Typhoid FeverTyphoid Fever( ( Enteric FeversEnteric Fevers ) )

an updatean update

Dr.T.V.Rao MDDr.T.V.Rao MD

Typhoid fevers are prevalent in Typhoid fevers are prevalent in many regions in the Worldmany regions in the World

Enteric FeversEnteric Fevers

The syndrome associated with enteric The syndrome associated with enteric fevers are produced only by a few of the fevers 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 observed In 1880s, the typhoid bacillus was first observed by Eberth in spleen sections and mesenteric by Eberth in spleen sections and mesenteric lymph nodes from a patient who died from lymph nodes from a patient who died from typhoid. Robert Koch confirmed a related finding typhoid. Robert Koch confirmed a related finding by Gaffky and succeeded in cultivating the by Gaffky and succeeded in cultivating the bacterium in 1881. But due to the lack of bacterium in 1881. But due to the lack of differential characters, separation of the typhoid differential characters, separation of the typhoid bacillus from other enteric bacteria was bacillus from other enteric bacteria was uncertain. uncertain.

. .

History of Sero DiagnosisHistory of Sero Diagnosis

In 1896, it was demonstrated that the In 1896, it was demonstrated that the serum from an animal immunized with the serum from an animal immunized with the typhoid bacillus agglutinated (clumped) the typhoid bacillus agglutinated (clumped) the typhoid bacterial cells, and it was shown typhoid bacterial cells, and it was shown that the serum of patients afflicted with that the serum of patients afflicted with typhoid likewise agglutinated the typhoid typhoid likewise agglutinated the typhoid bacillus. Serodiagnosis of typhoid was bacillus. Serodiagnosis of typhoid was thus made possible by 1896. thus made possible by 1896.

Typhoid MaryTyphoid Mary

A famous example is A famous example is “Typhoid” Mary “Typhoid” Mary Mallon, who was a Mallon, who was a food handler food handler responsible for responsible for infecting at least 78 infecting at least 78 people, killing 5. people, killing 5. These highly infectious These highly infectious carriers pose a great carriers pose a great risk to public health.risk to 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 the worked as a cook in New York City in the early 1900s. Public health pioneer early 1900s. Public health pioneer Sara Josephine Baker, MD, PhDSara Josephine Baker, MD, PhD tracked tracked her down after discovering that she was her down after discovering that she was the common link among many people who the common link among many people who had become ill from typhoid fever She was had become ill from typhoid fever She was traced to typhoid outbreaks a second time traced to typhoid outbreaks a second time so she was put in prison again where she so 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 by caused by Salmonella typhiSalmonella typhi.. It is It is transmitted through the ingestion of food transmitted through the ingestion of food or drink contaminated by the faeces or or drink contaminated by the faeces or urine of infected people. urine of infected people.

Para typhoid fevers are produced by other Para typhoid fevers are produced by other species named species named

Paratyphi A, B, CParatyphi A, B, C

Changing taxonomy of Changing taxonomy of Salmonella speciesSalmonella species

SalmonellaSalmonella are are Gram-negativeGram-negative bacteria bacteria which cause intestinal infections. The which cause intestinal infections. The taxonomy of taxonomy of SalmonellaSalmonella species is species is complicated. Formally, there are only two complicated. Formally, there are only two species within this genus: species within this genus: S. bongoriS. bongori and and 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 - entericaentericaII - II - salamaesalamaeIIIa -IIIa -arizonaearizonaeIIIb -IIIb -diarizonaediarizonaeIV - IV - houtenaehoutenaeV - V - bongoribongoriVI - VI - indicaindica

Bacteriology –Typhoid feverBacteriology –Typhoid fever

The Genus The Genus Salmonella belong to Salmonella belong to Enterobactericiae Enterobactericiae

Facultative anaerobeFacultative anaerobe

Gram negative bacilliGram negative bacilli

Distinguished from Distinguished from other bacteria by other bacteria by Biochemical and Biochemical and antigen structureantigen structure

Antigenic structure of Antigenic structure of SalmonellaSalmonella

Two sets of antigensTwo sets of antigens Detection by serotypingDetection by serotyping 1 1 Somatic or 0 AntigensSomatic or 0 Antigens contain long chain contain long chain polysaccharides ( LPS ) comprises of heat stable polysaccharides ( LPS ) comprises of heat stable polysaccharide commonly.polysaccharide commonly.

2 Flagellar or H Antigens2 Flagellar or H Antigens are strongly immunogenic are strongly immunogenic and induces antibody formation rapidly and in high titers and induces antibody formation rapidly and in high titers following infection or immunization. The flagellar antigen following 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 any of Paratyphoid fever can be caused by any of three serotypes of S. paratyphi A, B and three serotypes of S. paratyphi A, B and C. It is similar in its symptoms to typhoid C. It is similar in its symptoms to typhoid fever, but tends to be milder, with a lower fever, 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 the Persons with typhoid fever carry the bacteria in their bloodstream and intestinal bacteria in their bloodstream and intestinal tract. In addition, a small number of tract. In addition, a small number of persons, called carriers , recover from persons, called carriers , recover from typhoid fever but continue to carry the typhoid fever but continue to carry the bacteria. Both ill persons and carriers shed bacteria. Both ill persons and carriers shed 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, abdominal bradycardia, splenomegaly, abdominal symptoms and 'rose spots' which are clusters of symptoms and 'rose spots' which are clusters of pink mauls on the skin.pink mauls on the skin.

Complications such as intestinal hemorrhage or Complications such as intestinal hemorrhage or perforation can develop in untreated patients or perforation can develop in untreated patients or when treatment is delayedwhen treatment is delayed..

Pathology and Pathogenesis of Pathology and Pathogenesis of Enteric feverEnteric fever

Caused by Caused by S. typhiS. typhi S.paratyphiS.paratyphi A B CA B CThe organisms penetrate ileal mucosa reach mesentric The 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 ductIn 7 – 10 days through blood stream infect In 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 causing After multiplication bacilli pass into blood causing

secondary and heavier bactermia secondary and heavier bactermia

FeverFever

All the events coincides with Fever and other All the events coincides with Fever and other signs of clinical illnesssigns of clinical illnessFrom Gall bladder further invasion occurs in From Gall bladder further invasion occurs in intestinesintestinesInvolvement of peyr’s patches, gut lymphoid Involvement of peyr’s patches, gut lymphoid tissuetissueLead to inflammatory reaction, and infiltration Lead to inflammatory reaction, and infiltration with monocular cellswith monocular cellsLeads to Necrosis, Sloughing and formation of Leads 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 vagueDull continuous head acheDull continuous head acheAbdominal tenderness discomfort may Abdominal tenderness discomfort may present with constipation.present with constipation.May progress and present with step ladder May progress and present with step ladder pattern temperaturepattern temperatureTemperature fall by crisis in 3 – 4Temperature fall by crisis in 3 – 4thth week week

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 with May present with rash, rose spots 2 -4 rash, rose spots 2 -4 mm in diameter mm in diameter raised discrete raised discrete irregular blanching irregular blanching pink maculae's found pink maculae's found in front of chestin front of chestAppear in crops of Appear in crops of upto a dozen at a upto a dozen at a timetimeFade after 3 – 4 days Fade after 3 – 4 days

Complication in TyphoidComplication in Typhoid

Severe intestinal hemorrhage and Severe intestinal hemorrhage and intestinal perforationintestinal perforation

If not diagnosed can lead to fatal If not diagnosed can lead to fatal complications.complications.

RelapseRelapse

Apparent recovery can be followed by Apparent recovery can be followed by relapse in 5 – 10 % of untreated patientsrelapse in 5 – 10 % of untreated patients

On few occasions relapses can be severe On 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 up to In untreated patients mortality can be up to 20 %20 %Occasionally present with diarrhea may Occasionally present with diarrhea may mimic other infections, which is mimic other infections, which is particularly common in paratyphoid fever.particularly common in paratyphoid fever.Patient may present as gastro enteritis no Patient may present as gastro enteritis no different from that caused by other different from that caused by other S.enterica serotypes.S.enterica serotypes.

Typhoid carriersTyphoid carriers

Salmonella entericaSalmonella enterica causes approximately causes approximately 16 million cases of typhoid fever 16 million cases of typhoid fever worldwide, killing around 500,000 per worldwide, killing around 500,000 per year. One in thirty of the survivors, year. One in thirty of the survivors, however, become carriers. In carriers the however, become carriers. In carriers the bacteria remain hidden inside cells and the bacteria remain hidden inside cells and the gall bladder, causing new infections as gall bladder, causing new infections as they are shed from an apparently healthy they are shed from an apparently healthy host. host.

Academic progress on carrier Academic progress on carrier state in Typhoidstate in Typhoid

The factors that enable the bacteria to establish The factors that enable the bacteria to establish chronic infection were unclear. However, in a chronic infection were unclear. However, in a paper published this week in the Proceedings of paper published this week in the Proceedings of the National Academy of Science, researchers the National Academy of Science, researchers at the Institute of Food Research in Norwich and at the Institute of Food Research in Norwich and the Karolinska Institute in Sweden found that the the Karolinska Institute in Sweden found that the change of a single base pair in one change 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 by In Adults 5- 10 ml of Blood is collected by venepuncture inoculated into 50 – 100 ml venepuncture inoculated into 50 – 100 ml of Bile broth ( 0.5 % )of Bile broth ( 0.5 % )

Several other media are available used as Several other media are available used as per the availability of medium to suit their per the availability of medium to suit their laboratory conditions.laboratory conditions.

Blood Cultures in Typhoid Blood Cultures in Typhoid FeversFevers

Bacteremia occurs Bacteremia occurs early in the disease early in the disease Blood Cultures are Blood Cultures are positive in positive 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 in week and later in

25%25%

Identification of SalmonellaIdentification of Salmonella

Sub cultures are done after overnight Sub cultures are done after overnight incubation at 37incubation at 3700c,and subcultures are c,and subcultures are done on Mac Conkey's agardone on Mac Conkey's agar

Subcultures are repeated upto 10 days Subcultures 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 fermenting Isolates which are Non lactose fermenting Motile, Indole positiveMotile, Indole positiveUrease negativeUrease negativeFerment Glucose,Mannitol,MaltoseFerment Glucose,Mannitol,MaltoseDonot ferment Lactose, SucroseDonot ferment Lactose, SucroseTyphoid bacilli are anaerogenicTyphoid bacilli are anaerogenicSome of the Paratyphoid form acid and gasSome of the Paratyphoid form acid and gasFurther identification done by slide agglutination Further identification done by slide agglutination teststests

Slide agglutination testsSlide agglutination tests

In slide agglutination In slide agglutination tests a known serum tests a known serum and unknown culture and unknown culture isolate is mixed, isolate is mixed, clumping occurs clumping occurs within few minuteswithin few minutes

Commercial sera are Commercial sera are available for detection available 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 in Clot cultures are more productive in yielding better results in isolation.yielding better results in isolation.

A blood after clotting, the clot is lysed with A blood after clotting, the clot is lysed with Streptokinase ,but expensive to perform in Streptokinase ,but expensive to perform in developing countries.developing countries.

Bactek and Radiometric based Bactek and Radiometric based methods are in recent usemethods are in recent use

Bactek methods in Bactek methods in isolation of isolation of Salmonella is a rapid Salmonella is a rapid and sensitive method and sensitive method in early diagnosis of in early diagnosis of Enteric fever.Enteric fever.Many Microbiology Many Microbiology Diagnostic Diagnostic Laboratories are Laboratories are upgrading to Bactek upgrading to Bactek methodsmethods

Other methods in Isolation of Other 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 of Emerging Methods in Diagnosis of Enteric fevers.Enteric fevers.

Detection of circulating Detection of circulating antigen by antigen by Co - Co - agglutinationagglutination methods methods with use of Cowan’s with use of Cowan’s strain Staphylococcus strain 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 feces Typhoid bacilli can be isolated from feces or from bile aspiratesor from bile aspirates

Detection of Vi agglutinins in the Blood Detection 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 of In 1896 Widal A professor of pathology and internal pathology and internal medicine at the University of medicine at the University of Paris (1911–29), he Paris (1911–29), he developed a procedure for developed a procedure for diagnosing typhoid fever diagnosing typhoid fever based on the fact that based on the fact that antibodiesantibodies in the blood of an in the blood of an infected individual cause the infected individual cause the bacteria to bind together into bacteria to bind together into clumps (the Widal reaction). clumps (the Widal reaction).

Diagnosis of Enteric FeverDiagnosis of Enteric FeverWidal testWidal test

Serum agglutinins raise abruptly during the 2Serum agglutinins raise abruptly during the 2ndnd or 3 or 3rdrd weekweekThe widal test detects antibodies against O and H The widal test detects antibodies against O and H antigensantigensTwo serum specimens obtained at intervals of 7 – 10 Two 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 the Serial dilutions on unknown sera are tested against the antigens for respective Salmonellaantigens for respective SalmonellaFalse positives and False negative limits the utility of the False positives and False negative limits the utility of the testtestThe interpretative criteria when single serum specimens The interpretative criteria when single serum specimens are tested varyare tested varyCross reactions limits the specificityCross reactions limits the specificity

Significant Titers helps in Significant Titers helps in DiagnosisDiagnosis

Following Titers of Following Titers of antibodies against the antibodies against the antigens are significant antigens are significant when single sample is when single sample is tested tested

O > 1 in 160O > 1 in 160 H > 1 in 320H > 1 in 320 Testing a paired sample Testing a paired sample

for raise of antibodies for raise of antibodies carries a greater carries a greater significancesignificance

Widal test – Still a popular testWidal test – Still a popular test

The Widal test (Widal’s agglutination reaction) is The Widal test (Widal’s agglutination reaction) is routinely practised for the serodiagnosis of typhoid routinely practised for the serodiagnosis of typhoid fever by most of the laboratories. Several workers fever by most of the laboratories. Several workers have expressed doubt regarding the reliability of the have expressed doubt regarding the reliability of the test.  Several factors have contributed to this test.  Several factors have contributed to this uncertainty. These include poorly standardised uncertainty. These include poorly standardised antigens, the sharing of antigenic determinants with antigens, the sharing of antigenic determinants with other Salmonellae and the effects of immunisation other Salmonellae and the effects of immunisation with TAB vaccine. Another major problem relates to with TAB vaccine. Another major problem relates to the difficulty of interpreting Widal test results in the difficulty of interpreting Widal test results in areas where Salmonella typhi is endemic and where areas where Salmonella typhi is endemic and where the antibody titres of the normal population are often the 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 in Classically, a four-fold rise of antibody in paired sera Widal test is considered paired sera Widal test is considered diagnostic of typhoid fever. However, paired diagnostic of typhoid fever. However, paired sera are often difficult to obtain and specific sera are often difficult to obtain and specific chemotherapy has to be instituted on the chemotherapy has to be instituted on the basis of a single Widal test.  Furthermore, in basis of a single Widal test.  Furthermore, in areas where fever due to infectious causes is areas where fever due to infectious causes is a common occurrence the possibility exists a common occurrence the possibility exists that false positive reactions may occur as a that false positive reactions may occur as a result of non-typhoidresult of non-typhoid

Antimicrobial Therapy in Antimicrobial 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 several although convalescence may last several months. The antibiotic months. The antibiotic chloramphenicolchloramphenicolSome Some Trade Names Trade Names CHLOROMYCETINCHLOROMYCETINis used worldwide, but increasing resistance to it is used worldwide, but increasing resistance to it has prompted the use of other antibiotics (such has prompted the use of other antibiotics (such as as trimethoprim-sulfamethoxazoletrimethoprim-sulfamethoxazole BACTRIMBACTRIMSEPTRASEPTRAor or ciprofloxacinciprofloxacin

Drug resitance an Emerging Drug resitance an Emerging concernconcern

Previously Choramphenicol was the drug of Previously 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 and However, with the development more safer and more effective drugs the use of Choramphenicol more effective drugs the use of Choramphenicol has declined these days. has declined these days. 3rd generation 3rd generation cephalosporins, like Ceftriaxone, and cephalosporins, like Ceftriaxone, and Flouroquinolones, like ciprofloxacin and Flouroquinolones, like ciprofloxacin and levofloxacin are the drugs of choice for treatment levofloxacin are the drugs of choice for treatment of typhoid fever .of typhoid fever .Once again many strains are Once again many strains are sensitive to Choramphenicolsensitive to Choramphenicol

Vaccines for Typhoid PreventionVaccines for Typhoid Prevention

Two types of vaccines are available Two types of vaccines are available Oral and Inject ableOral and Inject ableOral – A live oral vaccine ( typhoral ) is a stable Oral – A live oral vaccine ( typhoral ) is a stable mutant of S.typhi strain Ty 21a lacking the mutant 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, with One capsule given orally taken before food, with glass of water or milk, on 1, 3, 5 days ( three glass of water or milk, on 1, 3, 5 days ( three doses )doses )

No antibiotics should be taken during the period No 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 polysaccharide antigen contains purified Vi polysaccharide antigen derived from S.typhi strain ty21derived from S.typhi strain ty21

Given as single subcutaneous or Given 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 of Both 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 in Vaccines are not effective in prevention of Paratyphoid feversprevention of Paratyphoid fevers

Simple hand hygiene and Simple hand hygiene and washing can reduce several washing can reduce several

cases of Typhoidcases of Typhoid

Created for Health and Created for Health and Educational awareness on Educational awareness on

Typhoid FeverTyphoid Fever

Dr.T.V.Rao MDDr.T.V.Rao MD

EmailEmail

doctortvrao@gmail.comdoctortvrao@gmail.com