Typhoid Fever

( Enteric Fevers )
an update
Dr.T.V.Rao MD
Typhoid fevers are prevalent in many
regions in the World
Enteric Fevers

 The syndrome associated with enteric

fevers are produced only by a few of the
Salmonella
 Salmonella typhi most important
 Salmonella paratyphi A, B,C
Historical landmarks in Typhoid
 In 1880s, the typhoid bacillus was first observed
by Eberth in spleen sections and mesenteric
lymph nodes from a patient who died from
typhoid. Robert Koch confirmed a related finding
by Gaffky and succeeded in cultivating the
bacterium in 1881. But due to the lack of
differential characters, separation of the typhoid
bacillus from other enteric bacteria was uncertain.
.
History of Sero Diagnosis
 In 1896, it was demonstrated that the
serum from an animal immunized with the
typhoid bacillus agglutinated (clumped) the
typhoid bacterial cells, and it was shown
that the serum of patients afflicted with
typhoid likewise agglutinated the typhoid
bacillus. Serodiagnosis of typhoid was thus
made possible by 1896.
Typhoid Mary
 A famous example is
“Typhoid” Mary Mallon,
who was a food handler
responsible for infecting
at least 78 people, killing
5. These highly infectious
carriers pose a great risk
to public health.
Typhoid Mary
 "Typhoid Mary," real name Mary Mallon,
worked as a cook in New York City in the
early 1900s. Public health pioneer
Sara Josephine Baker, MD, PhD tracked
her down after discovering that she was the
common link among many people who had
become ill from typhoid fever She was
traced to typhoid outbreaks a second time
so she was put in prison again where she
lived until she died.
Etiology of Typhoid fever
 Typhoid fever is a bacterial disease,
caused by Salmonella typhi. It is
transmitted through the ingestion of food or
drink contaminated by the faeces or urine
of infected people.
 Para typhoid fevers are produced by other
species named
Paratyphi A, B, C
Changing taxonomy of Salmonella
species
 Salmonella are Gram-negative bacteria
which cause intestinal infections. The
taxonomy of Salmonella species is
complicated. Formally, there are only two
species within this genus: S. bongori and S.
enterica (formerly called S. choleraesuis),
which are divided into six subspecies:
Different types of Salmonella
I - enterica
II - salamae
IIIa -arizonae
IIIb -diarizonae
IV - houtenae
V - bongori
VI - indica
Bacteriology –Typhoid fever
 The Genus
Salmonella belong to
Enterobactericiae
 Facultative anaerobe
 Gram negative bacilli
 Distinguished from
other bacteria by
Biochemical and
antigen structure
Antigenic structure of Salmonella
 Two sets of antigens
 Detection by serotyping
 1 Somatic or 0 Antigens contain long chain
polysaccharides ( LPS ) comprises of heat stable
polysaccharide commonly.

 2 Flagellar or H Antigens are strongly immunogenic and

induces antibody formation rapidly and in high titers following
infection or immunization. The flagellar antigen is of a dual
nature, occurring in one of the two phases.
Paratyphoid fevers on rise
 Paratyphoid fever can be caused by any of
three serotypes of S. paratyphi A, B and C.
It is similar in its symptoms to typhoid fever,
but tends to be milder, with a lower fatality
rate.
How a Typhoid fever spreads

 Salmonella Typhi lives only in humans.

Persons with typhoid fever carry the
bacteria in their bloodstream and intestinal
tract. In addition, a small number of
persons, called carriers , recover from
typhoid fever but continue to carry the
bacteria. Both ill persons and carriers shed
S. Typhi in their feces (stool).
Clinical features

Typhoid fever (enteric fever) is a septicemia,

illness characterized initially by fever, bradycardia,
splenomegaly, abdominal symptoms and 'rose
spots' which are clusters of pink mauls on the
skin.
Complications such as intestinal hemorrhage or
perforation can develop in untreated patients or
when treatment is delayed.
Pathology and Pathogenesis of
Enteric fever
 Caused by
S. typhi
S.paratyphi
A BC
The organisms penetrate ileal mucosa reach mesentric lymph
nodes via Lymphatics , Multiply,
Invade Blood stream via thoracic duct
In 7 – 10 days through blood stream infect
Liver, Gall Bladder,, spleen, Kidney, Bone marrow.
After multiplication bacilli pass into blood causing secondary
and heavier bactermia
Fever
 All the events coincides with Fever and other
signs of clinical illness
 From Gall bladder further invasion occurs in
intestines
 Involvement of peyr’s patches, gut lymphoid
tissue
 Lead to inflammatory reaction, and infiltration with
monocular cells
 Leads to Necrosis, Sloughing and formation of
chacterstic typhoid ulcers
Clinical presentation
 Ingestion to onset of fever varies from 3 –
50 days. ( 2 weeks )
 Insidious start, 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
Other manifestations
 Relative bradycardia
 Hepatomegaly
 Splenomegaly
Rashes in Typhoid
 May present with rash,
rose spots 2 -4 mm in
diameter raised
discrete irregular
blanching pink
maculae's found in
front of chest
 Appear in crops of
upto a dozen at a time
 Fade after 3 – 4 days
Complication in Typhoid

 Severe intestinal hemorrhage and intestinal

perforation
 If not diagnosed can lead to fatal
complications.
Relapse

 Apparent recovery can be followed by

relapse in 5 – 10 % of untreated patients
 On few occasions relapses can be severe
and may be fatal.
Immune Response in Typhoid
Morbidity and Mortality

 In untreated patients mortality can be up to

20 %
 Occasionally present with diarrhea may
mimic other infections, which is particularly
common in paratyphoid fever.
 Patient may present as gastro enteritis no
different from that caused by other
S.enterica serotypes.
Typhoid carriers
 Salmonella enterica causes approximately
16 million cases of typhoid fever worldwide,
killing around 500,000 per year. One in
thirty of the survivors, however, become
carriers. In carriers the bacteria remain
hidden inside cells and the gall bladder,
causing new infections as they are shed
from an apparently healthy host.
Academic progress on carrier state in
Typhoid
 The factors that enable the bacteria to establish
chronic infection were unclear. However, in a
paper published this week in the Proceedings of
the National Academy of Science, researchers at
the Institute of Food Research in Norwich and the
Karolinska Institute in Sweden found that the
change of a single base pair in one Salmonella
gene can determine if the bacteria cause short-
term illness or a long-term carrier state.
Diagnosis of
Enteric Fever
Blood cultures in Typhoid fever
 In Adults 5- 10 ml of Blood is collected by
venepuncture inoculated into 50 – 100 ml of
Bile broth ( 0.5 % )
 Several other media are available used as
per the availability of medium to suit their
laboratory conditions.
Blood Cultures in Typhoid Fevers
 Bacteremia occurs
early in the disease
 Blood Cultures are
positive in

1st week in 90%

2nd week in 75%
3rd week in 60%
4th week and later in
25%
Identification of Salmonella
 Sub cultures are done after overnight
incubation at 370c,and subcultures are
done on Mac Conkey's agar
 Subcultures are repeated upto 10 days
after futher incubation.
Salmonella on Mac Conkey's agar
Salmonella on XLD agar
Identifying Enteric Organisms
 Isolates which are Non lactose fermenting
 Motile, Indole positive
 Urease negative
 Ferment Glucose,Mannitol,Maltose
 Donot ferment Lactose, Sucrose
 Typhoid bacilli are anaerogenic
 Some of the Paratyphoid form acid and gas
 Further identification done by slide agglutination
tests
Slide agglutination tests
 In slide agglutination
tests a known serum
and unknown culture
isolate is mixed,
clumping occurs within
few minutes
 Commercial sera are
available for detection
of A, B,C1,C2,D, and E.
Clot culture
 Clot cultures are more productive in
yielding better results in isolation.
 A blood after clotting, the clot is lysed with
Streptokinase ,but expensive to perform in
developing countries.
Bactek and Radiometric based
methods are in recent use
 Bactek methods in
isolation of Salmonella
is a rapid and
sensitive method in
early diagnosis of
Enteric fever.
 Many Microbiology
Diagnostic
Laboratories are
upgrading to Bactek
methods
Other methods in Isolation of Enteric
Pathogens
 Feces Culture
 Urine Culture
 Bone marrow cultures ( Highly Sensitive )
Emerging Methods in Diagnosis of
Enteric fevers.
 Detection of circulating
antigen by Co -
agglutination methods with
use of Cowan’s strain
Staphylococcus coated
with antibodies
 PCR. The advent of PCR
technology has provided
unparalleled sensitivity
and specificity for the
diagnosis of typhoid
Diagnosis of Carriers
 Useful in public health purpose.
 Useful in screening food handlers, cooks, to
detect carrier state
 Typhoid bacilli can be isolated from feces
or from bile aspirates
 Detection of Vi agglutinins in the Blood can
be determinant of carrier state.
Widal Test
 In 1896 Widal A professor of
pathology and internal
medicine at the University of
Paris (1911–29), he
developed a procedure for
diagnosing typhoid fever
based on the fact that
antibodies in the blood of an
infected individual cause the
bacteria to bind together into
clumps (the Widal reaction).
Diagnosis of Enteric Fever
Widal test
 Serum agglutinins raise abruptly during the 2nd or 3rd week
 The widal test detects antibodies against O and H antigens
 Two serum specimens obtained at intervals of 7 – 10 days to
read the raise of antibodies.
 Serial dilutions on unknown sera are tested against the
antigens for respective Salmonella
 False positives and False negative limits the utility of the test
 The interpretative criteria when single serum specimens are
tested vary
 Cross reactions limits the specificity
Significant Titers helps in Diagnosis
 Following Titers of
antibodies against the
antigens are significant
when single sample is
tested
O > 1 in 160
H > 1 in 320
Testing a paired sample
for raise of antibodies
carries a greater
significance
Widal test – Still a popular test
 The Widal test (Widal’s agglutination reaction) is
routinely practised for the serodiagnosis of typhoid fever
by most of the laboratories. Several workers have
expressed doubt regarding the reliability of the test.
Several factors have contributed to this uncertainty.
These include poorly standardised antigens, the sharing
of antigenic determinants with other Salmonellae and the
effects of immunisation with TAB vaccine. Another major
problem relates to the difficulty of interpreting Widal test
results in areas where Salmonella typhi is endemic and
where the antibody titres of the normal population are
often not known.
Limitations of Widal test
 Classically, a four-fold rise of antibody in
paired sera Widal test is considered
diagnostic of typhoid fever. However, paired
sera are often difficult to obtain and specific
chemotherapy has to be instituted on the
basis of a single Widal test. Furthermore, in
areas where fever due to infectious causes is
a common occurrence the possibility exists
that false positive reactions may occur as a
result of non-typhoid
Antimicrobial Therapy in Typhoid
 With prompt antibiotic therapy, more than 99% of
the people with typhoid fever are cured, although
convalescence may last several months. The
antibiotic chloramphenicolSome Trade Names
CHLOROMYCETIN
is used worldwide, but increasing resistance to it
has prompted the use of other antibiotics (such as
trimethoprim-sulfamethoxazole
BACTRIM
SEPTRA
or ciprofloxacin
Drug resitance an Emerging concern
 Previously Choramphenicol was the drug of
choice for the treatment of typhoid fever.
However, with the development more safer and
more effective drugs the use of Choramphenicol
has declined these days. 3rd generation
cephalosporins, like Ceftriaxone, and
Flouroquinolones, like ciprofloxacin and
levofloxacin are the drugs of choice for treatment
of typhoid fever .Once again many strains are
sensitive to Choramphenicol
Vaccines for Typhoid Prevention

 Two types of vaccines are available

 Oral and Inject able
 Oral – A live oral vaccine ( typhoral ) is a stable
mutant of S.typhi strain Ty 21a lacking the
enzyme UDP Galactose -4-epimerase.
One capsule given orally taken before food, with
glass of water or milk, on 1, 3, 5 days ( three
doses )
No antibiotics should be taken during the period of
administration of vaccine
Vaccine - injectable

 The inject able vaccine, ( typhim –vi)

contains purified Vi polysaccharide antigen
derived from S.typhi strain ty21
 Given as single subcutaneous or
intramuscular injection
 Single dose is adequate.
Vaccines for Typhoid

Both vaccines are given to only > 5 years of

age.
Immunity lasts for 3 years
Need a booster
Vaccines are not effective in
prevention of Paratyphoid fevers
Simple hand hygiene and washing
can reduce several cases of Typhoid
Created for Health
and Educational
awareness on
Typhoid Fever
Dr.T.V.Rao MD
Email
doctortvrao@gmail.com