Typhoid fever

Dr Sharad Chaurasia

INTRODUCTIONTyphoid fever (Greek- Smoke, Fumes, Stupor) Systemic infection with bacterium Salmonella

enterica serotype typhi / paratyphi A/B.

EPIDEMIOLOGYOver 21.7 million cases/ annually>2 lacs deathAdditional >5.4 million cases – Paratyph.Developed countries- <15/ lacs populationDeveloping countries- 100-1000/lacs.

In an Indian urban slum showed incidence as high as 2/ 1,000 /yr for children under five

5.1/ 1,000/ yr for children under tenmajority of cases occurred in children aged 5

to 12 years and 24.8% of cases were in children up to 5 years of age

S. Typhi (75.7%) was the predominant serovar followed by S. Paratyphi A (23.8%)

maximum number of enteric fever cases occurred during April to June (dry season) followed by July to September (monsoon season

Typhoid fevers are prevalent in many regions in the World

Contd..Age – Children and young adults (5-25 years).Recent Study from Delhi shows Typhoid fever

also common in < 5 years of age.IP – 10-14 days (3-21 days).MOT – Faeco-oral/Urine-oral route.Through out the year esp. July-SeptemberROI – Man (Cases/Carriers)

OrganismSalmonella typhi, a Gram-negative bacteria.

Similar but often less severe disease is caused by Salmonella serotype paratyphi A.

The ratio of disease caused by S. typhi to that caused by S. paratyphi is about 10 to 1.

Many genes are shared with E. coli and at least 90% with S. typhimurium,

Polysaccharide capsule Vi: present in about 90% of all freshly isolated S. typhi and has a protective effect against the bactericidal action of the serum of infected patients.

Risk Factors

Impaired cell-mediated immunityAIDSCorticosteroid use MalignancyImpaired phagocytic functionHemoglobinopathiesChronic granulomatous diseaseMalariaHistoplasmosisSchistosomiasis

Risk FactorsExtremes of ageNeonatesElderlyDecreased gastric acidityAntacids or suppression of acid secretionAchlorhydriaAltered intestinal functionInflammatory bowel diseasePrior antibiotic therapy

Pathogenesis

Contd..Entry in GIT localization in Gut associated

lymphoid tissue Lymphatic channel thoracic duct circulation primary silent bacteremia localization in macrophages of RES in spleen, liver, bone marrow (incubation period 8-14 days) secondary bacteremia

Clinical Features

Acute non-complicated diseaseCharacterized by

Prolonged fever, classic stepladder rise uncommon. Disturbances of bowel function

Headache, malaise and anorexia.Bronchitic cough Exanthem (rose spots appr 25%) on the chest, abdomen and back.

Complicated disease10-15% of typhoid patients

CNS (3-35%): Encephalopathy, Typhoid meningitis, encephalomyelitis, Guillain-Barré syndrome, cranial or peripheral neuritis and psychotic symptoms, Coma Vigil.

GIT: occult blood in 10-20% of patients, and intestinal hemorrhage in upto 1%. Intestinal perforation has also been reported in up to 1% of hospitalized cases.

Others: Hepatitis, myocarditis, pneumonia, Empyema, disseminated intravascular, Osteomyelitis

DiagnosisIn endemic area, fever without evident cause

more than 7 days should be considered Typhoid until proved otherwise.

Blood culture – standard diagnostic method . +ve in 40-60%

Failure to isolate the organism (i) the limitations of laboratory media(ii) the presence of antibiotics (iii) the volume of the specimen cultured

Blood Cultures in Typhoid FeversBacteremia 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%

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.

Contd..(iv) the time of collection, patients with a history

of fever for 7 to 10 days being more likely than others to have a positive blood culture.

Bone marrow aspirate culture is the gold standard for the diagnosis of typhoid fever+ve 80-95%Inspite on antibiotics.

Stool culture +ve in 30% with acute Typhoid fever. Positivity rate increases with duration of illness.

Cultures also been made from blood clots, rose spots, intestinal secretion, urine.

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.

Immune Response in Typhoid

Widal TestMeasures antibody against O & H antigens of

S.typhi.Sensitivity-60%; specificity-80%. O antibodies appear on days 6-8 and H

antibodies on days 10-12Negative in up to 30% of culture-proven cases of

typhoid feverS. typhi shares O and H antigens with other

Salmonella serotypes and has cross-reacting epitopes with other Enterobacteriacae, and this can lead to false-positive results. Such results may also occur in other clinical conditions, e.g. malaria, typhus, bacteraemia caused by other organisms, and cirrhosis

Contd..This is acceptable so long as the results are

interpreted with care in accordance with appropriate local cut-off values for the determination of positivity

A 4 fold rise Ab titre in paired sera highly suggestive

>1:160 titre against O & H highly suggestive with relevent clinical findings.

New serological testSpecific antibodies usually only appear a

week after the onset of symptoms and signs. This should kept in mind when a negative serological test result is being interpreted.

New serological testsTyphidot (better), high negative predictive

valueDipstick test,DNA ProbePCR

CONTD..Typhidot –

Rapid serological test, detects IgM $ IgG antibody –OMP of s.typhi.

Becomes +ve within 2-3 days of infection.Sensitivity-90-98% ; specificity-75-90%.

Vi agglutinin reaction test- carrier.CBC- WBC low in relation to fever, leucocytosis

common young childrenThrombocytopenia marker of severe illness/

accompany DIC.

Oral drugsCotrimoxazole, Ampicillin, ChlorphenicolEarlier used as 1st line drugs, due to

resistance became 2nd line drugs.In endemic area >90% typhoid cases

treated at home with proper antibiotics & good nursing care.

Patients with persistent vomiting, decreased oral intake, severe diarrhea & abd. Distension require parenteral antibiotic preferably in hospital.

Fluoroquinolones

Optimal for the treatment of typhoid feverNot approved by drug controller general of India

<18 yrs. Age.Relatively inexpensive, well tolerated and more

rapidly and reliably effective than the former first-line drugs, viz. chloramphenicol, ampicillin, amoxicillin and trimethoprim-sulfamethoxazole.

The majority of isolates are still sensitive.

Contd..Attain excellent tissue penetration, kill S.

typhi in its intracellular stationary stage in monocytes/macrophages and achieve higher active drug levels in the gall bladder than other drugs.

Dose- 15-20 mg/kg/day BD -7 days for NASST and 10-14 days for NARST.

Rapid therapeutic response, i.e. clearance of fever and symptoms in three to five days, and very low rates of post-treatment carriage.

ChloramphenicolThe disadvantages of using chloramphenicol

include a relatively high rate of relapse (57%), long treatment courses (14-21 days) and the frequent development of a carrierstate in adults.

The recommended dosage is 50 – 75 (100mg for iv/im) mg per kg per day for 14 -21days divided into four doses per day, or for at least five to seven days after defervescence.

Oral administration gives slightly greater bioavailability than intramuscular (i.m.) or intravenous (i.v.) administration of the succinate salt.

CephalosporinsOral drugs:- Cefixime, Cefpodoxime.Parenteral-Ceftriaxone, cefotaxime,

cefoperazone.Cefotaxime: 40-80mg per kg per day in two

or three dosesCeftriaxone: 50-75 mg/kg/day OD/BD.Most convenient & widely used.Cefoperazone: 50-100 mg per kg per day

Contd..In uncomplicated typhoid fever- cefixime

DOC as emperical therapy.If by 5th day No clinical improvement &

culture inconclusive—ADD second line drugs eg. Azithromycin (drugs sensitivity pattern of the area).

In complicated typhoid- DOC 3rd gen. cephal. Parenteral eg. Ceftriaxone.

In severe life threatening infection – FQs. May be used. Aztreonam/ Imipenam may also be used.

hegazi8@hotmailcom 36

MEDICAL COMPLICATIONSacute bronchitis and frank lobar

pneumonia, toxic myocarditis, venous thrombosis, hemolytic anaemia, acute typhoid nephritis, typhoid meningitis and peripheral neuritis


MEDICAL COMPLICATIONSMyocarditis is extremely common, particularly in

the very toxic patient. The cardiac muscle is affected, even in convalescence, and this is shown by a rapid deterioration of the cardiovascular system in a relapse, or after the administration of a general anaesthetic.

Febrile albuminuria is common, but true acute typhoid nephritis is rare.

Peripheral neuritis and ‘tender toes’.

Mild hemolytic anaemia is fairly common in the very toxic typhoid patient. A marked degree is rare, and the mortality rate is high.

Dexamethasone for CNS complicationShould be immediately be treated with high-

dose intravenous dexamethasone in addition to antimicrobials

Initial dose of 3 mg/kg by slow i.v. infusion over 30 minutes

1 mg/kg 6 hourly for 2 days/ 8 doses.Mortality can be reduced by some 80-90% in

these high-risk patients


Typhoid Pneumonia Acute bronchitis is so common that it should

be considered as a manifestation of the disease itself rather than as a complication.

Typhoid lobar pneumonia presents with the typical symptoms and signs of lobar pneumonia

except that ‘rusty’ sputum is uncommon, and the white blood cell count is low.

It responds well to chloramphenicol. A patient with typhoid pneumonia,.

GI complicationPatients with intestinal haemorrhage need

intensive care, monitoring and blood transfusion.

Surgical consultation for suspected intestinal perforation is indicated. If perforation is confirmed, surgical repair should not be delayed longer than six hours.

Metronidazole and gentamicin or ceftriazone should be administered before and after surgery .

Early intervention is crucial, and mortality rates increase as the delay between perforation and surgery lengthens. Mortality rates vary between 10% and 32%.


The major surgical complications of typhoid fever may include:parotitis, intestinal perforation and haemorrhage,acute cholecystlitis, paralytic ileus, orchitis, pyelitis, cystitis, retention of urine,empyema, arthritis and osteomyelitis.

Relapse5-20% of typhoid fever cases that have

apparently been treated successfully.

A relapse is heralded by the return of fever soon after the completion of antibiotic treatment. The clinical manifestation is frequently milder than the initial illness. Cultures should be obtained and standard treatment should be administered.

Carrier- Temporary carrier(excreate bacilli upto 6-8 wks). eg.incubatory, convalescent state.3

Chronic carrier- excrete bacilli > 3 months after infection.

Paratyphoid fever A,B,C

Caused by Salmonella paratyphoid A,B,C.respectively.

in no way different from typhoid fever in , pathogenesis, pathology,clinical manifestations,

diagnosis, treatment and

Prophylaxis

Paratyphoid A,B:incubation period 2~15days, in

genaral,8~10 days.

milder in severity

fewer in complications.

Better in prognosis,

relapse more common in Paratyphoid A.

Treatment same as in typhoid fever.

Paratyphoid C:

Always sudden onset.

Rapid rise of temperature.

Presented in different forms-- Septicemia,

Gastroenteritis and Enteric fever

Complications--arthritis, abscess formation, cholecystitis, pulmonary complications are commonly seen.

Intestinal hemorrhage and perforation not as common as in typhoid fever.

PREVENTIONSafe drinking waterEffective sewage disposalHygienic food preparationMass immunisation:-

Classic heat-inactivated whole cell vaccine—51-88% protection

Local discomfort & swelling, systemic side effect.

VaccinationVi polysaccharide, is given in a single dose Protection begins seven days after injection, maximum protection being reached 28 days

after injection when the highest antibody concentration is obtained.

Protective efficacy was 72% one and half years after vaccination and was still 55% three years after a single dose.

In Asian countries where Vi-negative strains have been reported at the low average level of 3%.

Live oral vaccine Ty2lathree doses two days apart on an empty stomach.Protection as from 10-14 days after the third

dose. > 5 years. Protective efficacy of the enteric-coated capsule

formulation seven years after the last dose is still62% in areas where the disease is endemic; Antibiotics should be avoided for seven days

before or after the immunization

Contd..Vi conjugated vaccine:

Induce T cell dependent responseEfficacy- >90%Booster response Doses: 3 mths.- 2 yrs.-2doses at 4-8 wks.

Interval followed by booster at 2-2.5 yrs age. Route- intramuscular.

>2 yrs.- 2 doses at 4-8 wks. Interval.

MDR TYPHOIDClinical failure

presence of persistent symptoms or, development of complications .

Microbiological failure

positive blood / bone marrow culture at the end of treatment.

MDR Typhoid definition

Epidemiological- strains resistant =>2 antibiotics in vitro.Clinical- => 2 1st line drugs viz. Amp., Chlo., Cx. Incidence - 49-83% of mdr typhoid in indian children.Mediated by plasmid

Quinolone resistance is frequently mediated by single point mutations in the quinolone-resistance–determining region of the gyrA gene

MDRNalidixic acid resistant: MIC of fluoroquinolones for

these strains was 10 times that for fully susceptible strains.

Incidence - 49-83% of mdr typhoid in indian children.

Mediated by plasmid

Quinolone resistance is frequently mediated by single point mutations in the quinolone-resistance–determining region of the gyrA gene

DiagnosisHigh degree of suspicion viz. prolonged

fever, protracted course, unusual/ life threatening complication, slow response to treatment.

Culture reportsEpidemiological reports.

The future of typhoid feverCheap,Rapid and reliable serological testFluoroquinolone and cephalosporin resistant

caseCombination chemotherapyNew drugsmass vaccination in endemic areaTyphoid vaccination programme for school

children or, with advent of new conjugate vi vaccine, as part of EPI, should be considered.

Mary Mallon (September 23, 1869 – November 11, 1938)


Also known as Typhoid Mary

was the first person in the United States to be identified as a healthy carrier of typhoid fever.

She seemed a healthy woman when a health inspector knocked on her door in 1907, yet she was the cause of several typhoid outbreaks.

Mary Mallon (September 23, 1869 – November 11, 1938)Since Mary was the first "healthy carrier" of typhoid fever in the

United States, she did not understand how someone not sick could spread disease -- so she tried to fight back.

She was forcibly quarantined twice by public health authorities and died in quarantine.

Over the course of her career as a cook, she infected 47 people, three of whom died from the disease.

It was also possible that she was born with the disease, as her mother had typhoid fever during her pregnancy.


MaryMallon died on November 11, 1938 at the age of 69 due to pneumonia (not typhoid), six years after a stroke had left her paralyzed.

However, an autopsy found evidence of live typhoid bacteria in her gallbladder.

Her body was cremated with burial in Saint Raymond's Cemetery in the Bronx.

Salmonella serotype Food Cases Year

Salmonella newport Mangoes 78 1999

Salmonella muenchen Orange juice 207 1999

Salmonella agona Dry cereal 209 1998

Salmonella newport Sprouts 135 1996

Salmonella poona Cantaloupes >400 1991

Salmonella javiana Tomatoes 174 1990

Salmonella enteritidis Ice cream (egg)

~250,000 1996

Salmonella typhimurium Milk ~200,000 1984

Serogroup Example (serotype)* Characteristic syndrome

A S. paratyphi A Enteric fever

B S. paratyphi B Enteric fever or gastroenteritis

B S. typhimurium Gastroenteritis

B S. heidelberg Gastroenteritis, bacteremia

C S. paratyphi C Enteric fever

C S. choleraesuis Bacteremia

C S. newport Gastroenteritis

D S. typhi Enteric fever

D S. enteritidis Gastroenteritis

D S. dublin Bacteremia

Typhoid fever

Health & Medicine

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