Enteric fever. typhoid fever. in children. medical management.

1. Enteric Fever
Presented by Dr. Ankit Agarwal
Guided by: Dr. B.S. Natani
Dept. of Pediatrics
NIMS, Jaipur

2. Overview
• History
• Epidemiology
• Etiology
• Pathogenesis
• Clinical Features
• Complications
• Diagnosis
• Differential Diagnosis
• Treatment
• Prevention and Vaccination
• References

3. History
Thomas Willis: In 1659 credited with the first
description of Typhoid fever
Evidence of cases of Typhoid Fever dates back to 430 BC, when a devastating
illness killed one-third of the population of Athens. In 2006, a study detected
DNA sequences similar to Salmonella in dental pulp extracted from a burial pit
dated to the time of the outbreak.
Until the nineteenth century Typhoid Fever and
Typhus were considered the same. John Huxam
in 1739 first described the difference between the
two.
Thomas Willis

4. In 1880, Karl Joseph Eberth described a
typhoid bacillus. In 1884, pathologist Georg
Theodor August Gaffky confirmed Eberth's
findings, and the organism was given names
such as Eberth's bacillus, Eberthella typhi, and
Gaffky-Eberth bacillus.
French physician Pierre Charles Alexandre Louis
in 1829 first proposed the name “Typhoid Fever”-
meaning to resemble typhus.
In 1837 William Wood Gerhard was the first to
differentiate clearly between typhus fever and
typhoid
William Budd in 1856 described the feco-oral
method of transmission of Typhoid fever
Pierre Charles Alexandre
Louis
Karl Joseph Eberth

5. Georges-Fernand-Isidor
Widal
In 1896 Georges-Fernand-Isidor Widal described the
‘Widal agglutination reaction’ and called it “Sero-
Diagnosis”
In the same year Sir Almroth Edward Wright
developed an injectable heat killed whole cell vaccine for
Typhoid.
S. Paratyphi isolated in 1902 by H. Kayser
Mary Mallon, also known as Typhoid Mary. In 1907, she
became the first American carrier to be identified and
traced. She was a cook in New York and was associated
with 53 cases and 3 deaths. Health authorities told Mary
to give up working as a cook or have her gall bladder
removed. She was detained and quarantined after
another typhoid outbreak. She died of pneumonia after
26 years in quarantine.

6. Epidemiology
• Over 21.6 million cases of Typhoid annually
worldwide
• Over 2,00,000 deaths annually due to Typhoid
• Additional 5.4 million cases of Paratyphoid annually
• Indian subcontinent has the highest incidence of
the disease worldwide.
• Enteric Fever is endemic in India
• In India the incidence is 214.2/1,00,000/yr
• Age-Specific studies show that incidence in younger
children are higher (0-4y:2,730; 5-19y:1,170; 20-
40y:110 /1,00,000 per year)

8. Enteric Fever
is a collective term used for
Typhoid and Paratyphoid fevers.

9. • Typhoid fever is caused by Samonella enterica sub-
species enterica serovar Typhi (S. Typhi)
• Paratyphoid fever is caused by Samonella enterica sub-
species enterica serovar Paratyphi A, Paratyphi B (also
called S. schottmuelleri), Paratyphi C (also called S.
hirschfeldii)
• Belong to Enterobacteriaceae family
• Gram Negetive, Rod-shaped, non-spore-forming,
predominantly motile bacteria with and
peritrichous flagella
• Are chemoorganotrophs and facultative anaerobes.
Etiology

10. Antigenic Structure
• Salmonella posses following antigens on which
they are classified and identified:
1. Flagellar or H Antigen: present on the flagella
and is dual core heat labile protein. Strongly
Immunogenic. Agglutinate rapidly with antisera.
(Large, loose, fluffy clumps)
2. Somatic or O Antigen: phospholipid-protein-
polysaccharide complex. Integral part of cell wall.
Endotoxin. Heat Stable. Slow agglutination with
antisera (Compact, chalky, granular clumps)
3. Surface, Capsule or Vi Antigen: surface
polysaccharide antigen enveloping O antigen.
Heat labile. Act as Virulence factor. Poorly
immunogenic

12. Gram Staining of S. Typhi
S. Typhi showing
peritrichous flagella

13. Pathogenesis
• Humans are the only reservoir of S. Typhi and S.
Paratyphi A.
• S. Paratyphi B, and S. Paratyphi C also infect
dogs, cattle and poultry and can also transmit by
eggs or poorly cooked meat.
• Mode of Transmission : Feco-Oral Route (Most
Common). Less commonly urine of infected
person.
• Infectious Dose : 105 – 109 organisms.
• Incubation Period : usually 7 – 14 days (can be
upto 3 – 30 days depending upon the infecting
dose)

14. Ingestion of contaminated food or water
S. typhi reaches terminal ileum and invades gut mucosa
through specialized antigen-sampling cells known as M cells (Microform cells).
Within the Peyer patches in the terminal ileum. S. typhi is phagocytosed by
macrophages.
These macrophages then enter the mesenteric lymphoid system and then pass into
the blood stream via the lymphatics.
These bacteria are disseminated throughout the body and colonize the organs of
the reticuloendothelial system
They replicate within macrophages and are shed back into the blood, causing a
secondary bacteremia.

16. • The surface Vi polysaccharide capsular antigen found in
S. Typhi interferes with phagocytosis and an virulence
trait encoded by the PhoP regulon gives ability to survive
within macrophages after phagocytosis
• S. typhi avoids triggering of an early inflammatory
response in the gut and instead colonize deeper tissues
and organ systems.
• Produces an inflammatory response in the deeper
mucosal layers and underlying lymphoid tissue causing
hyperplasia of Peyer patches and subsequent necrosis
and sloughing of overlying epithelium.

17. • These ulcers can bleed but usually heal
without scarring or stricture formation.
• Inflammatory lesion may occasionally
penetrate the muscularis and serosa of the
intestine and produce perforation.
• The mesenteric lymph nodes, liver, and
spleen are hyperemic and generally have
areas of focal necrosis as well.
• A mononuclear response may be seen in the
bone marrow in association with areas of
focal necrosis.

18. Carriers
• The propensity to become a carrier follows the epidemiology
of gallbladder disease.
• Increasing with patient age and the antibiotic resistance of the
prevalent strains.
• Carriage are generally lower in children than adults.
• Types of Carriers:
– Convalescent carrier: passes bacilli in the excreta form
3weeks-3months after clinical cure of typhoid.
– Temporary carrier: passes bacilli in the excreta form 3months-
1year after clinical cure of typhoid
– Chronic faecal carrier: continues to pass bacilli intermittently in
the excreta at least one year after infection.
– Chronic urinary carrier: the renal pelvis is infected & bacilli
pass in urine

19. Clinical Features
• Mean age of onset in India is 10yrs.
• Onset is insidious and varies from a mild
illness with low-grade fever, malaise, and
slight, dry cough to a severe clinical picture
with abdominal discomfort and multiple
complications
• Presentation of typhoid may be more
dramatic in children younger than 5 yrs of
age, with comparatively higher rates of
complications and hospitalization.

20. Features of 1st week of illness
• Rising Step ladder type of fever, with chills but
rigors are rare
• Relative Bradycardia
• Dull, expressionless and toxic facies
• Dry skin with little sweating
• Coated tongue
• Musty, damp hay-like/baked bread like odour
• Vomiting
• Tender, doughy abdomen with slight guarding
• Constipation / Diarrhea (Pea Soup diarrhea)
• Occasionally minimal, non-productive cough
• Meningismus may occur early.

21. Dull, expressionless and toxic
facies
Coated Tongue
Pea Soup Stools

22. Features of 2nd week of illness
• Continuous High grade fever (39.5-40.5 C)
• Worsening of cough may occur
• Rose Spots
• Abdominal Pain and tenderness
• Soft tender splenomegaly
• Soft tender hepatomegaly

23. Rose Spots
• Faint salmon coloured macules on the trunk and
abdomen
• Appear in crops of 10-15
• First seen after 7-10 days of illness
• Last for upto 2-3 days
• Fades on pressure
• Difficult to see in dark-skinned children.

24. Features of 3rd week of illness
• Hepatosplenomegaly
• Intestinal bleeding or perforation
• Features of peritonitis
• Septic Shock
• Altered Sensorium
• In absence of acute complications or death,
symptoms gradually resolve over 2-4 weeks,
however, the illness may be associated with
malnutrition in a number of affected children

27. • Enteric fever caused by S. Paratyphi
organisms classically have a milder
course.
• However, there have been several
outbreaks of infection with drug-resistant
S. paratyphi A, suggesting that
paratyphoid fever may also be severe,
with significant morbidity and
complications

28. Complications
Gastrointestinal
Intestinal haemorrhage, perforation
Central nervous system
Encephalopathy, cerebral edema, subdural
empyema, cerebral abscess, meningitis,
ventriculitis, transient parkinsonism, motor neuron
disorders, ataxia, seizures, Guillain-Barré
syndrome, psychosis, optic neuritis
Hepatobiliary system
Cholecystitis, hepatitis, hepatic abscesses, splenic
abscess, peritonitis, paralytic ileus, acute
pancreatitis, splenic rupture

29. Pulmonary system
Pneumonia, empyema, bronchopleural
fistula, Bronchitis, pleural effusion,
pneumothorax
Cardiovascular system
Endocarditis, myocarditis, pericarditis,
arteritis, congestive heart failure, shock
Musculoskeletal System
Osteomyelitis, septic arthritis, Periostitis,
typhoid spine, muscular rupture, Psoas
abscess, gluteal abscess, cutaneous
vasculitis

30. Genitourinary system
Urinary tract infection, renal abscess, pelvic
infections, testicular abscess,
prostatitis, epididymitis, Glomerulonephritis,
pyelonephritis, cystitis
Haemopoeitic
Haemolysis, DIC, Hemophagocytosis
syndrome
Others
Bed sores, hypercalcaemia, decubitus
ulceration, abortion

31. Diagnosis
• Bacteriological diagnosis of enteric fever
consists of:
1. Isolation of the bacilli from patient (Culture)
2. Demonstration of antibodies in serum
(Serological)
3. Demonstration of typhoid antigen in serum or
urine (Serological)

32. Blood Culture
• Bacteremia occurs early in the disease
• Blood culture is positive in about
90% cases in 1st week
75% cases in 2nd week
60% cases in 3rd week
25% thereafter till subsidence of pyrexia
• Blood cultures rapidly becomes negative
on treatment with antibiotics.
Isolation of the bacilli from patient

33. Method of Blood Culture
• 5-10 ml of blood is collected and inoculated into a
culture bottle containing 50-100 ml of 0.5% bile broth.
• After incubation overnight at 37 oC, the bile broth is
sub cultured on MacConkey agar.
• Pale, non-lactose fermenting colonies that grow are
further subjected to biochemical tests.
• Salmonella will be motile, indole and urease negative
and ferment glucose, mannitol and maltose but not
lactose or sucrose.
• Typhoid bacillus will be anaerogenic while Paratyphoid
bacilli will form acid and gas from sugar.
• Further confirmation is done by slide agglutination of
the colonies
• Cultures should be declared negative only after the
broth is sub cultured every day for ten days.

34. MacConkey agar with LF and non-LF colonies

35. S. Typhi
Does not
fermet sugar to
produce acid
and gas
S.Paratyphi
Fermet sugar to
produce acid
and gas

36. • Other samples which can be cultured
1. Bone Marrow
2. Blood Clot
3. Feces
4. Urine
5. Bile
6. CSF
7. Pus from suppurative lesions
8. Sputum
9. Rose Spots

37. Wilson Blair Bismuth Sulphate Agar. Selective for S. Typhi

38. Demonstration of antibodies in serum
Widal Test
• This is a test for the measurement of H
and O agglutinins for typhoid and
paratyphoid bacilli in the patients sera.
• The antigens used in the test are the H
and O antigens of S. typhi and H antigens
of S. paratyphi A and B.
• Readymade Widal kits of stained antigen
are now available commercially for use

39. Interpreting the Widal Test
1. The agglutination titre will depend upon the stage of
the disease. Agglutinins usually appear by the end of
the first week and increases steadily till the third or
the fourth week, after which it declines gradually.
2. Demonstrating of a rise in titre of antibodies, by
testing two or more serum samples, is more
meaningful than a single test.
3. The result of a single test should be interpreted with
caution. It is difficult to lay down levels of significance
though it is generally stated that titres of 1/100 or
more of O agglutinins and 1/200 or more for H
agglutinins are significant.

40. 4. Agglutinins may be present on account of prior
disease, inapparent infection or immunization.
Therefore the mere presence of agglutinin in the
Widal test should not be taken as proof of typhoid
fever
5. Persons who have had a prior infection or
immunization may develop an anamnestic response
during an unrelated fever. This may be differentiated
by repetition of the test after a week. The anamnestic
response shows only a transient rise, while in entric
fever the rise is sustained.
6. Bacterial suspensions used as antigens should be
free form fimbria. False positive results may
otherwise occur.
7. Cases treated early with chloramphenicol may show
a poor agglutinin response.

41. Other test to detect circulating antibodies:
1. ELISA – e.g. Typhidot
Typhidot consists of a dot ELISA kit that detects IgM and IgG
antibodies against the outer membrane protein of S. typhi. The
typhidot test becomes positive within 2–3 days of infection and
separately identifies IgM and IgG antibodies. The most
important limitation of this test is that it is not quantitative and
result is only positive or negative.
2. Counterimmunoelectrophoresis(CIE)
3. Indirect Hemeagglutination

42. Demonstration of antigen in
serum/urine
1. Sensitized Staphylococcal coagglutination test.
2. PCR
Other investigations
• Results of other laboratory investigations are
nonspecific.
• CBC:
– Leukocytopenia in relation to the fever and toxicity. In younger
children leukocytosis is common and may reach 20,000-25,000
cells/μL.
– Thrombocytopenia: may be a marker of severe illness and
may accompany disseminated intravascular coagulopathy
• Liver function test results may be deranged, but
significant hepatic dysfunction is rare.

43. Differential Diagnosis
O t h e r S a l m o n e l l a I n f e c t i o n  GIT symptoms (V&D) are more
acute than the general
manifestations
 Pyrexia much lower and of shorter
duration
M a l a r i a  History of previous attacks
 More rapid onset
 Shivering and sweating
 High early pyrexia
 Relative infrequent abdominal
symptoms and signs
 Positive blood smear
I n f l u e n z a  More rapid onset
 High temperature,
 Severe sore throat and cough
 Absence of a palpable spleen and
rose spots.

44. B a c i l l a r y d y s e n t e r y  Acute onset
 Severe bloody diarrhea
 The signs and symptoms in
dysentery are usually abdominal
Typhus a n d o t h e r
r i c k e t t s i a l i n f e c t i o n s
 Acute onset
 High temperature at an early stage.
 Rigors are common
 Prostration is rapid.
 Rash is brownish red in colour, and
much more profuse and does not
fade on pressure.
 Leukocytosis
 Weil-Felix test becomes
significantly positive at about the
tenth day
Tu b e r c u l o s i s
( Ab d o m i n a l / P u l m o n a r y )
 The pyrexia and vague symptoms
and signs may be very similar.
 A chest X-ray, or laboratory
confirmation of typhoid, may be the
only sure method of diagnosis.
B r u c e l l o s i s  Onset tends to be more insidious.
 Painful joint is frequently present.

45. Treatment
• Majority of children with typhoid fever can be managed at home with oral
antibiotics and close medical follow-up for complications or failure of
response to therapy.
• Patients with persistent vomiting, severe diarrhea, and abdominal distention
may require hospitalization and parenteral antibiotic therapy.
• General Measure
– Adequate rest
– Adequate hydration
– correct fluid and electrolyte imbalance.
– Antipyretic therapy (Paracetamol 10-15 mg/kgevery 4-6 hr PO) should be
provided as required.
– Soft, easily digestible diet should be continued unless the patient has abdominal
distention or ileus.

46. Antimicrobials
• Traditional therapy with chloramphenicol or amoxicillin is
associated with relapse rates of 5-15% and 4-8%,
respectively
• Use of the quinolones and third generation cephalosporins is
associated with higher cure rates.
• The antibiotic treatment of typhoid fever is also influenced by
the prevalence of antimicrobial resistance. Emergence of
multidrug-resistant strains of S. Typhi (i.e., isolates fully
resistant to amoxicillin, trimethoprim-sulfamethoxazole, and
chloramphenicol) has necessitated treatment with
fluoroquinolones with cephalosporins as an alternative.
• The emergence of resistance to quinolones places
tremendous pressure on public health systems because
alternative therapeutic options are limited.
• Azithromycin may be an alternative antibiotic for children with
uncomplicated typhoid fever.

47. Guidelines for management of typhoid fever. WHO. July 2011

48. Dexamethasone (3 mg/kg for the initial dose, followed by 1 mg/kg every 6 hr
for 48 hr) is recommended for severely ill patients with shock, obtundation,
stupor, or coma;

49. Fluoroquinolones : A dilemma!!!
• The fluoroquinolone drugs are generally very well tolerated.
However, in some countries the use of fluoroquinolones is
relatively contraindicated in children because of concerns that
they may cause articular damage.
• There is now extensive experience in the use of these drugs
in large numbers of children with long term follow-up. Their
considerable benefits, particularly in areas where there
are no affordable oral alternatives, outweigh the putative
risk.
• The only known articular side effect is Achilles tendon rupture
in patients who are also taking corticosteroids, and this has
been reported only rarely.
• A Cochrane systematic review of the treatment of typhoid
fever also indicates that there is little evidence to support the
carte blanche administration of fluoroquinolones in all cases
of typhoid fever

50. Why Fluoroquinolones???
• High drug levels are achieved within the GI lumen
after oral administration  no need of isolation
• The MIC for most salmonella is extremely low
(<0.1mcg/ml)
• Bactericidal against Salmonella  low relapse
• Good Intracellular penetration  rapid onset and
high cure rate
• Ciprofloxacin is concentrated in the biliary tract, a
known site of persistent infection during chronic
carriage of salmonella  prevention of carrier
• Oral form and IV form are available  cheap

51. Treatment of Carriers
Drugs Duration Cure Rate
Amoxicillin or Ampicillin (100 mg/kg/d)
PLUS
probenecid (1 g orally or 23 mg/kg)
OR
TMP-SMZ (160- 800 mg twice daily)
6 weeks 60%
Ciprofloxacin (750mg twice daily)
OR
Norfloxacin (400mg twice daily)
28 days 80%
Cholecytectomy may be required in chronic cases not treated by
the above regimens and carriers with cholelithiasis
Guidelines for management of typhoid fever. WHO. July 2011

52. Prevention

53. Best prevention Scrub them off your hands

54. Simple hand hygiene and
washing can reduce several
cases of Typhoid

56. Vaccination
• Typhoid vaccination was part of India’s
national immunization program till 1985
• Types of Typhoid Vaccines
1. Whole cell inactivated typhoid/ paratyphoid
(TAB) Vaccine
2. Vi-capsular polysaccharide (Vi-PS) vaccine
3. live oral vaccine

57. Whole cell inactivated typhoid/ paratyphoid (TAB) Vaccine
• Type of Vaccine: Heat-inactivated phenol-
preserved whole-cell
• Protective Efficacy: 51-88%
• Age of vaccination: >6 mths of age
• Vaccination Schedule: 2 doses s.c 4 weeks apart
• Revaccination: 2 yrs
Discontinued due to side effects like fever, malaise,
local pain

58. Vi-capsular polysaccharide (Vi-PS) vaccine
• Type of Vaccine: Highly purified antigenic fraction of Vi antigen of
S. typhi
• Protective Efficacy: 55-72%
• Age of vaccination: >2 yrs of age
• Vaccination Schedule: single dose (25mcg of antigen) s.c. or i.m.
• Revaccination: 3yrs
 The vaccine is stable for 6 mths at 37ºC and for 2 yrs at 22ºC.
 It is not immunogenic in below 2 years of age and has no
immune memory
 Protection begins seven days after injection and maximum
reached at 28 days after injection

59. Live oral vaccine
• Type of Vaccine: live attenuated vaccine of Ty21a strain
• Protective Efficacy: 50-60%
• Age of vaccination: >6 yrs.
• Vaccination Schedule: 3 doses of enteric coated capsule(2-6
million bacteria) given on alternated days
• Revaccination:3yrs
 Antibiotics should not be given 3 days before and 7 days after
vaccination
 Protection starts from 10-14 days after 3rd dose.
 Also provides Herd Immunity
 Contraindicated in immunodeficiency

60. Newer Vaccines
• Vi-capsular polysaccharide conjugated with
Pseudomonas aeruginosa exotoxin A (Vi-rEPA)
• Vi-PS Conjugate Vaccine Conjugated with Tetanus
Toxoid (Pedatyph®) by Bio-Med Pvt. Ltd.
• Vi-polysaccharide conjugate vaccine conjugated
with Tetanus Toxoid from Bharat Biotech (Typbar-
TCV®)
• S. paratyphi A vaccine composed of the surface
O-specific polysaccharide conjugated with
tetanus toxoid

61. References
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3. Background document: The diagnosis, treatment and
prevention of typhoid fever. World Health Organization. May-
2003
4. Crump JA, Luby SP, Mintz ED (2004) The global burden of
typhoid fever. Bull World Health Organ 82:346-353.
5. Ghai Essential Pediatrics 8th Edition
6. Guidelines for managemet of typhoid fever. WHO. July 2011
7. Huang DB, DuPont HL: Problem pathogens: extra-intestinal
complications of Salmonella enterica serotype Typhi
infection, Lancet Infect Dis 5:341–348, 2005
8. K. D. Moudgil M.D., B. S. Narang M.D., Pathogenesis of
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62. 9. IAP guidebook on immunization 2013-2014
10. IAP Task Force Report: Management of Enteric Fever in Children.
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11. Manuela Raffatellu, R. Paul Wilson et al. Clinical pathogenesis of
typhoid fever. J Infect Developing Countries 2008; 2(4): 260-266.
12. Nelson Text of Pediatrics 19th Edition
13. Ochiai RL, Acosta CJ, Danovaro-Holliday MC et al. (2008) A study
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14. PG textbook of Pediatrics
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16. Victor Vaughan: A Biography of the pioneering Bacteriologist,
1851-1929 By Richard Adler
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63. Thank You…