Typhoid fever in children for medical students and doctors

1. - Dr. Lokanadha Reddy M V
Consultant Paediatrician
Sreenika children’s clinic
Bangalore
ENTERIC
FEVER/TYPHOID
FEVER

2. Salmonellosis - Why?
• Common and widely distributed
• Global major public health problem
• Affecting millions
• Food borne disease
• Significant mortality

3. ETIOLOGY
• Salmonella enterica serovars (Gm -ve)
• Typhi (S.Typhi) - Most common
• Paratyphi - very similar but less severe
• A
• B (Schotmulleri)
• C (Hirschfeldii)
• Disease ratio 10:1 (Typhi : Paratyphi)

4. EPIDEMIOLOGY
• 26.9 Million typhoid cases/year worldwide (80%)
• 1% mortality MC in Asia
• 5.4 Million paratyphoid cases/year (20%)
• 12 Million DALY
• More in children < 5 years, of incidence,
complications and hospitalisation

5. • Gram-Negative Facultative Rods
• Family - Enterobacteriaceae, like E.Coli
• Habitat - Intestinal tract of warm and cold blooded
animals
• Causes 2 diseases
• Enteric fever - Bloodstream infection
• AGE - Food-borne infection
MICROBIOLOGY

6. Gm -ve
Rods
Flagellated
Motile
Produce H2S
on thiosulphate

7. Enterobactiriaceae
• Eschericia Coli
• Shigella
• Citrobacter
Salmonella enterica
• Enterica (>99.5%)
• Salamae
• Arizonae
• Diarizonae
• Indica
• Bongori
• Houtenae
Family
Species
Subspecies
S.Typhi
S.Paratyphi A,B,C
Serovars

8. Somatic (O) /
Cell wall antigens
Surface
(Envelope)
antigens
Flagellar (H)
antigens
Heat stable
Alcohol resistant
May mask O
antigens
Heat labile
Used for
serological studies
Vi antigen occurs
in only 3 servers
Used for
serological studies
Typhi, Paratyphi C
and Dublin
Antigenic structure

9. Cultures: XLD agar
Blood agar
HE agar

10. • Exotoxins: Enterotoxin, Cytotoxin have role in
diarrhoeal symptoms
• Genetics: Plasmids in salmonella code for antibiotic
resistance
• Most specific gene products - Vi (virulence)
polysaccharide capsule, seen in 90% of S.Typhi and
has protective effect against bactericidal action of
serum of infected patients
• Antibiotic susceptibility: Resistance to Ampicillin,
streptomycin, chloramphenicol, sulphonamides.
Colistin resistance is not yet observed.
• DOC till 1972 was chloramphenicol. In 1972
chloramphenicol-resistant strains emerged.

11. EPIDEMIOLOGY
• Resistant to Ampicillin, chloramphenicol &
Cotrimoxazole
• Increased resistance to Nalidixic acid (Quinolone) and
Fluoroquinolones
• Mode of transmission: Ingestion of foods or water
contaminated with human feces, seafoods
contaminated with sewage water
• Risk factors : Antacids, PPI, H2 blockers - reduce
infective dose

12. PATHOGENESIS
Infective dose
105 -109
Gut mucosa -
terminal ileum
Street food
contaminated
water
M cells, Enterocytes
Paracellular route
Attaches to
microvilli & stays
in payers patches
Mesenteric lymph
nodes
Blood
(1o Bacteremia)
Asymptomatic, B/C -ve
Reticuloendothelial
system - replicates in
macrophages
Liver,
spleen,
GB,BM
Blood
(2o Bacteremia)
Clinical symptoms
End of Inc. Period
(4-14 days)
Down regulates host
inflammatory response
Re-exp. of PP via Bile
Pro-inflam. ck (IL-6,IL-1B,TNF-a) —> Fever
Enterotoxin, cytotoxin —> Diarrhoea
Host Risk factors : HIV, H.pylori

14. PATHOLOGICAL
CHANGES
INTESTINE:
• Hyperplasia of payers patches —> subsequent
necrosis and sloughing of overlying epithelium —>
Ulcers —>heal without scarring or stricture
• Occasionally ulcer may penetrate muscularis and
serosa causing intestinal perforation
MLN, LIVER, SPLEEN: Hyperaemic with focal necrosis
BM: Mononuclear response with focal necrosis

15. CLINICAL FEATURES
• IP : 7-14 days (3-30 days)
• Mild illness : Low-grade fever, malaise, slight dry cough
• Severe illness : Abdominal discomfort and complications
• Factors influencing severity : Duration of illness before initiating
correct therapy, choice of antibiotics, age, previous exposure or
vaccine, virulence of strain, infective dose, host immune factors
• More dramatic presentation & complications in < 5 years
• Infancy : Diarrhoea, toxicity, DIC, more fatality
• Rare in children : Relative bradycardia, neurologic
manifestations, GI bleeding (common in adults)

16. CLINICAL FEATURES

17. CLINICAL FEATURES
• Fever : Prolonged High grade (up to 105’F) with chills and rigors,
Initially low-grade at onset and rises gradually, classic step ladder
pattern is rare. Child is not active during inter-febrile period.
Unlike viral fever which peaks at the onset of fever.
• Rash : 25% have macular or maculopapular rash (rose spots) -
7th-10th day (2nd week), in crops of 10-15 on lower chest and
abdomen, lasting 2-3 days
• Hepatosplenomegaly : seen in 35% cases and 15% cases
respectively
• Malaise, dull headache, anorexia, nausea, abdominal discomfort,
coated tongue
• Bronchitis like picture in early days with rhonchi and crepitations

18. CLINICAL FEATURES
• Diarrhoea: With fever is a common presentation, classical
pea soup diarrhoea seen in early days.
• Later constipation ensues with mild abdominal distension,
diffuse tenderness and paralytic ileus. Early constipation may
be due to obstruction of hypertrophied payer’s patches.
• Atypical presentation in malaria endemic areas
• Multidrug-resistant Typhoid : more severe, more toxicity,
complications and mortality
• Usually resolves in 2-4 weeks
• Drug-resistant Paratyphoid also can be severe

19. COMPLICATIONS
• LIVER: Altered liver function is seen in many but
clinically significant jaundice, hepatitis and cholecystitis
are rare and a/w adverse outcomes
• INTESTINE: Hemorrhage (<1%) and perforation (0.5-
1%) are rare in children. Seen in 2nd-3rd week
• Perforation -> markedly increased abdominal
pain(RLQ), tenderness, vomiting, peritonitis features
like Tachycardia, hypotension, rigidity, guarding.
Rising TLC, left shift and free air in AXR are seen.
• TOXIC MYOCARDITIS: Rare, a/w arrhythmias,
Sinoatrial block, cariogenic shock

20. COMPLICATIONS
• CNS: uncommon in children. Delirium, psychosis,
raised ICT, Acute cerebellar ataxia, chorea, deafness,
GBS. Mortality is more(50%) but recovery is complete
with no sequelae. Called severe or complicated enteric
fever.
• OTHERS: Fatal BM necrosis, DIC, HUS,
pyelonephritis, nephrotic syndrome, meningitis,
endocarditis, parotitis, orchitis, suppurative
lymphadenitis
• CARRIER: Chronic carrier rates lower in children

22. DIAGNOSIS
• BLOOD CULTURE: Gold standard, positive in 40-
60% cases in 1st week. Sensitivity 90% in 1st week
to 40% in 4th week. Bile-broth media/BACTEC.
Sufficient blood 10ml in adults/5ml in children in 1:5
ratio of blood: media to be collected
• STOOL CULTURE: Positive after 1st week.
Occasionally positive in incubation period
• URINE CULTURE : Positive after 1st week
• BONE MARROW CULTURE: More sensitive but
invasive, may help in PUO evaluation

23. DIAGNOSIS
• CBC:
• TLC: Frequently low in relation to fever and toxicity like 4000-
5000 cells/uL, but a wide range is seen. In younger children
leukocytosis is common up to 20,000-25,000 cells/uL
• Eosinopenia, Neutrophilic predominance can be there
• PLT : Usually normal. Thrombocytopenia + Anemia is a marker
of severe illness and a/w DIC
• CRP : High, vs Low in dengue/viral fevers
• LFT : may be deranged but significant hepatic
dysfunction/jaundice is rare. AST/ALT may rise to 2-3 times

24. DIAGNOSIS
• WIDAL TEST : Measures antibodies against O and H antigens. Becomes
positive after 5 days of fever
• Lacks sensitivity and specificity in endemic areas
• Many false-positive and false-negatives occur
• Diagnosis of typhoid on widal alone is prone to error
• O titres - 1:160 -> acute enteric fever (appears early)
• H titres - 1: 160 -> Past infection/immunised(positive in recovery)
• Rising titres to four-fold are significant but its time-consuming process
• Positive results may represent previous infection
• Widal does not access Vi Antigens, so its not false positive for newer
vaccines but may be for classical TA vaccine.

25. DIAGNOSIS
• TYPHIDOT:
• A dot ELISA kit that detects IgM and IgG antibodies to OMP-
outer membrane protein
• Becomes positive in 2-3 days
• Sensitivity - 100% and specificity - 80%
• Limitation: Only Qualitative not quantitative like widal test
IgM IgG Interpretation
+ + Acute enteric fever
+ - Early acute infection
- + Past infection

26. DIAGNOSIS
• Newer tests using MABs directly detect S.Typhi
specific antigens in serum or Vi Ag in urine.
These are not proved efficient.
• Nested PCR using H1-d primers is promising and
provides rapid diagnosis.
• “BASU” - Blood culture, Agglutination (widal) test,
Stool culture and Urine culture in 1st, 2nd, 3rd
and 4th weeks.

27. DIFFERENTIAL
DIAGNOSIS
• ACUTE GASTRO-ENTERITIS
• BRONCHITIS, BRONCHO-PNEUMONIA
• MALARIA
• SEPSIS
• TUBERCULOSIS, BRUCELLOSIS, LEPTOSPITOSIS
• VIRAL FEVERS, DENGUE, ACUTE HEPATITIS,
INFECTIOUS MONONUCLEOSUS

28. TREATMENT
• Early diagnosis and appropriate treatment
• Vast majority can be managed at home with oral
antibiotics and close follow-up for complications or
failure of response to Rx
• Hospitalisation and IV antibiotics : Persistent
vomiting, severe diarrhoea, abdominal distension
• Adequate Rest, Hydration and correction of fluid
and electrolyte imbalance.

29. TREATMENT
• ISOLATION : should be nursed with precautions
• ANTIPYRETICS : Paracetamol 10-15mg/kg PO every 4-6
Hours. Ibuprofen can be used. Salicylates are
contraindicated - shock.
• DIET : Soft, easily digestible diet except in abdominal
distension or ileus
• ANTIBIOTICS : Critical to minimise complications
• STEROIDS: Dexa 3mg/kg ->1mg/kg Q6H x 48 hrs only in
cases of severely ill with shock, (CNS signs) obtundation,
stupor or coma. May mask abdominal signs.

31. TREATMENT
• CEFTRIAXONE :
• DOC for MDR typhoid as it is common
• Start 75-100 mg/kg/day OD/BD x 5-7 days
• Once afebrile, change to oral Cefixime x 10
days
• Superior to Cefotaxime because of its biliary
excretion (kills bacteria in GB)

32. TREATMENT
• CEFIXIME :
• 20 mg/kg/day in two doses orally x 10-14 days
for mild cases
• Can be used as follow up Rx for IV Ceftriaxone
• As a rule 1st/2nd gen. cephalosporins and
aminoglycosides are not useful in treatment

33. TREATMENT
• CHLORAMPHENICOL :
• 50 mg/kg/day orally x 14 days in areas without resistant bacteria
• IV is given only if oral intake is not possible as 75mg/kg/day
• SE: Bone marrow suppression rarely. Undetectable reticulocytes
gives the clue. “Gray baby syndrome”.
• Afebrile within 7 days of Rx
• If no response then unlikely to respond to Ampicillin, Amoxicillin,
Cotrimoxazole
• Used apart from Aztreonam/Cotrimoxazole, in patients with
penicillin or ceftriaxone allergy.

34. TREATMENT
• CIPROFLOXACIN :
• DOC for Adults and Children >12 years
• < 12 years can be given if ceftriaxone fails or in life-threatening cases
• Dosage: IV 20 mg/kg/day Q8-12H x 7-10 days
• Relatively safe in children
• If culture shows sensitivity to be downgraded to cipro because of lower
relapse rates
• AZITHROMYCIN :
• 20 mg/kg/day (double dose) x 5 days

35. PRACTICAL TIPS
• As a general rule treatment (Ceftraixone) is until 5-7
days after defervescence
• For any Rx response is slow and takes 3-7 days
• Do not give laxatives or enema for constipation -can
cause perforation
• Add Metronidazole and Aminoglycoside if perforation
or peritonitis is suspected
• Osteomyelitis or Meningitis - Rx for 4-6 weeks

36. PRACTICAL TIPS
• If eosinophils appear which were absent earlier, indicates
recovery
• Recovery signs : Subjective improvement, less toxic, improved
appetite, general feeling better, improved feel of abdomen - soft
and not distended, increasing interval between fever spikes, fever
responding better and faster to antipyretics, lower fever spikes
than earlier.
• If two antibiotics fail consider MDR typhoid. Stop the antibiotic
and observe for 2-3 days if child is not toxic and ill.
• Repeat physical examination, CBC, CXR may help in difficult
cases

37. PROGNOSIS
• Depends on age, early diagnosis and appropriate Rx, general
health, nutrition salmonella serotype and complications
• RELAPSE: Despite App. Rx 5-15% may have relapse after initial
clinical response. Milder illness. More with cephalosporins than
with Fluoroquinolones/Azithromycin
• Chronic Carriers : who excrete S.Typhi > 3 mo. <2% in children
and increases with age.
• Rx : Amoxicillin (100 mg/kg/day) with probenecid (30 mg/ kg/day)
or cotrimoxazole (10 mg/kg/day) for 6-12 weeks is recommended.
If the strain is nalidixic acid sensitive, quinolones for 28 days is
better
• A chronic urinary carrier is seen in schistosomiasis

38. • REFERENCES
• Nelson’s Textbook of pediatrics - 20th Edition
• OP Ghai Textbook of pediatrics - 8th Edition
• Santosh kumar manual of pediatric practice -
4th Edition
• Amdekar Lessons from grand rounds 2
• Todar’s textbook of bacteriology - online edition