This document provides an overview of enteric fever (typhoid fever). It defines the disease as an acute, life-threatening illness caused by Salmonella typhi or paratyphi bacteria. It predominantly affects developing countries with poor sanitation. The disease spreads through ingestion of contaminated food or water. It describes the pathogenesis as the bacteria invading the intestines through Peyer's patches before spreading to the liver, spleen and bone marrow. Clinical features include sustained high fever, abdominal pain, diarrhea or constipation. Management involves taking a thorough history, physical exam, diagnostic tests like blood cultures, and treating with antibiotics.

1. ENTERIC FEVER
BY
Dr. Ernest Osemudiamen Salami,
Paediatrics Department,
Central Hospital,
Benin City.

2. OUTLINE
 Introduction
 Definition
 Epidemiology
 Aetiology
 Risk Factors
 Relevant Anatomy/Physiology
 Pathogenesis
 Pathophysiology
 Clinical Features
 Management
 History
 Examination
 Differential Diagnoses
 Investigations
 Treatment
 Prevention
 Prognosis
 Conclusion
 Reference

3. INTRODUCTION
 Enteric fever is also called typhoid fever.
 It is a public health problem, especially in the
developing nations, due to the poor sanitary
conditions that characterize these regions.
 It is a potentially fatal multi-systemic illness
 Notable for the emergence of drug resistance

4. DEFINITION
 Typhoid fever is an acute, life threatening infectious
disease characterized by:
 High fever
 Rose colored spots on the chest or abdomen
 Abdominal pain
 Occasionally, intestinal bleeding

5. EPIDEMIOLOGY
 Typhoid fever occurs worldwide, but primarily in
developing nations where the sanitary conditions
are poor.
 It is endemic in Asia, Africa, Latin America, the
Carribean, and Oceania.
 Roughly 21.6 million new cases of enteric fever occur
worldwide.
 It causes about 200 000 deaths per year; and these
deaths are predominant in children of school age or
younger
 A particular study done in a teaching hospital in
Nigeria gave an incidence of suspected typhoid of
30.5 per 1000 admission
 Male predilection: M:F =1.7:1

6. AETIOLOGY
 Salmonella species may be divided into:
 Typhoid Salmonella –
Salmonella enterica serotype typhi
Salmonella enterica serotype paratyphi;
S. paratyphi is further divided into –
 S. paratyphi A
 S. paratyphi B (Schotmulleri)
 S. paratyphi C (Hirschfeldii).
 Nontyphoid Salmonella – e.g. S. enteritidis, S.
typhimurium; they are implicated in gastroenteritis.

7.  Salmonella typhi/paratyphi is a gram negative,
non-lactose fermenting, flagellated (motile)
bacillus belonging to the Enterobacteriacea
family.
 They are facultative intracellular pathogens
 Both possess two antigens;
 Somatic (O) antigen
 Flagella (H) antigen
 S. typhi possesses in addition a Vi polysaccharide
capsular antigen. This accounts for its greater
infectivity. It resists destruction by macrophages
even after phagocytosis.

8. S. typhi compared S. paratyphi causes:
 80% of all cases of enteric fever
 Runs a more severe course than that of its
counterpart.
 Requires a lower inoculum to cause an
infection compared to S. paratyphi.

9. RISK FACTORS
 Younger age group: Younger individuals are at an
increase risk of infection.
Reasons for this is that neonates and young infants
have:
 Hypochlorhydria
 Rapid gastric emptying.
 In infants who typically take fluids, the inoculum size
required to produce disease is also comparatively
smaller because of faster transit through the stomach.
 Underdeveloped geographical areas: Living in
regions of poor sanitary conditions i.e. the
underdeveloped nations of Africa, Asia, e.t.c…

10.  Poor sanitary conditions
 Poor hand hygiene
 Patronizing food vendors
 Unsanitary preparation of food
 Drinking unboiled/unpurified water
 Medical/Surgical history
 Previous gastrectomy
 H. pylori infection
 Use of antacids, H2 receptor blockers and PPIs
 Use of broad spectrum antibiotics
 Immunocompromised states
 HIV/AIDS
 Malnutrition
 Steroid therapy
 HbSS genotype
 Genetic resistance/susceptibility
 Cystic fibrosis patients may be resistant to the infection
 MHC-II, MHC-III

11. ANATOMY/PHYSIOLOGY
 The gastrointestinal tract (GIT) is made up of the mouth,
pharynx, oesophagus, stomach, duodenum, jejunum,
ileum, caecum, appendix, ascending, transverse,
descending and pelvic colon, rectum, anal canal, and
anus.
 There are the accessory organs of the GIT important for
digestion such as salivary glands, pancreas, liver and
gallbladder.
 The reticuloendothelial system (RES) (mononuclear
phagocyte system) is a network of connective tissue
fibers inhabited by phagocytic cells such as
macrophages ready to attack and ingest microbes.
 It is important for fighting infections and include the
lymph nodes, liver, spleen, bone marrow.

13. PATHOGENESIS
 Humans are the only reservoir of S.
typhi/paratyphi.
 The disease is contracted through the ingestion
of the organism in contaminated food or water.
 Infective dose is about 105 -109 organisms.
 On ingestion, the bacteria enter the stomach
and are able to survive in a pH as low as
1.5.

14.  With gastric emptying, they are propelled alongside with
gastrointestinal contents to the terminal ileum.
 At the terminal ileum, the bacteria use the flagella to
attach to the epithelium overlying Peyer patches,
 They are then phagocytized by the epithelial M cells by
a process known as bacteria mediated endocytosis
(BME)
 Enveloped within endocytic vesicles, these bacteria
are transported through the cytoplasm of the epithelial
cell to the basolateral membrane
 Here, they are presented to the macrophages within
the Peyer patches.

16.  The invasion of the Peyer patches produces an
inflammatory response in the deeper mucosal
layers and underlying lymphoid tissue,
 This leads to hyperplasia of Peyer patches and
subsequent necrosis and sloughing of overlying
epithelium leading to ulcerations
 The resulting ulcers bleed
 They usually heal without stricture formation or scarring.

17.  Within the macrophages, four things are
worthy of note about S. typhi;
 It evades immune recognition by other cells
using the Vi capsular antigen.
 It uses the macrophages as a vehicle to travel
undetected by the immune system
 It resists digestion by preventing implantation of
NADPH oxidase and NOS into the vacuole
membrane
 It employs the cell machinery for its reproduction.

18.  From the Peyer patches, S. typhi, still carried within
the macrophages enter the mesenteric lymphoid
system
 and then pass through the thoracic duct and other
lymphatics into the bloodstream.
 This is called primary bacteremia
 This primary bacteremia is transient and usually
asymptomatic

19.  This is because these bacteria are immediately
phagocytosed by macrophages in the RES.
 They colonize the
 gallbladder
 RES – the;
 liver,
 spleen,
 lymph nodes,
 bone marrow;
 where they continue to multiply within
macrophages.

20.  When a critical density is reached,
 the macrophages undergo apoptosis and rupture to
release the bacteria into the bloodstream a second
time.
 This is called secondary bacteraemia, and heralds
the onset of clinical symptoms.
 This bacteraemia spreads to other organs to cause
the extra-intestinal manifestations of the disease,
such as meningitis, endocarditis, pneumonia,
osteomyelitis, reactive arthritis, sepsis etc.

21.  The gallbladder is infected via either bacteremia or
direct extension of infected bile.
 The organism therefore re-enters the
gastrointestinal tract in the bile and re-infects the
Peyer patches (enterohepatic circulation)
 Bacteria that do not reinfect the host are typically
shed in the stool and are then available to infect
other hosts.
 This is how asymptomatic carriers transmit the
organism.

22. PATHOPHYSIOLOGY
 The incubation period ranges from 4 - 14 days,
depending on the inoculating dose of viable
bacteria.
 The clinical syndrome of fever and systemic
symptoms is produced by a release of
proinflammatory cytokines (IL-6, IL-1β, and TNF-α)
from the infected cells.
 Diarrhea is caused by
 A yet-uncharacterized cholera-like toxin (watery
diarrhea) and
 Sometimes also by ileal inflammation (mucous
diarrhea).

23.  Hyperplasia of Peyer patches and subsequent
inflammation(enteritis), necrosis and sloughing of
overlying epithelium results in ulcers,. These lead to
periumbilical abdominal pain, and sometimes
bloody stool.
 The periumbilical pain usually progresses to
become generalized due to additional colitis and
gastritis.

24.  Constipation is caused by
 Hyperplasia of the Peyer patches, and
 Inflammatory oedema
 Both of which cause a reduction in luminal size of the
intestine at the affected site.
 Necrosis of hyperplastic Peyer patches as it
overgrows its blood supply is what leads to
intestinal perforation.
 Anaemia may also be apparent and is caused by
 GI bleeding (intestinal haemorrhage)
 Haemolysis
 Transient bone marrow suppression

25. CLINICAL FEATURES
First Week
 Fever: The temperature rises slowly, usually has
stepladder pattern((i.e., fever rises one day, falls
the subsequent morning, and continues to form
peaks and troughs).
 Headache
 Cough
 Malaise

27. Second Week
 Fever becomes high grade, getting as high as 40°C
 Faget’s sign (sphygmothermic dissociation) may
be present at this stage. It is the unusual pairing of
fever with bradycardia. It may be absent in children.
 Abdominal pain – periumbilical, thereafter, becomes
generalized.
 Diarrhoea – there may be the typical “pea-soup”
stool which is khaki-green in colour.

29.  Constipation
 Hepatomegaly/splenomegaly or both.
 Altered sensorium – confusion and delirium may be
apparent
 Rose spots – rose coloured maculopapular or
papular blanchable rash
 located on the lower chest and upper abdomen.
 They may not be so obvious on dark-skinned
individuals.

31. Third Week – “Week of Complications”
 The patient becomes more toxic and anorexic
 Notable weight loss
 Chances of complications in the 3rd week are high.
 The intestinal complications that may occur
include:
 Intestinal perforation
 Intestinal haemorrhage

32. EXTRAINTESTINAL (INFECTIOUS) COMPLICATIONS
ORGAN SYSTEM PREVALENCE
(%)
COMPLICATIONS
Central nervous
system
3-35 Encephalopathy, cerebral edema,
meningitis, subdural empyema, cerebral
abscess, etc
Cardiovascular
system
1-5 Endocarditis, pericarditis, myocarditis,
congestive heart failure
Pulmonary system 1-6 Pneumonia, empyema
Musculoskeletal
system
<1 Osteomyelitis, septic arthritis
Hepatobilliary
system
1-26 Cholecystitis, hepatitis, hepatic abscesses,
splenic abscess, peritonitis, persistent
gallbladder carriage.
Genitourinary
system
<1 Urinary tract infection, renal abscess,
pelvic infections, testicular abscess,
prostatitis, epididymitis, persistent urinary
bladder carriage.

33. Fourth Week – “Week of Convalescence”
The fourth week of the illness is characterized by
gradual improvement, but in developing countries up
to 30% of those infected will die, and 10% of
untreated survivors will relapse.

34. MANAGEMENT

35. HISTORY
 Patients commonly present with high grade fever,
are usually very weak, with headache, abdominal
pain, loose stool, and sometimes constipation
 Onset and duration of illness: The duration of
symptoms is usually prolonged before presentation,
commonly up to a week or more
 Analysis of presenting complaints can help rule
out/rule in differentials and complications.

36.  History of the following is also important;
 Permanent residence,
 Travel history (travel to endemic and outbreak
areas)
 Food and water hygiene
 Socioeconomic status and lifestyle
 Past Medical and Surgical History
 Gastric surgeries
 Drugs that decrease gastric acidity

37. PHYSICAL EXAMINATION
 General examination
 Toxic and acutely ill looking
 May be malnourished
 High grade fever
 May be pale
 Usually dehydrated
 CNS examination
 Altered consciousness e.g. lethargy
 Signs of meningeal irritation

38.  Abdominal examination
 Uncomplicated cases
Rose spots
Distended
Movement with respiration
Periumbilical tenderness with guarding
Bowel sounds may be present
 Intestinal perforation
Guarding and rigidity
Does not move with respiration
Rebound tenderness+++
Bowel sounds may be absent.

39.  CVS examination
 Pulse
Bradycardia
May be dicrotic
May be fast and thready in shock – due to
diarrhoea and/or intestinal haemorrhage.
 Extremities may be cold and clammy
 BP
Normal, OR
Hypotension
 Auscultation – haemic murmur or S3 – if
there is anaemia.

40.  Respiratory system examination
 Tachypnoea
 Dyspnoea
 Crepitations – if complicated by bronchopneumonia
 Musculoskeletal system examination
 Limping while walking
 Swelling on the extremity
 Sinus discharge
 Bony tenderness – in osteomyelitis

41. DIFFERENTIAL DIAGNOSES
 Dysentery
 Acute appendicitis; pain precedes fever, perforated
typhoid ileitis looks more toxic
 Malaria
 Meningitis
 Bronchopneumonia
 Osteomyelitis
 Septic arthritis

42. INVESTIGATIONS
 Culture of the blood, stool, urine (mainstay of diagnosis,
but positive in 40-60% of cases)
 Blood culture – 1st week – gold standard for diagnosis
 Stool culture – 2nd week
 Urine culture – 3rd week
 Bone marrow culture –
 Merits
 Large number of organisms present here
 Highly sensitive up to 90%
 Remains sensitive in >50% of cases despite several days of
antibiotics
 Demerits
 Difficult to perform
 Invasive and extremely painful
 Expensive

43.  Full blood count –
 Leukopenia and relative lymphocytosis. Young children
may have leukocytosis
 Thrombocytopenia (a marker of severe illness)
 PCV may be low
 Widal test:
 It is a serological test which detects agglutinating
antibodies against the O and H antigens of S.
typhi/paratyphi.
 It is positive if there is a four-fold increase in the
antibody titres in two samples; or a single tire of
at least 1:160 for both O and H.

44. It has low sensitivity and specificity and hnce false-
positives are very common.
This is due to;
 Past infections
 Vaccinations
 Cross-reaction with the antigens of other
pathogens.
 Rapid diagnostic serological tests: These are
superior to widal test

45.  IDL Tubex test:
 Detects IgM antibodies against O polysaccharide
which develop during the clinical course of the illness.
 Hence, they are unaffected by previous infections or
vaccinations.
 The possibility of cross reactivity cannot be
completely ruled out
 Typhidot test:
 Detects IgM and IgG antibodies against a 50-kDa
outer membrane antigen.
 It has similar performance characteristics as IDL
Tubex assay.
 They are not recommended for the
diagnosis of enteric fever.

46.  Investigations to know the extent of the
disease
 Abdominal xray, erect and supine – may show
free gas in the peritoneal cavity
 Serum electrolytes; hyponatraemia, hypokalaemia
 Lumbar puncture

47. TREATMENT
 An early diagnosis of typhoid fever and institution of
appropriate treatment are essential.
 The vast majority of children with typhoid 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.

48.  The general principles of management include:
 Antibiotic therapy
 Fluid therapy
 Correction of electrolyte imbalance
 Antipyretic therapy
 Nutrition
 Adequate rest

49. ANTIBIOTIC THERAPY
(MMIDSP GUIDELINES)
 The choice of antibiotics is subject to individual preference and clinical
experience, as well as cost considerations and regional resistance
patterns
 For uncomplicated disease
 Drug of choice (DOC): Oral Cefixime @ 20mg/kg/day
 Second line agents include
 Azithromycin @ 10-20mg/kg/day
 Chloramphenicol @ 50mg/kg/day
 Amoxicillin
 Ciprofloxacin
 Cotrimoxazole
***
MMIDSP = The Medical Microbiology & Infectious Diseases Society of
Pakistan

50.  For severe/complicated disease
 Drugs of choice: IV Ceftriaxone/IV Cefotaxime @
100mg/kg/day
 Second line agents
 Chloramphenicol (in higher than usual doses)
 Cotrimoxazole (in higher than usual doses)
 Ciprofloxacin
 Aztreonam
 Parenteral antibiotic is continued until;
 Fever has resolved,
 Oral intake improved
 Complications resolved

51.  Thereafter, therapy can be switched to Oral
Cefixime to complete a total duration of 14days.
 Other drugs that can be used to complete therapy –
azithromycin, cotrimoxazole and amoxicillin.

52. INDICATIONS FOR SURGERY
 Surgical care is indicated if there is
Intestinal perforation.
Simple closure of the perforation OR
Small bowel resection (multiple perforations)
Cholecystitis not ameliorated by antibiotics
may need chlecystectomy.

53. PREVENTION
 Improved sanitation and provision of clean water.
 Travellers should avoid drinking untreated water.
 In endemic situations, consumption of street foods,
cut fruit, should be discouraged
 Attempts should be made to target food handlers
and high-risk groups for S. Typhi carriage
screening.

54.  Once identified, chronic carriers must be counseled
as to the risk for disease transmission and the
importance of handwashing
 Vaccination (gives partial protection);
recommended for those in endemic areas and
those travelling into such regions.
 Globally, 2 vaccines are currently available
An oral, live-attenuated preparation of the
Ty21a strain of S. typhi
An injectable inactivated preparation of the Vi
capsular polysaccharide of S. typhi

55. PROGNOSIS
The prognosis for a patient with enteric fever depends
on
 The rapidity of diagnosis and institution of appropriate
antibiotic therapy
 Patient’s age
 General state of health
 Nutritional status
 The causative Salmonella serotype
 Presence of complications.
 Infants and children with underlying malnutrition and
patients infected with multidrug-resistant isolates are
at higher risk for adverse outcomes.

56.  Despite appropriate therapy, 2-4% of infected
children may experience relapse after initial clinical
response to treatment. It is dependent on the
choice of drug therapy.
 Relapse rates are higher with the beta-lactams
such as ceftriaxone, amoxicillin as compared to the
fluoroquinolones and azithromycin.
 Individuals who excrete S. Typhi for ≥3 mo after
infection are regarded as chronic carriers.

57.  The risk for becoming a carrier is low in children
(<2% for all infected children) and increases with
age.
 The usual site of carriage is the gallbladder
 A chronic urinary carrier state can develop in
children with schistosomiasis or any other
abnormality of the urinary tract
 Those that shed the organism for < 3 mo after
onset of the acute illness are called convalescent
carriers

58. CONCLUSION
 Enteric fever has attained global distribution and is
an important cause of morbidity and mortality.
 Good knowledge of this infectious pathology is
important for early diagnosis and early initiation of
therapy in order to avert life threatening
complications.

59. THANK YOU FOR
LISTENING!

60. REFERENCE
 Nelson Textbook of Paediatrics, Robert M. Kliegman
 Ghai Essential Paediatrics, Vinrod K. Paul
 Clinical Textbook of Medicine, Parveen Kumar
 Davidson’s Principles and Practice of Medcine, Brian R.
Walker
 Textbook of Pathology, Harsh Mohan
 Park'sTextbook of Preventive and Social Medicine 23rd
Ed, K. Park
 Jawetz Medical Microbiology 26th Ed, Geo. F. Brooks
 https://emedicine.medscape.com/article/231135
 https://www.ncbi.nlm.nih.gov/books/NBK557513/