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Enteric (Typhoid) Fever

Typhoid and paratyphoid fevers, which are transmitted by the fecal–oral route, are important causes of fever in India, sub-Saharan Africa and Latin America. Elsewhere they are relatively rare. Enteric fevers are caused by infection with Salmonella typhi and S. paratyphi A and B. After a few days of bacteriaemia, the bacilli localize, mainly in the lymphoid tissue of the small intestine, resulting in typical lesions in the Peyer’s patches and follicles. These swell at first, then ulcerate and usually heal. After clinical recovery, about 5% of patients become chronic carriers; the bacilli may live in the gallbladder for months or years and pass intermittently in the stool and less commonly in the urine.
The disease was initially called typhoid fever because of its clinical similarity to typhus. However, in the early 1800s, typhoid fever was clearly defined pathologically as a unique illness on the basis of its association with enlarged Peyer’s patches and mesenteric lymph nodes. In 1869, given the anatomic site of infection, the term enteric fever was proposed as an alternative designation to distinguish typhoid fever from typhus. However, to this day, the two designations are used interchangeably

EPIDEMIOLOGY

In contrast to other Salmonella serotypes, the etiologic agents of enteric fever—S. typhi and S. paratyphi serotypes A, B, and C—have no known hosts other than humans. Most commonly, food-borne or waterborne transmission results from fecal contamination by ill or asymptomatic chronic carriers
A high incidence of enteric fever correlates with poor sanitation and lack of access to clean drinking water. In endemic regions, enteric fever is more common in urban than rural areas and among young children and adolescents. Risk factors include contaminated water or ice, flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill household contacts, lack of hand washing and toilet access, and evidence of prior Helicobacter pylori infection (an association probably related to chronically reduced gastric acidity). It is estimated that there is one case of paratyphoid fever for every four cases of typhoid fever, but the incidence of infection associated with S. paratyphi A appears to be increasing, especially in India; this increase may be a result of vaccination for S. typhi.

Characteristics of Salmonella

  • Motile, non-sporulating, non-encapsulating, gram negative rods.
  • Grow aerobically and are capable of facultative anaerobic growth.
  • Can be killed by heating to 54.4°C for 1 hour or 60°C for 15 minutes
  • Possesses somatic O antigen and flagellar H antigen.
  • Vi capsular antigen in S serotype Typhi interferes with phagocytosis by binding of C3 to the surface of bacterium.
  • Survival within the macrophages after phagocytosis determines virulence and encoded by phoP regulon.

PATHOLOGY OF TYPHOID 

  • Hyperplasia of Payer patches with necrosis and sloughing of overlying epithelium
  • Intestinal ulcers
  • Mucosa and lymphatic tissue of the intestinal tract are inflamed and necrotic
  • Ulcers heal without scarring- thus strictures and• Ulcers heal without scarring- thus strictures and intestinal obstruction virtually never occur
  • Hyperplasia of RES system with proliferation of mononuclear cells
  • Focal inflammation in form of abscess, septic arthritis, osteomylelitis, pyelonephritis, meningitis, endophthalmitis

 

Pathogenesis of Typhoid

Enteric Fever pathogenesis

CLINICAL COURSE OF ENTERIC FEVER

Enteric fever is a misnomer, in that the hallmark features of this disease—fever and abdominal pain—are variable. While fever is documented at presentation in >75% of cases, abdominal pain is reported in only 30–40%. Thus, a high index of suspicion for this potentially fatal systemic illness is necessary when a person presents with fever and a history of recent travel to a developing country.

The incubation period for S. typhi averages 10–14 days but ranges from 3–21 days,the onset may be insidious. depending on the inoculum size and the host’s health and immune status. The temperature rises in a stepladder fashion for 4 or 5 days with malaise, increasing headache, drowsiness and aching in the limbs.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. Constipation may be present, although in children diarrhoea and vomiting may be prominent early in the illness. The pulse is often slower than would be expected from the height of the temperature,  i.e. a relative bradycardia. At the end of the first week, a rash may appear on
the upper abdomen and on the back as sparse, slightly raised, rose-red spots, which fade on pressure. It is usually visible only on white skin. Cough and epistaxis occur. Around the 7th–10th day the spleen becomes palpable. Constipation is then succeeded by diarrhoea and abdominal distension with tenderness. Bronchitis and delirium may develop. If untreated, by the end of the 2nd week the patient may be profoundly ill.

S. paratyphi A is thought to cause milder disease than S. typhi, with predominantly gastrointestinal symptoms.

 

CLINICAL FEATURES OF ENTERIC FEVER

Signs

  • Rash (rose spot) – faint salmon –colored, blanching, maculopapular, trunk, chest -30% after the first week
  • Resolved after 2-5 days without leaving a trace.
  • Hepatosplenomegaly (3-6%)
  • Epistaxis
  • Relative bradycardia
GI Symptoms:
  • Diarrhea or Constipation

Neurologic Symptoms:

  • Meningitis, Guillain-Barré syndrome,Neuritis

Neuropsychiatric symptoms:

  • Muttering delirium or coma vigil with picking at bedclothes or imaginary objects

Late complications:
Gastrointestinal bleeding (10–20%) and intestinal perforation (1–3%) most commonly occur in the third and fourth weeks of illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer’s patches at the initial site of Salmonella infiltration.

complication of typhoid fever

Enteric fever complication

DIAGNOSIS

Since the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to be considered in any febrile traveler returning from a developing region, especially the Indian subcontinent, the Philippines, or Latin America. Other diagnoses that should be considered in these travelers include malaria, hepatitis, bacterial enteritis, dengue fever, rickettsial infections, leptospirosis, amebic liver abscesses, and acute HIV infection . Other than a positive culture, no specific laboratory test is diagnostic for enteric fever. In 15–25% of cases, leukopenia and neutropenia are detectable. Leukocytosis is more common among children, during the first 10 days of illness, and in cases complicated by intestinal perforation or secondary infection. Other nonspecific laboratory findings include moderately elevated liver function tests and muscle enzyme levels.

The definitive diagnosis of enteric fever requires the isolation of S. typhi or S. paratyphi from blood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions. The sensitivity of blood culture is only 40–80%, probably because of high rates of antibiotic use in endemic areas and the small quantities of S. typhi (i.e., <15 organisms/mL) typically present in the blood. Since almost all S. typhi organisms in blood are associated with the mononuclear-cell/platelet fraction, centrifugation of blood and culture of the buffy coat can substantially reduce the time to isolation of the organism but do not increase sensitivity.

Bone marrow culture is 55–90% sensitive, and, unlike that of blood culture, its yield is not reduced by up to 5 days of prior antibiotic therapy. Culture of intestinal secretions (best obtained by a noninvasive duodenal string test) can be positive despite a negative bone marrow culture. If blood, bone marrow, and intestinal secretions are all cultured, the yield is >90%. Stool cultures, while negative in 60–70% of cases during the first week, can become positive during the third week of infection in untreated patients.

Several serologic tests, including the classic Widal test for “febrile agglutinins,” are available. None of these tests is sufficiently sensitive or specific to replace culture-based methods for the diagnosis of enteric fever in developed countries. PCR and DNA probe assays to detect S. typhi in blood have been identified but have not yet been developed for clinical use.

Treatment: Enteric (Typhoid) Fever

Antibiotic Therapy for Enteric Fever in Adults
Indication Agent Dosage (Route) Duration, Days
Empirical Treatment
Ceftriaxonea 1–2 g/d (IV) 7–14
Azithromycin 1 g/d (PO) 5
Fully Susceptible
Ciprofloxacinb (first line) 500 mg bid (PO) or 400 mg q12h (IV) 5–7
Amoxicillin (second line) 1 g tid (PO) or 2 g q6h (IV) 14
Chloramphenicol 25 mg/kg tid (PO or IV) 14–21
Trimethoprim-sulfamethoxazole 160/800 mg bid (PO) 7–14
Multidrug-Resistant
Ciprofloxacin 500 mg bid (PO) or 400 mg q12h (IV) 5–7
Ceftriaxone 2–3 g/d (IV) 7–14
Azithromycin 1 g/d (PO)c 5
Nalidixic Acid–Resistant
Ceftriaxone 2–3 g/d (IV) 7–14
Azithromycin 1 g/d (PO) 5
High-dose ciprofloxacin 750 mg bid (PO) or 400 mg q8h (IV) 10–14
aOr another third-generation cephalosporin [e.g., cefotaxime, 2 g q8h (IV); or cefixime, 400 mg bid (PO)].bOr ofloxacin, 400 mg bid (PO) for 2–5 days.cOr 1 g on day 1 followed by 500 mg/d PO for 6 days.

Supportive Therapy

  • Steroid therapy is indicated in enteric fever with shock, obtundation, coma, or stupor (Dexamethasone 3mg/kg for initial dose followed by 1mg/kg Q 6H for 48 hours).
  • Fluid and electrolytes maintenance.
  • Tepid sponging for high fever.
  • Paracetamol.

 

REFERENCE
1.Harrison’s Principles of Internal Medicine, 18th Edition

2.Davidson’s Principles and Practice of Medicine, 21st Edition

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