Typhoid Fever: Investigations and Treatment

Typhoid Fever: Investigations and Treatment

We continue our Back to College series on Typhoid Fever by bringing to your Typhoid Fever: Investigations and Treatment.

Laboratory Studies

The diagnosis of typhoid fever (enteric fever) is primarily clinical.

Importantly, the reported sensitivities of tests for S typhi vary greatly in the literature, even among the most recent articles and respected journals.


The criterion standard for diagnosis of typhoid fever has long been culture isolation of the organism. Cultures are widely considered 100% specific.

Culture of bone marrow aspirate is 90% sensitive until at least 5 days after commencement of antibiotics. However, this technique is extremely painful, which may outweigh its benefit.

Blood, intestinal secretions (vomitus or duodenal aspirate), and stool culture results are positive for S typhi in approximately 85%-90% of patients with typhoid fever who present within the first week of onset. They decline to 20%-30% later in the disease course. However, In particular, stool culture may be positive for S typhi several days after ingestion of the bacteria secondary to inflammation of the intraluminal dendritic cells. Furthermore, in the illness, stool culture results are positive because of bacteria shed through the gallbladder.

Multiple blood cultures (>3) yield a sensitivity of 73% to 97%. Large-volume (10-30 mL) blood culture and clot culture may increase the likelihood of detection. Additionally, Stool culture alone yields a sensitivity of less than 50%, and urine culture alone is even less sensitive. Furthermore, Cultures of punch-biopsy samples of rose spots reportedly yield a sensitivity of 63% and may show positive results even after administration of antibiotics. Moreover, a single rectal swab culture upon hospital admission can be expected to detect S typhi in 30%-40% of patients. S typhi has also been isolated from the cerebrospinal fluid, peritoneal fluid, mesenteric lymph nodes, resected intestine, pharynx, tonsils, abscess, and bone, among others.

Widal Test

This test measures agglutinating antibody levels against O and H antigens.The levels are measured by using doubling dilutions of sera in large test tubes. Usually, O antibodies appear on days 6-8 and H antibodies on days 10-12 after the onset of the disease.

The test is usually performed on an acute serum (at first contact with the patient). Moreover, at least 1 ml of blood should be collected each time in order to have a sufficient amount of serum. Furthermore, the test has only moderate sensitivity and specificity.

It can be negative in up-to 30% of culture-proven cases of typhoid fever. Additionally, this may be because of prior antibiotic therapy that has blunted the antibody response.

On the other hand, S. typhi shares O and H antigens with other Salmonella serotypes and has cross-reacting epitopes with other Enterobacteriacae, and this can lead to false-positive results. Furthermore, such results may also occur in other clinical conditions, e.g. malaria, typhus, bacteraemia caused by other organisms, and cirrhosis.

Principle of Widal Test:

Antibody in serum produce in the response to salmonella oraganisum,the kit contains antigen suspension that are killed bacteria and they were stained to enhance the reading of agglutination test.

The blue stained antigen are specific to the somatic antigen (O- Ag)

While the red stained antigen are specific to the flagella antigens (H- Ag).

Salmonella typhi O and H agglutinin titres > 1:80 and > 1:160 were considered to be significant with 88% sensitivity and 98% specificity respectively.

  1. Quantitaive slide test
  2. Qualitative tube test
  • Agglutinin starts appearing in serum by the end of 1st week with sharp rise in 2nd and 3rd week and the titre remains steady till 4th week after which it declines.
  • The titre of the patient serum using Widal test antigen suspensions is the highest dilution of the serum sample that gives a visible agglutination.


Slide Agglutination Widal Test

Add 1 drop of test sample (25µl) into each reaction circle labeled as O, H, AH, BH according to given antigen solution,and observe the agglutination.


Positive:  Agglutination within a minute | Negative: No Agglutination

New Diagnostic Tests: Current Status and Usefulness

There is a need for a quick and reliable diagnostic test for typhoid fever as an alternative to the Widal test.

  • Recent advances include the IDL Tubex® test marketed by a Swedish company, which reportedly can detect IgM O9 antibodies from patients within a few minutes.
  • Another rapid serological test, Typhidot®, takes three hours to perform. It was developed in Malaysia for the detection of specific IgM and IgG antibodies against a 50 kD antigen of S. typhi. A newer version of the test, Typhidot-M®, was recently developed to detect specific IgM antibodies only. It’s available in India.
  • The dipstick test, developed in the Netherlands, is based on the binding of S. typhi-specific IgM antibodies in samples to S. typhi lipopolysaccharide (LPS) antigen and the staining of bound antibodies by an anti-human IgM antibody conjugated to colloidal dye particles.
  • Tropical PCR – It can detect salmonella enteric serotype Typhi, Paratyphi A,B & C.It is
    • Sample: Blood, Bone Marrow, Urine, Stool, Serum
    • Sensitivity: 69-85%
    • Specificity: 98-100%



Definitive treatment of typhoid fever (enteric fever) is based on susceptibility. As a general principle of antimicrobial treatment, intermediate susceptibility should be regarded as equivalent to resistance.

Until susceptibilities are determined, antibiotics should be empirical for which there are various recommendations. The recommend combination treatment with ceftriaxone and ciprofloxacin when neither the sensitivities nor the geographical origin of the bacteria is known.

Oral rehydration therapy was rediscovered in 1960s. It provided a simple way to prevent many of the deaths of diarrheal diseases.

Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin. Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice. Cefixime is a suitable oral alternative.

Typhoid fever, when properly treated, is not fatal in most cases. Antibiotics, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin, and ciprofloxacin, have been commonly used to treat typhoid fever in microbiology. Treatment of the disease with antibiotics reduces the case-fatality rate to about 1%.

Without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly, abdominal symptoms and, occasionally, pneumonia. In white-skinned patients, pink spots, which fade on pressure, appear on the skin of the trunk in up to 20% of cases.

In the third week, untreated cases may develop gastrointestinal and cerebral complications. These complications may prove fatal in up to 10–20% of cases. The highest case fatality rates are reported in children under 4 years. Around 2–5% of those who contract typhoid fever become chronic carriers. This happens as Bacteria persist in the biliary tract after symptoms have resolved.


Dexamethasone may decrease the likelihood of mortality in severe typhoid fever cases. These cases are complicated by delirium, obtundation, stupor, coma, or shock if bacterial meningitis has been definitively ruled out by cerebrospinal fluid studies.

Surgical Intervention

Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefer simple closure of the perforation with drainage of the peritoneum. Additionally, Small-bowel resection is indicated for patients with multiple perforations.

If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Moreover, Cholecystectomy is not always successful in eradicating the carrier state because of persisting hepatic infection.


Gilman RH, Terminel M, Levine MM, Hernandez-Mendoza P, Hornick RB. Relative efficacy of blood, urine, rectal swab, bone-marrow, and rose-spot cultures for recovery of Salmonella typhi in typhoid fever. Lancet.