Enteric fever or Salmonella Enterica serotype typhi is a viral infection that causes infection.

1. E N T E R I C
F E V E ( T Y P H O I D
F E V E R
JAMES LUKE GARLO JR,
BSc(H O N S ), MD, MLCPS
(INTERNAL MEDICINE)

2. OUTLINE
• Introduction
• Epidemiology
• Magnitude of the problem in Africa
• Etiology
• Risk Factors
• Pathogenesis
• Clinical Features
• Diagnosis
• Management

3. INTRODUCTION
• Enteric fever severe systemic illness characterized by fever and abdominal pain.
• The term "enteric fever" is a collective term that refers to both typhoid and
paratyphoid fever, and "typhoid" and "enteric fever" are often used
interchangeably.
• The term typhoid derived from the ancient Greek word for cloud, was chosen to
emphasize the severity and long-lasting neuropsychiatric effects among the
untreated.
• Typhoid thrives in conditions of poor sanitation, crowding, and social chaos.

4. EPIDEMIOLOGY
• Worldwide, enteric fever is most prevalent in impoverished areas that are
overcrowded with poor access to sanitation.
• South-central Asia, Southeast Asia, and southern Africa are regions with high
incidence of S. Typhi infection (more than 100 cases per 100,000 person-years)
• Enteric fever is more common in children and young adults than in older patients.
• Humans are the only reservoir for S. Typhi and S. Paratyphi A, thus a history of
travel to settings in which sanitation is poor or contact with a known typhoid case
or carrier is useful for identifying people at risk of infection outside of endemic
areas, although a specific source or contact is identified in a minority of cases.

5. EPIDEMIOLOGY
• Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000
population) and kills an estimated 200,000 people every year.
• With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term
febrile illness requiring a median of 6 days of hospitalization
• It has no racial predilection.
• Most documented typhoid fever cases involve school-aged children and young adults.
• There is often a seasonal pattern in endemic areas, with transmission starting at the end
of the dry season when water is sparse and sanitation may be poor, and continuing into
the rains, when infected water may be easily dispersed.

6. THE PROBLEM IN AFRICA
• Salmonella infections are among the commonest bacterial isolates from blood cultures
throughout Africa.
• Most cases are in Asia, but typhoid remains endemic in some areas of Africa, and
epidemics are also reported.
• Invasive non-typhoid salmonella (NTS) infections, a long-standing and common cause of
illness and death in African infants and children, have further increased among children
and significantly increased among adults as a result of the HIV epidemic.
• Whenever an African patient has few signs, yet is ill with a fever, invasive Salmonella
infection (either typhoid or non-typhoid) is high on the list of differential diagnoses.

7. ETIOLOGY: MICROBIOLOGY
• The organism classically responsible for the enteric fever syndrome
is S. enterica serotype Typhi (formerly S. typhi).
• S. enterica serotype Typhi causes disease only in humans; it has no
known animal reservoir.
– Infection therefore implies direct contact with an infected individual or
indirect contact via contaminated food or water.
• Salmonellae are Gram-negative, motile, facultatively anaerobic
bacilli, which produce acid on glucose fermentation, reduce nitrates
and do not ferment lactose.

8. ETIOLOGY: MICROBIOLOGY
• Others S. enterica serotypes also called typhoidal salmonella that
cause enteric fever include
– Salmonella paratyphi A, Salmonella paratyphi B, Salmonella Paratyphi C
• Infection due to S. Paratyphi species is less common than infection
due to S. enterica serotype Typhi.
– S. Paratyphi only causes disease in humans.
– S. Paratyphi species are generally thought to cause milder illnesses than S.
Typhi

9. RISK FACTORS
• Typhoidal salmonella have no nonhuman/animal vectors.
• Oral transmission via food or beverages handled by an often asymptomatic
individual—a carrier—who chronically sheds the bacteria through stool or, less
commonly, urine.
• Oral transmission via sewage-contaminated water or shellfish (especially in the
developing world)
• Paratyphi is more commonly transmitted in food from street vendors.
– It is believed that some such foods provide a friendly environment for the microbe.
• Hand-to-mouth transmission after using a contaminated toilet and neglecting
hand hygiene.

10. RISK FACTORS
• Typhoidal salmonella can survive a stomach pH as low as 1.5.
• Anything that decreases stomach acidity many facilitate S typhi
infection.
– Antacids
– histamine-2 receptor antagonists (H2 blockers)- Ranitidine, cimetidine
– proton pump inhibitors- Omeprazole
– gastrectomy
– Achlorhydria
• Genetic Polymorphisms: PARK2 and PACGR
• Evidence of prior Helicobacter pylori infection (an association probably
related to chronically reduced gastric acidity).

11. PATHOGENESIS
• Salmonellae must survive the acidic barrier in the stomach and then
colonize the small intestine (distal ileum).
• A relatively high inoculum (105) organisms or more is needed to
overcome the barrier imposed by low gastric pH (acidity).
• In general, the greater the infectious dose, the higher the attack rate
and the shorter the incubation period
• If gastric acid is reduced, for example, by achlorhydria or acid
suppressive medication (omeprazole), a lower infecting dose than 105
is required.

12. PATHOGENESIS
• The entry of S. Typhi into the epithelial cell of the small bowel appears to be
mediated by the cystic fibrosis transmembrane conductance regulator (CFTR)
protein.
– mutations in cystic fibrosis transmembrane conductance receptor (CFTR), which is
expressed on the gut membrane decreases susceptibility to enteric fever.
– 2% to 5% of white persons are heterozygous for the CFTR mutation
• After invading and crossing the gut epithelial cells, the bacteria are taken up by
phagocytic mononuclear cells which lie on the basal surface of the gut
epithelium and are transported to the Peyer’s patches and other local mucosa-
associated lymphoid tissue (MALT) of the small intestine/bowel.

13. PATHOGENESIS
• The infection disseminates from the small bowel, via the
lymphatics, to the reticuloendothelial system including the
bone marrow, spleen and liver, where a chronic infection is
established.
• This primary phase of small bowel infection is rapid and
causes no more than a mild transient enterocolitis in a few
cases.

14. PATHOGENESIS
• Salmonellae survive and replicate intracellularly in tissue
macrophages during an incubation period of approximately 5–
21 days after primary infection, then the infection becomes
bacteremia and typically presents with fever.
• Organisms may be seeded to other sites during bacteremia,
especially damaged or abnormal tissue in the renal tract,
endothelium, bone and joints, or biliary system, where
metastatic infections may arise.

15. PATHOGENESIS
• Organisms that reach the gallbladder may persist and re-enter the gut in
bile, setting up a later secondary small bowel infection.
• Unlike the mild primary infection, this secondary infection causes
severe Peyer’s patch inflammation, which is the basis of both the
abdominal symptoms and late complications that occur in some cases
of typhoid fever, and the basis of high-level shedding and person-to-
person transmission of typhoid fever.

16. CLASSIC TYPHOID FEVER SYNDROME
• The most prominent symptom is prolonged fever (38.8°–40.5°C; 101.8°– 104.9°F),
which can continue for up to 4 weeks if untreated.
– The fever rises progressively in a stepwise fashion.
• Over the course of the first week of illness, a wide variety gastrointestinal
symptoms of the disease develop:
– Abdominal Pain: Diffuse abdominal pain and, in some cases, fierce colicky right upper
quadrant pain.
– Constipation: Inflamed Peyer patches narrow the bowel lumen to the point of causing partial
obstruction that may persist for the duration of the illness.
• If untreated the individual may develop a dry cough, dull frontal headache,
delirium, and severe malaise associated with marked stupor.

17. CLASSIC TYPHOID FEVER SYNDROME
• Seven to ten days into the illness, the fever plateaus at 103-104°F (39-
40°C).
• The patient develop Rose Spots, salmon-colored, blanching, truncal,
maculopapular lesions that are 1-4 cm wide and fewer than 5 in
number.
– These generally resolve within 2-5 days.
– They are caused by bacterial emboli to the dermis.
• During the second week the signs and symptoms listed above progress.
– The abdomen becomes distended, and soft splenomegaly is common.
– Relative bradycardia and dicrotic pulse (double beat, the second beat weaker
than the first) may develop.

18. CLASSIC TYPHOID FEVER SYNDROME
• In the third week, the still febrile individual grows more toxic and anorexic
with significant weight loss.
• The conjunctivae are injected, and the patient is tachypneic with a thready
pulse and crackles over the lung bases.
• Abdominal distension is severe, and some patients experience foul, green-
yellow, liquid diarrhea (pea soup diarrhea).
• The individual may descend into the typhoid state, which is characterized by
apathy, confusion, and even psychosis.
• Necrotic Peyer patches may lead to bowel perforation and peritonitis. This
complication is often unheralded and may be masked by corticosteroids.
• At this point, overwhelming toxemia, myocarditis, or intestinal hemorrhage
may cause death.

19. CLASSIC TYPHOID FEVER SYNDROME
• If the individual survives to the fourth week, the fever, mental state,
and abdominal distension slowly improve over a few days.
• Intestinal and neurologic complications may still occur in surviving
untreated individuals.
• Weight loss and debilitating weakness last months.
• Some survivors become asymptomatic S typhi carriers and have the
potential to transmit the bacteria indefinitely.

20. TREATED TYPHOID FEVER SYNDROME
• If appropriate treatment is initiated within the first few days of full-
blown illness, the disease begins to remit after about 2 days, and the
patient's condition markedly improves within 4-5 days.
• Any delay in treatment increases the likelihood of complications and
recovery time.

21. CHRONIC CARRIERS
• Chronic Salmonella carriage is defined as excretion of the
organism in stool or urine >12 months after acute infection.
–Rates of chronic carriage after S. Typhi infection range from 1 to 6
percent
• Chronic carriers appear to reach an immunologic
equilibrium in which they are chronically colonized
(usually in the biliary tract) and may excrete large numbers
of organisms but do not develop clinical disease

22. CHRONIC CARRIERS
• Chronic carriage occurs more frequently in females and in
patients with cholelithiasis or other biliary tract
abnormalities
• Chronic carriage in the urine is rare and almost always
associated with an abnormality in the urinary tract (eg,
urolithiasis, prostatic hyperplasia) or concurrent bladder
infection with Schistosoma

23. DIAGNOSIS
• Enteric fever in Africa is frequently over-diagnosed, largely based
on the Widal test, which has significant limitations.
• The possibility of enteric fever should be considered in a febrile
patient living in, traveling from, or visiting from an endemic area.
• Duration of fever for more than three days or accompanying
gastrointestinal symptoms (abdominal pain, diarrhea, or
constipation) should heighten the suspicion.

24. DIAGNOSIS
• Culture: The criterion standard for diagnosis of typhoid fever has long been
culture isolation of the organism. Cultures are considered to be 100% specific.
• A high volume of blood sampled (eg, two to three 20 mL blood cultures in
adults) optimizes the yield of blood cultures.
• Other specimens can be cultured, including bone marrow, which yields the most
sensitive culture but is invasive and usually not warranted..
• Thus, when cultures are negative or not available, as in some resource-limited
settings, the diagnosis of enteric fever is often made presumptively based on a
protracted febrile illness without other explanation.
• Empiric therapy is often appropriate in the absence of an alternative diagnosis
because of the risk for severe sequelae with untreated enteric fever

25. DIAGNOSIS
• Specific serologic test:
• The Widal test, Tubex test, Typhidot test, ELISA test
• Assays that identify Salmonella antibodies or antigens support the
diagnosis of typhoid fever, but these results should be confirmed
with cultures or DNA evidence.

26. DIAGNOSIS
• The Widal test was the mainstay of typhoid fever diagnosis for decades.
– It is used to measure agglutinating antibodies against H and O antigens of S typhi.
– Neither sensitive nor specific, the Widal test is no longer an acceptable clinical
method.
– Limited used in endemic areas because positive results may represent previous
infection.
– The minimum titers defined as positive for the O (surface polysaccharide) antigens
and H (flagellar) antigens must be determined for individual geographic areas;
they are higher in developing regions than in the United States

27. DIAGNOSIS
• The Widal test:
– Positive after 7-10 days of infection. O and H antigens are found.
– After that, the titers starts to fall.
– O-antigen appears before H-antigen.
– Rising O-antigen is very important for the diagnosis.
– Positive Widal is seen after vaccination, in the case of a previous
infection, or typhoid fever.

28. DIAGNOSIS
• Tubex, which measures immunoglobulin (Ig)M antibodies to S. Typhi
lipopolysaccharide, had sensitivity and specificity of 78 and 87 percent,
respectively.
• Typhidot, which measures IgM or IgG responses to an outer membrane
protein, had overall average sensitivity and specificity of 84 and 79
percent, respectively.
• ELISA: Anti-Vi antibodies are not useful for the diagnosis of acute illness

29. DIFFERENTIAL DIAGNOSIS
• Malaria
• Gastroenteritis
• Febrile illness
• Meningitis
• CAP

30. MANAGEMENT
• Treatment of enteric fever has been complicated by the development
and rapid global spread of typhoidal organisms resistant to ampicillin,
TMP-SFX and chloramphenicol.
• Additionally, development of increasing resistance to
fluoroquinolones and cephalosporins is a growing challenge.
• Enteric fever is usually treated with a single antibacterial drug.
• Fluoroquinolone, Azithromycin, third generations cephalosporins, and
carbapenems.
• Older drugs no longer used unless there's a proven susceptibility are
chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole.

31. MANAGEMENT
• In many parts of South Asia, over 80% of S. Typhi isolates among clinical cases
are non-susceptible to fluroquinolones even though few years prior it was a
drug that was proven to be highly successful in treating S. Typhi.
• Fluroquinolone resistant isolates have been reported in Nigeria and rates are
rising in Africa.
• In some cases, these resistant isolates have been classified as a subclass of the
multidrug resistant (MDR) H58 typhoid strain that had widely disseminated
throughout Asia and some African countries

32. MANAGEMENT
• Multidrug resistant strains (MDR) strains (ie, those resistant
to ampicillin, trimethoprim-sulfamethoxazole,
and chloramphenicol) are prevalent worldwide, though they
have been in decline as other antibiotics have been more widely
used for treatment of enteric fever.
• Because of this, ampicillin, trimethoprim-sulfamethoxazole,
and chloramphenicol fell out of favor as first-line agents for
treatment of enteric fever

33. MANAGEMENT
• Extensively drug-resistant (XDR) strains (ie, those resistant to
five antibiotics: ampicillin, trimethoprim-
sulfamethoxazole, chloramphenicol, fluoroquinolones, and
third-generation cephalosporins) has been described.
– Susceptible to azithromycin, carbapenems and tigecycline
• Most S. Typhi and S. Paratyphi isolates remain susceptible
to azithromycin and ceftriaxone, although resistant isolates have been
reported.
• Ceftriaxone resistance is increasing

34. MANAGEMENT
• Antibiotic selection depends upon the severity of illness, local
resistance patterns, whether oral medications are feasible, the clinical
setting, and available resources.
• The main options are fluoroquinolones, third-generation
cephalosporins, and azithromycin and carbapenems.
• In some circumstances, older agents such
as chloramphenicol, ampicillin, or trimethoprim-
sulfamethoxazole may be appropriate, but these drugs are generally
not used widely because of the prevalence of resistance.

35. MANAGEMENT
• Severe disease: For patients who have severe disease (eg,
systemic toxicity, depressed consciousness, prolonged fever,
organ system dysfunction, or other feature that prompts
hospitalization), initial therapy with a parenteral agent is
appropriate.
• The geographic region where infection was likely acquired
helps inform the choice of parenteral agent because of the
risk of resistance in certain locations

36. MANAGEMENT
• Surgical care is indicated in cases of intestinal perforation or
extraintestinal complications (arteritis, organ abscesses).
• If antibiotic treatment fails to eradicate the hepatobiliary
carriage, gall bladder can be resected.
• Patient should stay home and rest until full recovery.
• Wash hands and avoid preparing food for others during
course of illness.
• Dispose of feces and urine safely and properly.

37. MANAGEMENT: OTHERS
• Adjunctive corticosteroids for severe infection — For
patients with suspected or known enteric fever and severe
systemic illness (delirium, obtundation, stupor, coma, or
shock), we suggest adjunctive dexamethasone (3 mg/kg
followed by 1 mg/kg every 6 hours for a total of 48 hours)

38. MANAGEMENT: OTHERS
• Patients with ileal perforation — For patients with ileal
perforation, prompt surgical intervention is usually
indicated, as is broader antimicrobial coverage to cover
peritonitis and potential secondary bacteremia with enteric
organisms.
• The extent of surgical intervention remains controversial;
the best surgical procedure appears to be segmental
resection of the involved intestine, when possible

39. MANAGEMENT: OTHERS
• Relapse — Relapse of enteric fever after clinical cure can occur
in immunocompetent individuals; in such cases, it typically
occurs two to three weeks after resolution of fever.
• The risk of relapse depends on the antibiotic used to treat the
initial infection.
• Relapse rates are highest with chloramphenicol, a bacteriostatic
agent, (10 to 25 percent)
• Relapsed infection should be treated with an additional course
of antibiotics, guided by susceptibility testing..

40. MANAGEMENT: OTHERS
• Chronic carriers: Fluoroquinolone therapy
(eg, ciprofloxacin 500 to 750 mg orally twice daily
or ofloxacin 400 mg orally twice daily) for four weeks is a
reasonable approach.
• If eradication is not achieved but thought necessary from a
public health perspective, an additional prolonged antibiotic
course and cholecystectomy may be warranted

41. REFERENCES
• Harrison Principles and Practice of Medicine
• Uptodate clinical resource
• Principles of Medicine in Africa
• Medscape

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