Approach
Fever in a patient with the appropriate travel history should raise the suspicion of typhoid as a diagnosis. Characteristic physical findings (e.g., bradycardia, rose spots) may or may not be present and basic laboratory tests can assist in diagnosis. Definitive diagnosis depends on isolation of the organism, mainly from blood, while serological tests are still much less reliable. Key risk factors include: overcrowded living in endemic areas, poor sanitation/untreated water in endemic areas, poor personal hygiene in endemic areas, visiting endemic countries (e.g., Indian subcontinent, Mexico), travel to areas with poor sanitation within endemic countries, ignoring hygiene rules while travelling in endemic countries, and longer duration of stay in an endemic country.
Signs and symptoms
The hallmark of typhoid infection is fever. Classically, the temperature rises incrementally during the first few days in a step-wise fashion after which a persistent fever, with a temperature of 39°C to 41°C (102°F to 106°F), is established. This is accompanied in many patients with prostration and an apathetic-lethargic state (the so-called 'tuphos' of the ancient Greeks, the source of the terms typhus and typhoid). This typical persistent fever, however, is not frequently noted, probably due to the wide use of antipyretics.
Patients typically present after the onset of fever with influenza-like symptoms including chills (although rigors are rare), a dull frontal headache, malaise, anorexia, and nausea, but with few physical signs. Cough is a relatively frequent symptom, while secondary pneumonia is a rare occurrence. In the majority of cases, abdominal signs and symptoms eventually appear. These include abdominal pain, constipation, diarrhoea, nausea, and vomiting. Again, the exact percentage of patients with diarrhoea due to typhoid infection is hard to establish, because other gastrointestinal coinfections may exist.
Physical examination hardly aids the clinician in establishing the diagnosis, because all patients are febrile and the temperature pattern is rarely diagnostic. The examination occasionally reveals relative bradycardia, but this sign is neither universal nor diagnostic. Rose spots (blanching erythematous maculopapular lesions usually 2-4 mm in diameter) are reported in 5% to 30% of cases.[Figure caption and citation for the preceding image starts]: Rose spots on the chest of a patient with typhoid feverCDC/Armed Forces Institute of Pathology, Charles N. Farmer; used with permission [Citation ends].
[Figure caption and citation for the preceding image starts]: Rose spots on abdomen of a patient with typhoid feverCDC/Armed Forces Institute of Pathology, Charles N. Farmer; used with permission [Citation ends].
They usually occur on the abdomen and chest and are easily missed in dark-skinned patients. In one study that compared Salmonella typhi to S paratyphi in travellers, rose spots were not found in S paratyphi infection.[31] Hepatomegaly and splenomegaly may exist.
Laboratory tests
Diagnosis of enteric fever can be difficult due to the often non-specific nature of symptoms, overlap with other febrile illnesses and relatively poor sensitivity of diagnostic tests. For a definitive diagnosis of typhoid and paratyphoid (enteric) fever, the World Health Organization recommends bacterial isolation from blood cultures or bone marrow cultures.[1][57] Bone marrow cultures are more sensitive (up to 90%) but in clinical practice blood cultures are the mainstay of diagnosis given the invasive nature of bone marrow sampling.[58] Increased sensitivity of bone marrow culture compared with blood culture is due to higher bacterial concentration in bone marrow.[57] Sensitivity of blood cultures is widely acknowledged to be sub-optimal with estimates ranging between 40% and 87%.[58][59] It should be noted that most of the studies reporting lower blood culture sensitivity were carried out before modern blood culture media and continuously monitored blood culture instruments were available and generally used low volumes of blood for culture. New techniques are likely to show higher sensitivities.[57][60]
Because the number of bacteria in the blood in typhoid patients is usually low, it is important that an adequate volume of blood is taken for culture.[61] One systematic review and meta-analysis examining factors affecting blood culture sensitivity identified a significant, although modest, relationship between specimen volume and blood culture sensitivity. The authors estimate that blood culture as a typhoid diagnostic method increases from 51% for 2 mL of blood to 65% for 10 mL, or by 3% for each additional millilitre.[58] Other factors influencing sensitivity of blood cultures include pre-treatment with antibiotics and duration of illness at the time of sampling. The optimum time for blood culture is considered to be in the first or second week of the illness, although cultures can still remain positive in the third week in the absence of antimicrobial exposure.[57]
In areas of endemicity where antimicrobials are frequently started prior to definitive diagnosis, sensitivity from blood culture can be as low as 40%. In these circumstances bone marrow culture provides a higher chance of recovery of the organism (up to 90%).[57][62] The organism may also be cultured from a biopsy sample of the rose spots, which has been reported to be positive in 70% of patients, although in practice rose spots are rarely present.[57]
Stool culture may occasionally be positive even when blood culture is negative, especially if it is taken more than 1 week after the beginning of the fever. S enterica may be isolated from faeces in up to 30% of patients especially if more than one sample is taken.[57] Because prolonged stool carriage of S typhi occurs, a positive stool culture is interpreted with caution and the diagnosis is established only when accompanied by a typical clinical setting. This limitation does not hold true for travellers originating from non-endemic countries. Urine culture might also be positive after the first week of the infection, although its sensitivity is much less than stool culture (isolated in <1% of patients with typhoid fever).[57]
The Widal’s test, which is now over 100 years old, measures antibodies against O and H antigens of S typhi. Low specificity and sensitivity decreases its diagnostic utility. In addition, prior typhoid vaccination may cause a positive test.[63] In general, the Widal's test is not considered a reliable test and is not recommended.[59]
There is a need for a quick and reliable diagnostic test that supersedes the Widal's test. The optimal test should approach 100% in sensitivity, specificity, and positive and negative predictive values, with the need for a single acute sample only. In addition it should have the capacity to diagnose both S typhi and S paratyphi. To this end, a number of new tests are being developed. However, a Cochrane review found that rapid diagnostic tests have only moderate diagnostic accuracy.[64]
Biochemistry and haematology laboratory tests are important though are non-specific. Mild liver function abnormalities are common, with transaminase levels often 2 to 3 times the upper limit of normal. Leukopenia and thrombocytopenia occur, but are neither universal nor diagnostic, and may occur in other tropical diseases such as dengue and malaria.[59] In younger children leukocytosis is a common finding.[59]
Antimicrobial susceptibility testing is needed for all confirmed infections to guide treatment.
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