of patients

Agglutination- Widal
H Ab, early, persists longer, anamnestic, less cross-reactive O Ab late, declines slowly, cross-reactive Slide method not recommended 4-fold rise diagnostic O & H diagnostic in non-endemic, and <10y in endemic Low specificity: lack of standardization Cross-reactivity O>H Anamnestic reaction H>O Persistent Ab H>O Vaccination H>O Low sensitivity: Early presentation Released soluble Ag Non-responders

Prior antibiotics Fulminant disease

Widal Test
For the diagnosis of enteric

fever. Two types of antigen and agglutination patterns: H or flagellar Ag large loose and fluffy clumps O or somatic Ag fine granular chalky deposits
Negative reaction button like

deposit

Rapid tests
Multi-Test Dip-S-Ticks tests for five pathogens, including Salmonella serotype Typhi. dipstick format that detects anti-O, anti-H, anti-Vi, IgM, or IgG antibodies in patient serum, plasma, or heparinized whole blood. only detects IgG antibodies, had poor specificity

IDL TUBEX TF)


polystyrene particle agglutination

semiquantitative colorimetric test detects anti-O:9 antibody titres in patient specimens on visual examination.

Typhidot (IgM/IgG)
Test is based on the qualitative detection of specific IgM/ IgG antibodies to a

specific 50 kDa outer membrane protein (OMP) antigen on S. Typhi

Characteristic

Multi-Test Dip-S-Ticks 10

TyphiDot

TUBEX

Widal

Approximate cost (U.S. dollars)/specimen No. of tests/kit Antibody Antigen

2.14

4.00

0.50

50 IgM and IgG O,H and Vi

56 IgM or IgG OMP

30 IgM O9

55 IgM and IgG O, H, and Vi

Amt of serum needed (l)


Reaction time (min) Temp for storage (C) Sensitivity

10
90 2-8 78-96

2.5
60 2-8 66-88

35-40(one drop) 300(two dilutions)


3 2-8 65-88 5 2-8 49-77

Specificity

27-73

66-98

71-100

50-92

OLSEN ET AL, J. CLIN.MICROBIOL, 2004

Treatment

Principles of Internal medicine Harrison's 17th Retail

Multidrug resistant strains (MDR)


resistant to chloramphenicol, ampicillin, co-trimoxazole
In India, antibiotic resistance among S. Typhi has been

reported since 1960


The incidence reported 60%

first outbreak of multidrug resistant S. typhi (MDRST) was

reported in Calicut

MDR Salmonella typhi

Number of S. Typhi isolates resistant to antibiotics by disc diffusion

method.

Nagshetty et al; 2010

Indian Network for Surveillance of Antimicrobial Resistance Group

WHO South-East Asia Journal of Public Health 2012

Choudhary et al;IJMR 2013

Shanta Dutta et al; 2005

Prevention
Control of reservoir
Cases

Early diagnosis, notification, isolation, Rx, disinfection, followup Carriers Identification by culture, serology, Rx, surgery, surveillance, health education Control of sanitation

avoid risky foods & drinks:

buy bottled water or boil water for at least 1 minute; COOK and CLEAN food thoroughly, avoid raw vegetables and fruits Education of general public, especially in developing countries; identification of all carriers and sources of contamination of water supplies

Immunisation

Typhoid vaccines
Ty21a
an oral live attenuated S. Typhi vaccine (given on days 1, 3, 5, and 7,

with a booster every 5 years) One capsule is to be swallowed approximately 1 hour before a meal with a cold or luke-warm Protection for 5 years

Typhoid Vi Polysaccharide Vaccine


a parenteral vaccine of purified Vi polysaccharide from the bacterial

capsule 25mg in 0.5ml im single dose with boosters every 2y

Vi-rEPA vaccine :
recently developed
Vi is bound to a nontoxic recombinant protein that is identical to

Pseudomonas aeruginosa exotoxin A In 2- to 4-year-olds, two injections of Vi-rEPA induced higher T-cell responses and higher levels of serum IgG antibody to Vi than did Vi CPS in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and 88% efficacy at 43 months and was very well tolerated

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