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Typhoid FeverTyphoid Fever
(( Enteric FeversEnteric Fevers ))
an updatean update
Dr.T.V.Rao MDDr.T.V.Rao MD
Typhoid fevers are prevalent inTyphoid fevers are prevalent in
many regions in the Worldmany regions in the World
Enteric FeversEnteric Fevers
The syndrome associated with entericThe syndrome associated with enteric
fevers are produced only by a few of thefevers are produced only by a few of the
SalmonellaSalmonella
Salmonella typhi most importantSalmonella typhi most important
Salmonella paratyphi A, B,CSalmonella paratyphi A, B,C
Historical landmarks in TyphoidHistorical landmarks in Typhoid
In 1880s, the typhoid bacillus was first observedIn 1880s, the typhoid bacillus was first observed
by Eberth in spleen sections and mesentericby Eberth in spleen sections and mesenteric
lymph nodes from a patient who died fromlymph nodes from a patient who died from
typhoid. Robert Koch confirmed a related findingtyphoid. Robert Koch confirmed a related finding
by Gaffky and succeeded in cultivating theby Gaffky and succeeded in cultivating the
bacterium in 1881. But due to the lack ofbacterium in 1881. But due to the lack of
differential characters, separation of the typhoiddifferential characters, separation of the typhoid
bacillus from other enteric bacteria wasbacillus from other enteric bacteria was
uncertain.uncertain.
..
History of Sero DiagnosisHistory of Sero Diagnosis
In 1896, it was demonstrated that theIn 1896, it was demonstrated that the
serum from an animal immunized with theserum from an animal immunized with the
typhoid bacillus agglutinated (clumped)typhoid bacillus agglutinated (clumped)
the typhoid bacterial cells, and it wasthe typhoid bacterial cells, and it was
shown that the serum of patients afflictedshown that the serum of patients afflicted
with typhoid likewise agglutinated thewith typhoid likewise agglutinated the
typhoid bacillus. Serodiagnosis of typhoidtyphoid bacillus. Serodiagnosis of typhoid
was thus made possible by 1896.was thus made possible by 1896.
Typhoid MaryTyphoid Mary
A famous example isA famous example is
“Typhoid” Mary“Typhoid” Mary
Mallon, who was aMallon, who was a
food handlerfood handler
responsible forresponsible for
infecting at least 78infecting at least 78
people, killing 5.people, killing 5.
These highlyThese highly
infectious carriersinfectious carriers
pose a great risk topose a great risk to
public health.public health.
Typhoid MaryTyphoid Mary
"Typhoid Mary," real name Mary Mallon,"Typhoid Mary," real name Mary Mallon,
worked as a cook in New York City in theworked as a cook in New York City in the
early 1900s. Public health pioneerearly 1900s. Public health pioneer
Sara Josephine Baker, MD, PhDSara Josephine Baker, MD, PhD trackedtracked
her down after discovering that she washer down after discovering that she was
the common link among many people whothe common link among many people who
had become ill from typhoid fever She washad become ill from typhoid fever She was
traced to typhoid outbreaks a second timetraced to typhoid outbreaks a second time
so she was put in prison again where sheso she was put in prison again where she
lived until she died.lived until she died.
Etiology of Typhoid feverEtiology of Typhoid fever
Typhoid fever is a bacterial disease,Typhoid fever is a bacterial disease,
caused bycaused by Salmonella typhiSalmonella typhi.. It isIt is
transmitted through the ingestion of foodtransmitted through the ingestion of food
or drink contaminated by the faeces oror drink contaminated by the faeces or
urine of infected people.urine of infected people.
Para typhoid fevers are produced by otherPara typhoid fevers are produced by other
species namedspecies named
Paratyphi A, B, CParatyphi A, B, C
Changing taxonomy ofChanging taxonomy of
Salmonella speciesSalmonella species
SalmonellaSalmonella areare Gram-negativeGram-negative bacteriabacteria
which cause intestinal infections. Thewhich cause intestinal infections. The
taxonomy oftaxonomy of SalmonellaSalmonella species isspecies is
complicated. Formally, there are only twocomplicated. Formally, there are only two
species within this genus:species within this genus: S. bongoriS. bongori andand
S. entericaS. enterica (formerly called(formerly called S.S.
choleraesuischoleraesuis), which are divided into six), which are divided into six
subspecies:subspecies:
Different types of SalmonellaDifferent types of Salmonella
I -I - entericaenterica
II -II - salamaesalamae
IIIa -IIIa -arizonaearizonae
IIIb -IIIb -diarizonaediarizonae
IV -IV - houtenaehoutenae
V -V - bongoribongori
VI -VI - indicaindica
Bacteriology –Typhoid feverBacteriology –Typhoid fever
The GenusThe Genus
Salmonella belong toSalmonella belong to
EnterobactericiaeEnterobactericiae
Facultative anaerobeFacultative anaerobe
Gram negative bacilliGram negative bacilli
Distinguished fromDistinguished from
other bacteria byother bacteria by
Biochemical andBiochemical and
antigen structureantigen structure
Antigenic structure ofAntigenic structure of
SalmonellaSalmonella
Two sets of antigensTwo sets of antigens
Detection by serotypingDetection by serotyping
11 Somatic or 0 AntigensSomatic or 0 Antigens contain long chaincontain long chain
polysaccharides ( LPS ) comprises of heat stablepolysaccharides ( LPS ) comprises of heat stable
polysaccharide commonly.polysaccharide commonly.
2 Flagellar or H Antigens2 Flagellar or H Antigens are strongly immunogenicare strongly immunogenic
and induces antibody formation rapidly and in high titersand induces antibody formation rapidly and in high titers
following infection or immunization. The flagellar antigenfollowing infection or immunization. The flagellar antigen
is of a dual nature, occurring in one of the two phases.is of a dual nature, occurring in one of the two phases.
Paratyphoid fevers on riseParatyphoid fevers on rise
Paratyphoid fever can be caused by anyParatyphoid fever can be caused by any
of three serotypes of S. paratyphi A, B andof three serotypes of S. paratyphi A, B and
C. It is similar in its symptoms to typhoidC. It is similar in its symptoms to typhoid
fever, but tends to be milder, with a lowerfever, but tends to be milder, with a lower
fatality rate.fatality rate.
How a Typhoid fever spreadsHow a Typhoid fever spreads
SalmonellaSalmonella Typhi lives only in humans.Typhi lives only in humans.
Persons with typhoid fever carry thePersons with typhoid fever carry the
bacteria in their bloodstream and intestinalbacteria in their bloodstream and intestinal
tract. In addition, a small number oftract. In addition, a small number of
persons, called carriers , recover frompersons, called carriers , recover from
typhoid fever but continue to carry thetyphoid fever but continue to carry the
bacteria. Both ill persons and carriersbacteria. Both ill persons and carriers
shedshed S.S. Typhi in their feces (stool).Typhi in their feces (stool).
Clinical featuresClinical features
Typhoid fever (enteric fever) is a septicemia,Typhoid fever (enteric fever) is a septicemia,
illness characterized initially by fever,illness characterized initially by fever,
bradycardia, splenomegaly, abdominalbradycardia, splenomegaly, abdominal
symptoms and 'rose spots' which are clusters ofsymptoms and 'rose spots' which are clusters of
pink mauls on the skin.pink mauls on the skin.
Complications such as intestinal hemorrhage orComplications such as intestinal hemorrhage or
perforation can develop in untreated patients orperforation can develop in untreated patients or
when treatment is delayedwhen treatment is delayed..
Pathology and Pathogenesis ofPathology and Pathogenesis of
Enteric feverEnteric fever
Caused byCaused by
S. typhiS. typhi
S.paratyphiS.paratyphi
A B CA B C
The organisms penetrate ileal mucosa reach mesentricThe organisms penetrate ileal mucosa reach mesentric
lymph nodes via Lymphatics , Multiply,lymph nodes via Lymphatics , Multiply,
Invade Blood stream via thoracic ductInvade Blood stream via thoracic duct
In 7 – 10 days through blood stream infectIn 7 – 10 days through blood stream infect
Liver, Gall Bladder,, spleen, Kidney, Bone marrow.Liver, Gall Bladder,, spleen, Kidney, Bone marrow.
After multiplication bacilli pass into blood causingAfter multiplication bacilli pass into blood causing
secondary and heavier bactermiasecondary and heavier bactermia
FeverFever
All the events coincides with Fever and otherAll the events coincides with Fever and other
signs of clinical illnesssigns of clinical illness
From Gall bladder further invasion occurs inFrom Gall bladder further invasion occurs in
intestinesintestines
Involvement of peyr’s patches, gut lymphoidInvolvement of peyr’s patches, gut lymphoid
tissuetissue
Lead to inflammatory reaction, and infiltrationLead to inflammatory reaction, and infiltration
with monocular cellswith monocular cells
Leads to Necrosis, Sloughing and formation ofLeads to Necrosis, Sloughing and formation of
chacterstic typhoid ulcerschacterstic typhoid ulcers
Clinical presentationClinical presentation
Ingestion to onset of fever varies from 3 –Ingestion to onset of fever varies from 3 –
50 days. ( 2 weeks )50 days. ( 2 weeks )
Insidious start, early symptoms are vagueInsidious start, early symptoms are vague
Dull continuous head acheDull continuous head ache
Abdominal tenderness discomfort mayAbdominal tenderness discomfort may
present with constipation.present with constipation.
May progress and present with step ladderMay progress and present with step ladder
pattern temperaturepattern temperature
Temperature fall by crisis in 3 – 4Temperature fall by crisis in 3 – 4thth
weekweek
Events in a Typical typhoid FeverEvents in a Typical typhoid Fever
Other manifestationsOther manifestations
Relative bradycardiaRelative bradycardia
HepatomegalyHepatomegaly
SplenomegalySplenomegaly
Rashes in TyphoidRashes in Typhoid
May present withMay present with
rash, rose spots 2 -4rash, rose spots 2 -4
mm in diametermm in diameter
raised discreteraised discrete
irregular blanchingirregular blanching
pink maculae's foundpink maculae's found
in front of chestin front of chest
Appear in crops ofAppear in crops of
upto a dozen at aupto a dozen at a
timetime
Fade after 3 – 4 daysFade after 3 – 4 days
Complication in TyphoidComplication in Typhoid
Severe intestinal hemorrhage andSevere intestinal hemorrhage and
intestinal perforationintestinal perforation
If not diagnosed can lead to fatalIf not diagnosed can lead to fatal
complications.complications.
RelapseRelapse
Apparent recovery can be followed byApparent recovery can be followed by
relapse in 5 – 10 % of untreated patientsrelapse in 5 – 10 % of untreated patients
On few occasions relapses can be severeOn few occasions relapses can be severe
and may be fatal.and may be fatal.
Immune Response in TyphoidImmune Response in Typhoid
Morbidity and MortalityMorbidity and Mortality
In untreated patients mortality can be upIn untreated patients mortality can be up
to 20 %to 20 %
Occasionally present with diarrhea mayOccasionally present with diarrhea may
mimic other infections, which ismimic other infections, which is
particularly common in paratyphoid fever.particularly common in paratyphoid fever.
Patient may present as gastro enteritis noPatient may present as gastro enteritis no
different from that caused by otherdifferent from that caused by other
S.enterica serotypes.S.enterica serotypes.
Typhoid carriersTyphoid carriers
Salmonella entericaSalmonella enterica causes approximatelycauses approximately
16 million cases of typhoid fever16 million cases of typhoid fever
worldwide, killing around 500,000 perworldwide, killing around 500,000 per
year. One in thirty of the survivors,year. One in thirty of the survivors,
however, become carriers. In carriers thehowever, become carriers. In carriers the
bacteria remain hidden inside cells andbacteria remain hidden inside cells and
the gall bladder, causing new infections asthe gall bladder, causing new infections as
they are shed from an apparently healthythey are shed from an apparently healthy
host.host.
Academic progress on carrierAcademic progress on carrier
state in Typhoidstate in Typhoid
The factors that enable the bacteria to establishThe factors that enable the bacteria to establish
chronic infection were unclear. However, in achronic infection were unclear. However, in a
paper published this week in the Proceedings ofpaper published this week in the Proceedings of
the National Academy of Science, researchersthe National Academy of Science, researchers
at the Institute of Food Research in Norwich andat the Institute of Food Research in Norwich and
the Karolinska Institute in Sweden found that thethe Karolinska Institute in Sweden found that the
change of a single base pair in onechange of a single base pair in one SalmonellaSalmonella
gene can determine if the bacteria cause short-gene can determine if the bacteria cause short-
term illness or a long-term carrier state.term illness or a long-term carrier state.
Diagnosis of Enteric FeverDiagnosis of Enteric Fever
Blood cultures in Typhoid feverBlood cultures in Typhoid fever
In Adults 5- 10 ml of Blood is collected byIn Adults 5- 10 ml of Blood is collected by
venepuncture inoculated into 50 – 100 mlvenepuncture inoculated into 50 – 100 ml
of Bile broth ( 0.5 % )of Bile broth ( 0.5 % )
Several other media are available used asSeveral other media are available used as
per the availability of medium to suit theirper the availability of medium to suit their
laboratory conditions.laboratory conditions.
Blood Cultures in TyphoidBlood Cultures in Typhoid
FeversFevers
Bacteremia occursBacteremia occurs
early in the diseaseearly in the disease
Blood Cultures areBlood Cultures are
positive inpositive in
11stst
week in 90%week in 90%
22ndnd
week in 75%week in 75%
33rdrd
week in 60%week in 60%
44thth
week and later inweek and later in
25%25%
Identification of SalmonellaIdentification of Salmonella
Sub cultures are done after overnightSub cultures are done after overnight
incubation at 37incubation at 3700
c,and subcultures arec,and subcultures are
done on Mac Conkey's agardone on Mac Conkey's agar
Subcultures are repeated upto 10 daysSubcultures are repeated upto 10 days
after futher incubation.after futher incubation.
Salmonella on Mac Conkey's agarSalmonella on Mac Conkey's agar
Salmonella on XLD agarSalmonella on XLD agar
Identifying Enteric OrganismsIdentifying Enteric Organisms
Isolates which are Non lactose fermentingIsolates which are Non lactose fermenting
Motile, Indole positiveMotile, Indole positive
Urease negativeUrease negative
Ferment Glucose,Mannitol,MaltoseFerment Glucose,Mannitol,Maltose
Donot ferment Lactose, SucroseDonot ferment Lactose, Sucrose
Typhoid bacilli are anaerogenicTyphoid bacilli are anaerogenic
Some of the Paratyphoid form acid and gasSome of the Paratyphoid form acid and gas
Further identification done by slide agglutinationFurther identification done by slide agglutination
teststests
Slide agglutination testsSlide agglutination tests
In slide agglutinationIn slide agglutination
tests a known serumtests a known serum
and unknown cultureand unknown culture
isolate is mixed,isolate is mixed,
clumping occursclumping occurs
within few minuteswithin few minutes
Commercial sera areCommercial sera are
available for detectionavailable for detection
of A, B,Cof A, B,C1,1,CC2,2,D, and E.D, and E.
Clot cultureClot culture
Clot cultures are more productive inClot cultures are more productive in
yielding better results in isolation.yielding better results in isolation.
A blood after clotting, the clot is lysed withA blood after clotting, the clot is lysed with
Streptokinase ,but expensive to perform inStreptokinase ,but expensive to perform in
developing countries.developing countries.
Bactek and Radiometric basedBactek and Radiometric based
methods are in recent usemethods are in recent use
Bactek methods inBactek methods in
isolation ofisolation of
Salmonella is a rapidSalmonella is a rapid
and sensitive methodand sensitive method
in early diagnosis ofin early diagnosis of
Enteric fever.Enteric fever.
Many MicrobiologyMany Microbiology
DiagnosticDiagnostic
Laboratories areLaboratories are
upgrading to Bactekupgrading to Bactek
methodsmethods
Other methods in Isolation ofOther methods in Isolation of
Enteric PathogensEnteric Pathogens
Feces CultureFeces Culture
Urine CultureUrine Culture
Bone marrow cultures ( Highly Sensitive )Bone marrow cultures ( Highly Sensitive )
Emerging Methods in Diagnosis ofEmerging Methods in Diagnosis of
Enteric fevers.Enteric fevers.
Detection of circulatingDetection of circulating
antigen byantigen by Co -Co -
agglutinationagglutination methodsmethods
with use of Cowan’swith use of Cowan’s
strain Staphylococcusstrain Staphylococcus
coated with antibodiescoated with antibodies
PCR.PCR. The advent of PCR
technology has provided
unparalleled sensitivity
and specificity for the
diagnosis of typhoid
Diagnosis of CarriersDiagnosis of Carriers
Useful in public health purpose.Useful in public health purpose.
Useful in screening food handlers, cooks,Useful in screening food handlers, cooks,
to detect carrier stateto detect carrier state
Typhoid bacilli can be isolated from fecesTyphoid bacilli can be isolated from feces
or from bile aspiratesor from bile aspirates
Detection of Vi agglutinins in the BloodDetection of Vi agglutinins in the Blood
can be determinant of carrier state.can be determinant of carrier state.
Widal TestWidal Test
In 1896 Widal A professor ofIn 1896 Widal A professor of
pathology and internalpathology and internal
medicine at the University ofmedicine at the University of
Paris (1911–29), heParis (1911–29), he
developed a procedure fordeveloped a procedure for
diagnosing typhoid feverdiagnosing typhoid fever
based on the fact thatbased on the fact that
antibodiesantibodies in the blood of anin the blood of an
infected individual cause theinfected individual cause the
bacteria to bind together intobacteria to bind together into
clumps (the Widal reaction).clumps (the Widal reaction).
Diagnosis of Enteric FeverDiagnosis of Enteric Fever
Widal testWidal test
Serum agglutinins raise abruptly during the 2Serum agglutinins raise abruptly during the 2ndnd
or 3or 3rdrd
weekweek
The widal test detects antibodies against O and HThe widal test detects antibodies against O and H
antigensantigens
Two serum specimens obtained at intervals of 7 – 10Two serum specimens obtained at intervals of 7 – 10
days to read the raise of antibodiesdays to read the raise of antibodies..
Serial dilutions on unknown sera are tested against theSerial dilutions on unknown sera are tested against the
antigens for respective Salmonellaantigens for respective Salmonella
False positives and False negative limits the utility of theFalse positives and False negative limits the utility of the
testtest
The interpretative criteria when single serum specimensThe interpretative criteria when single serum specimens
are tested varyare tested vary
Cross reactions limits the specificityCross reactions limits the specificity
Significant Titers helps inSignificant Titers helps in
DiagnosisDiagnosis
Following Titers ofFollowing Titers of
antibodies against theantibodies against the
antigens are significantantigens are significant
when single sample iswhen single sample is
testedtested
O > 1 in 160O > 1 in 160
H > 1 in 320H > 1 in 320
Testing a paired sampleTesting a paired sample
for raise of antibodiesfor raise of antibodies
carries a greatercarries a greater
significancesignificance
Widal test – Still a popular testWidal test – Still a popular test
The Widal test (Widal’s agglutination reaction) isThe Widal test (Widal’s agglutination reaction) is
routinely practised for the serodiagnosis of typhoidroutinely practised for the serodiagnosis of typhoid
fever by most of the laboratories. Several workersfever by most of the laboratories. Several workers
have expressed doubt regarding the reliability of thehave expressed doubt regarding the reliability of the
test. Several factors have contributed to thistest. Several factors have contributed to this
uncertainty. These include poorly standardiseduncertainty. These include poorly standardised
antigens, the sharing of antigenic determinants withantigens, the sharing of antigenic determinants with
other Salmonellae and the effects of immunisationother Salmonellae and the effects of immunisation
with TAB vaccine. Another major problem relates towith TAB vaccine. Another major problem relates to
the difficulty of interpreting Widal test results inthe difficulty of interpreting Widal test results in
areas where Salmonella typhi is endemic and whereareas where Salmonella typhi is endemic and where
the antibody titres of the normal population are oftenthe antibody titres of the normal population are often
not known.not known.
Limitations of Widal testLimitations of Widal test
Classically, a four-fold rise of antibody inClassically, a four-fold rise of antibody in
paired sera Widal test is consideredpaired sera Widal test is considered
diagnostic of typhoid fever. However, paireddiagnostic of typhoid fever. However, paired
sera are often difficult to obtain and specificsera are often difficult to obtain and specific
chemotherapy has to be instituted on thechemotherapy has to be instituted on the
basis of a single Widal test. Furthermore, inbasis of a single Widal test. Furthermore, in
areas where fever due to infectious causes isareas where fever due to infectious causes is
a common occurrence the possibility existsa common occurrence the possibility exists
that false positive reactions may occur as athat false positive reactions may occur as a
result of non-typhoidresult of non-typhoid
Antimicrobial Therapy inAntimicrobial Therapy in
TyphoidTyphoid
With prompt antibiotic therapy, more than 99%With prompt antibiotic therapy, more than 99%
of the people with typhoid fever are cured,of the people with typhoid fever are cured,
although convalescence may last severalalthough convalescence may last several
months. The antibioticmonths. The antibiotic chloramphenicolchloramphenicolSomeSome
Trade NamesTrade Names
CHLOROMYCETINCHLOROMYCETIN
is used worldwide, but increasing resistance to itis used worldwide, but increasing resistance to it
has prompted the use of other antibiotics (suchhas prompted the use of other antibiotics (such
asas trimethoprim-sulfamethoxazoletrimethoprim-sulfamethoxazole
BACTRIMBACTRIM
SEPTRASEPTRA
oror ciprofloxacinciprofloxacin
Drug resitance an EmergingDrug resitance an Emerging
concernconcern
Previously Choramphenicol was the drug ofPreviously Choramphenicol was the drug of
choice for the treatment of typhoid fever.choice for the treatment of typhoid fever.
However, with the development more safer andHowever, with the development more safer and
more effective drugs the use of Choramphenicolmore effective drugs the use of Choramphenicol
has declined these days.has declined these days. 3rd generation3rd generation
cephalosporins, like Ceftriaxone, andcephalosporins, like Ceftriaxone, and
Flouroquinolones, like ciprofloxacin andFlouroquinolones, like ciprofloxacin and
levofloxacin are the drugs of choice for treatmentlevofloxacin are the drugs of choice for treatment
of typhoid fever .of typhoid fever .Once again many strains areOnce again many strains are
sensitive to Choramphenicolsensitive to Choramphenicol
Vaccines for Typhoid PreventionVaccines for Typhoid Prevention
Two types of vaccines are availableTwo types of vaccines are available
Oral and Inject ableOral and Inject able
Oral – A live oral vaccine ( typhoral ) is a stableOral – A live oral vaccine ( typhoral ) is a stable
mutant of S.typhi strain Ty 21a lacking themutant of S.typhi strain Ty 21a lacking the
enzyme UDP Galactose -4-epimerase.enzyme UDP Galactose -4-epimerase.
One capsule given orally taken before food, withOne capsule given orally taken before food, with
glass of water or milk, on 1, 3, 5 days ( threeglass of water or milk, on 1, 3, 5 days ( three
doses )doses )
No antibiotics should be taken during the periodNo antibiotics should be taken during the period
of administration of vaccineof administration of vaccine
Vaccine - injectableVaccine - injectable
The inject able vaccine, ( typhim –vi)The inject able vaccine, ( typhim –vi)
contains purified Vi polysaccharidecontains purified Vi polysaccharide
antigen derived from S.typhi strain ty21antigen derived from S.typhi strain ty21
Given as single subcutaneous orGiven as single subcutaneous or
intramuscular injectionintramuscular injection
Single dose is adequate.Single dose is adequate.
Vaccines for TyphoidVaccines for Typhoid
Both vaccines are given to only > 5 years ofBoth vaccines are given to only > 5 years of
age.age.
Immunity lasts for 3 yearsImmunity lasts for 3 years
Need a boosterNeed a booster
Vaccines are not effective inVaccines are not effective in
prevention of Paratyphoid feversprevention of Paratyphoid fevers
Simple hand hygiene andSimple hand hygiene and
washing can reduce severalwashing can reduce several
cases of Typhoidcases of Typhoid
Created for Health andCreated for Health and
Educational awareness onEducational awareness on
Typhoid FeverTyphoid Fever
Dr.T.V.Rao MDDr.T.V.Rao MD
EmailEmail
doctortvrao@gmail.comdoctortvrao@gmail.com

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Typhoid fever microbiology

  • 1. Typhoid FeverTyphoid Fever (( Enteric FeversEnteric Fevers )) an updatean update Dr.T.V.Rao MDDr.T.V.Rao MD
  • 2. Typhoid fevers are prevalent inTyphoid fevers are prevalent in many regions in the Worldmany regions in the World
  • 3. Enteric FeversEnteric Fevers The syndrome associated with entericThe syndrome associated with enteric fevers are produced only by a few of thefevers are produced only by a few of the SalmonellaSalmonella Salmonella typhi most importantSalmonella typhi most important Salmonella paratyphi A, B,CSalmonella paratyphi A, B,C
  • 4. Historical landmarks in TyphoidHistorical landmarks in Typhoid In 1880s, the typhoid bacillus was first observedIn 1880s, the typhoid bacillus was first observed by Eberth in spleen sections and mesentericby Eberth in spleen sections and mesenteric lymph nodes from a patient who died fromlymph nodes from a patient who died from typhoid. Robert Koch confirmed a related findingtyphoid. Robert Koch confirmed a related finding by Gaffky and succeeded in cultivating theby Gaffky and succeeded in cultivating the bacterium in 1881. But due to the lack ofbacterium in 1881. But due to the lack of differential characters, separation of the typhoiddifferential characters, separation of the typhoid bacillus from other enteric bacteria wasbacillus from other enteric bacteria was uncertain.uncertain. ..
  • 5. History of Sero DiagnosisHistory of Sero Diagnosis In 1896, it was demonstrated that theIn 1896, it was demonstrated that the serum from an animal immunized with theserum from an animal immunized with the typhoid bacillus agglutinated (clumped)typhoid bacillus agglutinated (clumped) the typhoid bacterial cells, and it wasthe typhoid bacterial cells, and it was shown that the serum of patients afflictedshown that the serum of patients afflicted with typhoid likewise agglutinated thewith typhoid likewise agglutinated the typhoid bacillus. Serodiagnosis of typhoidtyphoid bacillus. Serodiagnosis of typhoid was thus made possible by 1896.was thus made possible by 1896.
  • 6. Typhoid MaryTyphoid Mary A famous example isA famous example is “Typhoid” Mary“Typhoid” Mary Mallon, who was aMallon, who was a food handlerfood handler responsible forresponsible for infecting at least 78infecting at least 78 people, killing 5.people, killing 5. These highlyThese highly infectious carriersinfectious carriers pose a great risk topose a great risk to public health.public health.
  • 7. Typhoid MaryTyphoid Mary "Typhoid Mary," real name Mary Mallon,"Typhoid Mary," real name Mary Mallon, worked as a cook in New York City in theworked as a cook in New York City in the early 1900s. Public health pioneerearly 1900s. Public health pioneer Sara Josephine Baker, MD, PhDSara Josephine Baker, MD, PhD trackedtracked her down after discovering that she washer down after discovering that she was the common link among many people whothe common link among many people who had become ill from typhoid fever She washad become ill from typhoid fever She was traced to typhoid outbreaks a second timetraced to typhoid outbreaks a second time so she was put in prison again where sheso she was put in prison again where she lived until she died.lived until she died.
  • 8. Etiology of Typhoid feverEtiology of Typhoid fever Typhoid fever is a bacterial disease,Typhoid fever is a bacterial disease, caused bycaused by Salmonella typhiSalmonella typhi.. It isIt is transmitted through the ingestion of foodtransmitted through the ingestion of food or drink contaminated by the faeces oror drink contaminated by the faeces or urine of infected people.urine of infected people. Para typhoid fevers are produced by otherPara typhoid fevers are produced by other species namedspecies named Paratyphi A, B, CParatyphi A, B, C
  • 9. Changing taxonomy ofChanging taxonomy of Salmonella speciesSalmonella species SalmonellaSalmonella areare Gram-negativeGram-negative bacteriabacteria which cause intestinal infections. Thewhich cause intestinal infections. The taxonomy oftaxonomy of SalmonellaSalmonella species isspecies is complicated. Formally, there are only twocomplicated. Formally, there are only two species within this genus:species within this genus: S. bongoriS. bongori andand S. entericaS. enterica (formerly called(formerly called S.S. choleraesuischoleraesuis), which are divided into six), which are divided into six subspecies:subspecies:
  • 10. Different types of SalmonellaDifferent types of Salmonella I -I - entericaenterica II -II - salamaesalamae IIIa -IIIa -arizonaearizonae IIIb -IIIb -diarizonaediarizonae IV -IV - houtenaehoutenae V -V - bongoribongori VI -VI - indicaindica
  • 11. Bacteriology –Typhoid feverBacteriology –Typhoid fever The GenusThe Genus Salmonella belong toSalmonella belong to EnterobactericiaeEnterobactericiae Facultative anaerobeFacultative anaerobe Gram negative bacilliGram negative bacilli Distinguished fromDistinguished from other bacteria byother bacteria by Biochemical andBiochemical and antigen structureantigen structure
  • 12. Antigenic structure ofAntigenic structure of SalmonellaSalmonella Two sets of antigensTwo sets of antigens Detection by serotypingDetection by serotyping 11 Somatic or 0 AntigensSomatic or 0 Antigens contain long chaincontain long chain polysaccharides ( LPS ) comprises of heat stablepolysaccharides ( LPS ) comprises of heat stable polysaccharide commonly.polysaccharide commonly. 2 Flagellar or H Antigens2 Flagellar or H Antigens are strongly immunogenicare strongly immunogenic and induces antibody formation rapidly and in high titersand induces antibody formation rapidly and in high titers following infection or immunization. The flagellar antigenfollowing infection or immunization. The flagellar antigen is of a dual nature, occurring in one of the two phases.is of a dual nature, occurring in one of the two phases.
  • 13. Paratyphoid fevers on riseParatyphoid fevers on rise Paratyphoid fever can be caused by anyParatyphoid fever can be caused by any of three serotypes of S. paratyphi A, B andof three serotypes of S. paratyphi A, B and C. It is similar in its symptoms to typhoidC. It is similar in its symptoms to typhoid fever, but tends to be milder, with a lowerfever, but tends to be milder, with a lower fatality rate.fatality rate.
  • 14. How a Typhoid fever spreadsHow a Typhoid fever spreads SalmonellaSalmonella Typhi lives only in humans.Typhi lives only in humans. Persons with typhoid fever carry thePersons with typhoid fever carry the bacteria in their bloodstream and intestinalbacteria in their bloodstream and intestinal tract. In addition, a small number oftract. In addition, a small number of persons, called carriers , recover frompersons, called carriers , recover from typhoid fever but continue to carry thetyphoid fever but continue to carry the bacteria. Both ill persons and carriersbacteria. Both ill persons and carriers shedshed S.S. Typhi in their feces (stool).Typhi in their feces (stool).
  • 15. Clinical featuresClinical features Typhoid fever (enteric fever) is a septicemia,Typhoid fever (enteric fever) is a septicemia, illness characterized initially by fever,illness characterized initially by fever, bradycardia, splenomegaly, abdominalbradycardia, splenomegaly, abdominal symptoms and 'rose spots' which are clusters ofsymptoms and 'rose spots' which are clusters of pink mauls on the skin.pink mauls on the skin. Complications such as intestinal hemorrhage orComplications such as intestinal hemorrhage or perforation can develop in untreated patients orperforation can develop in untreated patients or when treatment is delayedwhen treatment is delayed..
  • 16. Pathology and Pathogenesis ofPathology and Pathogenesis of Enteric feverEnteric fever Caused byCaused by S. typhiS. typhi S.paratyphiS.paratyphi A B CA B C The organisms penetrate ileal mucosa reach mesentricThe organisms penetrate ileal mucosa reach mesentric lymph nodes via Lymphatics , Multiply,lymph nodes via Lymphatics , Multiply, Invade Blood stream via thoracic ductInvade Blood stream via thoracic duct In 7 – 10 days through blood stream infectIn 7 – 10 days through blood stream infect Liver, Gall Bladder,, spleen, Kidney, Bone marrow.Liver, Gall Bladder,, spleen, Kidney, Bone marrow. After multiplication bacilli pass into blood causingAfter multiplication bacilli pass into blood causing secondary and heavier bactermiasecondary and heavier bactermia
  • 17. FeverFever All the events coincides with Fever and otherAll the events coincides with Fever and other signs of clinical illnesssigns of clinical illness From Gall bladder further invasion occurs inFrom Gall bladder further invasion occurs in intestinesintestines Involvement of peyr’s patches, gut lymphoidInvolvement of peyr’s patches, gut lymphoid tissuetissue Lead to inflammatory reaction, and infiltrationLead to inflammatory reaction, and infiltration with monocular cellswith monocular cells Leads to Necrosis, Sloughing and formation ofLeads to Necrosis, Sloughing and formation of chacterstic typhoid ulcerschacterstic typhoid ulcers
  • 18. Clinical presentationClinical presentation Ingestion to onset of fever varies from 3 –Ingestion to onset of fever varies from 3 – 50 days. ( 2 weeks )50 days. ( 2 weeks ) Insidious start, early symptoms are vagueInsidious start, early symptoms are vague Dull continuous head acheDull continuous head ache Abdominal tenderness discomfort mayAbdominal tenderness discomfort may present with constipation.present with constipation. May progress and present with step ladderMay progress and present with step ladder pattern temperaturepattern temperature Temperature fall by crisis in 3 – 4Temperature fall by crisis in 3 – 4thth weekweek
  • 19. Events in a Typical typhoid FeverEvents in a Typical typhoid Fever
  • 20. Other manifestationsOther manifestations Relative bradycardiaRelative bradycardia HepatomegalyHepatomegaly SplenomegalySplenomegaly
  • 21. Rashes in TyphoidRashes in Typhoid May present withMay present with rash, rose spots 2 -4rash, rose spots 2 -4 mm in diametermm in diameter raised discreteraised discrete irregular blanchingirregular blanching pink maculae's foundpink maculae's found in front of chestin front of chest Appear in crops ofAppear in crops of upto a dozen at aupto a dozen at a timetime Fade after 3 – 4 daysFade after 3 – 4 days
  • 22. Complication in TyphoidComplication in Typhoid Severe intestinal hemorrhage andSevere intestinal hemorrhage and intestinal perforationintestinal perforation If not diagnosed can lead to fatalIf not diagnosed can lead to fatal complications.complications.
  • 23. RelapseRelapse Apparent recovery can be followed byApparent recovery can be followed by relapse in 5 – 10 % of untreated patientsrelapse in 5 – 10 % of untreated patients On few occasions relapses can be severeOn few occasions relapses can be severe and may be fatal.and may be fatal.
  • 24. Immune Response in TyphoidImmune Response in Typhoid
  • 25. Morbidity and MortalityMorbidity and Mortality In untreated patients mortality can be upIn untreated patients mortality can be up to 20 %to 20 % Occasionally present with diarrhea mayOccasionally present with diarrhea may mimic other infections, which ismimic other infections, which is particularly common in paratyphoid fever.particularly common in paratyphoid fever. Patient may present as gastro enteritis noPatient may present as gastro enteritis no different from that caused by otherdifferent from that caused by other S.enterica serotypes.S.enterica serotypes.
  • 26. Typhoid carriersTyphoid carriers Salmonella entericaSalmonella enterica causes approximatelycauses approximately 16 million cases of typhoid fever16 million cases of typhoid fever worldwide, killing around 500,000 perworldwide, killing around 500,000 per year. One in thirty of the survivors,year. One in thirty of the survivors, however, become carriers. In carriers thehowever, become carriers. In carriers the bacteria remain hidden inside cells andbacteria remain hidden inside cells and the gall bladder, causing new infections asthe gall bladder, causing new infections as they are shed from an apparently healthythey are shed from an apparently healthy host.host.
  • 27. Academic progress on carrierAcademic progress on carrier state in Typhoidstate in Typhoid The factors that enable the bacteria to establishThe factors that enable the bacteria to establish chronic infection were unclear. However, in achronic infection were unclear. However, in a paper published this week in the Proceedings ofpaper published this week in the Proceedings of the National Academy of Science, researchersthe National Academy of Science, researchers at the Institute of Food Research in Norwich andat the Institute of Food Research in Norwich and the Karolinska Institute in Sweden found that thethe Karolinska Institute in Sweden found that the change of a single base pair in onechange of a single base pair in one SalmonellaSalmonella gene can determine if the bacteria cause short-gene can determine if the bacteria cause short- term illness or a long-term carrier state.term illness or a long-term carrier state.
  • 28. Diagnosis of Enteric FeverDiagnosis of Enteric Fever
  • 29. Blood cultures in Typhoid feverBlood cultures in Typhoid fever In Adults 5- 10 ml of Blood is collected byIn Adults 5- 10 ml of Blood is collected by venepuncture inoculated into 50 – 100 mlvenepuncture inoculated into 50 – 100 ml of Bile broth ( 0.5 % )of Bile broth ( 0.5 % ) Several other media are available used asSeveral other media are available used as per the availability of medium to suit theirper the availability of medium to suit their laboratory conditions.laboratory conditions.
  • 30. Blood Cultures in TyphoidBlood Cultures in Typhoid FeversFevers Bacteremia occursBacteremia occurs early in the diseaseearly in the disease Blood Cultures areBlood Cultures are positive inpositive in 11stst week in 90%week in 90% 22ndnd week in 75%week in 75% 33rdrd week in 60%week in 60% 44thth week and later inweek and later in 25%25%
  • 31. Identification of SalmonellaIdentification of Salmonella Sub cultures are done after overnightSub cultures are done after overnight incubation at 37incubation at 3700 c,and subcultures arec,and subcultures are done on Mac Conkey's agardone on Mac Conkey's agar Subcultures are repeated upto 10 daysSubcultures are repeated upto 10 days after futher incubation.after futher incubation.
  • 32. Salmonella on Mac Conkey's agarSalmonella on Mac Conkey's agar
  • 33. Salmonella on XLD agarSalmonella on XLD agar
  • 34. Identifying Enteric OrganismsIdentifying Enteric Organisms Isolates which are Non lactose fermentingIsolates which are Non lactose fermenting Motile, Indole positiveMotile, Indole positive Urease negativeUrease negative Ferment Glucose,Mannitol,MaltoseFerment Glucose,Mannitol,Maltose Donot ferment Lactose, SucroseDonot ferment Lactose, Sucrose Typhoid bacilli are anaerogenicTyphoid bacilli are anaerogenic Some of the Paratyphoid form acid and gasSome of the Paratyphoid form acid and gas Further identification done by slide agglutinationFurther identification done by slide agglutination teststests
  • 35. Slide agglutination testsSlide agglutination tests In slide agglutinationIn slide agglutination tests a known serumtests a known serum and unknown cultureand unknown culture isolate is mixed,isolate is mixed, clumping occursclumping occurs within few minuteswithin few minutes Commercial sera areCommercial sera are available for detectionavailable for detection of A, B,Cof A, B,C1,1,CC2,2,D, and E.D, and E.
  • 36. Clot cultureClot culture Clot cultures are more productive inClot cultures are more productive in yielding better results in isolation.yielding better results in isolation. A blood after clotting, the clot is lysed withA blood after clotting, the clot is lysed with Streptokinase ,but expensive to perform inStreptokinase ,but expensive to perform in developing countries.developing countries.
  • 37. Bactek and Radiometric basedBactek and Radiometric based methods are in recent usemethods are in recent use Bactek methods inBactek methods in isolation ofisolation of Salmonella is a rapidSalmonella is a rapid and sensitive methodand sensitive method in early diagnosis ofin early diagnosis of Enteric fever.Enteric fever. Many MicrobiologyMany Microbiology DiagnosticDiagnostic Laboratories areLaboratories are upgrading to Bactekupgrading to Bactek methodsmethods
  • 38. Other methods in Isolation ofOther methods in Isolation of Enteric PathogensEnteric Pathogens Feces CultureFeces Culture Urine CultureUrine Culture Bone marrow cultures ( Highly Sensitive )Bone marrow cultures ( Highly Sensitive )
  • 39. Emerging Methods in Diagnosis ofEmerging Methods in Diagnosis of Enteric fevers.Enteric fevers. Detection of circulatingDetection of circulating antigen byantigen by Co -Co - agglutinationagglutination methodsmethods with use of Cowan’swith use of Cowan’s strain Staphylococcusstrain Staphylococcus coated with antibodiescoated with antibodies PCR.PCR. The advent of PCR technology has provided unparalleled sensitivity and specificity for the diagnosis of typhoid
  • 40. Diagnosis of CarriersDiagnosis of Carriers Useful in public health purpose.Useful in public health purpose. Useful in screening food handlers, cooks,Useful in screening food handlers, cooks, to detect carrier stateto detect carrier state Typhoid bacilli can be isolated from fecesTyphoid bacilli can be isolated from feces or from bile aspiratesor from bile aspirates Detection of Vi agglutinins in the BloodDetection of Vi agglutinins in the Blood can be determinant of carrier state.can be determinant of carrier state.
  • 41. Widal TestWidal Test In 1896 Widal A professor ofIn 1896 Widal A professor of pathology and internalpathology and internal medicine at the University ofmedicine at the University of Paris (1911–29), heParis (1911–29), he developed a procedure fordeveloped a procedure for diagnosing typhoid feverdiagnosing typhoid fever based on the fact thatbased on the fact that antibodiesantibodies in the blood of anin the blood of an infected individual cause theinfected individual cause the bacteria to bind together intobacteria to bind together into clumps (the Widal reaction).clumps (the Widal reaction).
  • 42. Diagnosis of Enteric FeverDiagnosis of Enteric Fever Widal testWidal test Serum agglutinins raise abruptly during the 2Serum agglutinins raise abruptly during the 2ndnd or 3or 3rdrd weekweek The widal test detects antibodies against O and HThe widal test detects antibodies against O and H antigensantigens Two serum specimens obtained at intervals of 7 – 10Two serum specimens obtained at intervals of 7 – 10 days to read the raise of antibodiesdays to read the raise of antibodies.. Serial dilutions on unknown sera are tested against theSerial dilutions on unknown sera are tested against the antigens for respective Salmonellaantigens for respective Salmonella False positives and False negative limits the utility of theFalse positives and False negative limits the utility of the testtest The interpretative criteria when single serum specimensThe interpretative criteria when single serum specimens are tested varyare tested vary Cross reactions limits the specificityCross reactions limits the specificity
  • 43. Significant Titers helps inSignificant Titers helps in DiagnosisDiagnosis Following Titers ofFollowing Titers of antibodies against theantibodies against the antigens are significantantigens are significant when single sample iswhen single sample is testedtested O > 1 in 160O > 1 in 160 H > 1 in 320H > 1 in 320 Testing a paired sampleTesting a paired sample for raise of antibodiesfor raise of antibodies carries a greatercarries a greater significancesignificance
  • 44. Widal test – Still a popular testWidal test – Still a popular test The Widal test (Widal’s agglutination reaction) isThe Widal test (Widal’s agglutination reaction) is routinely practised for the serodiagnosis of typhoidroutinely practised for the serodiagnosis of typhoid fever by most of the laboratories. Several workersfever by most of the laboratories. Several workers have expressed doubt regarding the reliability of thehave expressed doubt regarding the reliability of the test. Several factors have contributed to thistest. Several factors have contributed to this uncertainty. These include poorly standardiseduncertainty. These include poorly standardised antigens, the sharing of antigenic determinants withantigens, the sharing of antigenic determinants with other Salmonellae and the effects of immunisationother Salmonellae and the effects of immunisation with TAB vaccine. Another major problem relates towith TAB vaccine. Another major problem relates to the difficulty of interpreting Widal test results inthe difficulty of interpreting Widal test results in areas where Salmonella typhi is endemic and whereareas where Salmonella typhi is endemic and where the antibody titres of the normal population are oftenthe antibody titres of the normal population are often not known.not known.
  • 45. Limitations of Widal testLimitations of Widal test Classically, a four-fold rise of antibody inClassically, a four-fold rise of antibody in paired sera Widal test is consideredpaired sera Widal test is considered diagnostic of typhoid fever. However, paireddiagnostic of typhoid fever. However, paired sera are often difficult to obtain and specificsera are often difficult to obtain and specific chemotherapy has to be instituted on thechemotherapy has to be instituted on the basis of a single Widal test. Furthermore, inbasis of a single Widal test. Furthermore, in areas where fever due to infectious causes isareas where fever due to infectious causes is a common occurrence the possibility existsa common occurrence the possibility exists that false positive reactions may occur as athat false positive reactions may occur as a result of non-typhoidresult of non-typhoid
  • 46. Antimicrobial Therapy inAntimicrobial Therapy in TyphoidTyphoid With prompt antibiotic therapy, more than 99%With prompt antibiotic therapy, more than 99% of the people with typhoid fever are cured,of the people with typhoid fever are cured, although convalescence may last severalalthough convalescence may last several months. The antibioticmonths. The antibiotic chloramphenicolchloramphenicolSomeSome Trade NamesTrade Names CHLOROMYCETINCHLOROMYCETIN is used worldwide, but increasing resistance to itis used worldwide, but increasing resistance to it has prompted the use of other antibiotics (suchhas prompted the use of other antibiotics (such asas trimethoprim-sulfamethoxazoletrimethoprim-sulfamethoxazole BACTRIMBACTRIM SEPTRASEPTRA oror ciprofloxacinciprofloxacin
  • 47. Drug resitance an EmergingDrug resitance an Emerging concernconcern Previously Choramphenicol was the drug ofPreviously Choramphenicol was the drug of choice for the treatment of typhoid fever.choice for the treatment of typhoid fever. However, with the development more safer andHowever, with the development more safer and more effective drugs the use of Choramphenicolmore effective drugs the use of Choramphenicol has declined these days.has declined these days. 3rd generation3rd generation cephalosporins, like Ceftriaxone, andcephalosporins, like Ceftriaxone, and Flouroquinolones, like ciprofloxacin andFlouroquinolones, like ciprofloxacin and levofloxacin are the drugs of choice for treatmentlevofloxacin are the drugs of choice for treatment of typhoid fever .of typhoid fever .Once again many strains areOnce again many strains are sensitive to Choramphenicolsensitive to Choramphenicol
  • 48. Vaccines for Typhoid PreventionVaccines for Typhoid Prevention Two types of vaccines are availableTwo types of vaccines are available Oral and Inject ableOral and Inject able Oral – A live oral vaccine ( typhoral ) is a stableOral – A live oral vaccine ( typhoral ) is a stable mutant of S.typhi strain Ty 21a lacking themutant of S.typhi strain Ty 21a lacking the enzyme UDP Galactose -4-epimerase.enzyme UDP Galactose -4-epimerase. One capsule given orally taken before food, withOne capsule given orally taken before food, with glass of water or milk, on 1, 3, 5 days ( threeglass of water or milk, on 1, 3, 5 days ( three doses )doses ) No antibiotics should be taken during the periodNo antibiotics should be taken during the period of administration of vaccineof administration of vaccine
  • 49. Vaccine - injectableVaccine - injectable The inject able vaccine, ( typhim –vi)The inject able vaccine, ( typhim –vi) contains purified Vi polysaccharidecontains purified Vi polysaccharide antigen derived from S.typhi strain ty21antigen derived from S.typhi strain ty21 Given as single subcutaneous orGiven as single subcutaneous or intramuscular injectionintramuscular injection Single dose is adequate.Single dose is adequate.
  • 50. Vaccines for TyphoidVaccines for Typhoid Both vaccines are given to only > 5 years ofBoth vaccines are given to only > 5 years of age.age. Immunity lasts for 3 yearsImmunity lasts for 3 years Need a boosterNeed a booster Vaccines are not effective inVaccines are not effective in prevention of Paratyphoid feversprevention of Paratyphoid fevers
  • 51. Simple hand hygiene andSimple hand hygiene and washing can reduce severalwashing can reduce several cases of Typhoidcases of Typhoid
  • 52. Created for Health andCreated for Health and Educational awareness onEducational awareness on Typhoid FeverTyphoid Fever Dr.T.V.Rao MDDr.T.V.Rao MD EmailEmail doctortvrao@gmail.comdoctortvrao@gmail.com