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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
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,
Salmonella Taxonomy
Salmonella
S.enterica
S.bongori
- 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
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
Gaffky- isolated organism from spleen, feces & blood 1884 -86 Pfeiffer & Kalle- developed heat killed phenol preserved vaccine
1896
1896
192040
Widal Agglutinating Ab
1948
Epidemiology
Agent: S.typhi & paratyphi
Host:
Age
SEX : M>F
TIME
October
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.
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
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
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
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.
infected with non-typhoidal salmonellae become chronic carriers which may last for a few weeks to years.
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
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 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
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
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
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
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.
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
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
Age: >1y in 1-4% Sex: F>M, Risk factors: biliary disease, bladder schistos.
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 + +
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
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
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
Characteristic
Multi-Test Dip-S-Ticks 10
TyphiDot
TUBEX
Widal
2.14
4.00
0.50
30 IgM O9
10
90 2-8 78-96
2.5
60 2-8 66-88
Specificity
27-73
66-98
71-100
50-92
Treatment
reported in Calicut
method.
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
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
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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