Approach Considerations
Any individual with asignificant febrile illness who has traveled to endemic areas or who has been exposed to a case of Typhoid should be ruled out for this disease.
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.
Culture
The criterion standard for diagnosis of typhoid fever has long been culture isolation of the organism. Cultures are considered 100% to be 100% specific.
Culture of bone marrow aspirate is 90% sensitive until at least 5 days after the start of antibiotics. it is quite painful and seldom utilized unless adequate cultures(see below ) were not obtained prior to starting empiric antibiotics. [38]
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. 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. Later in the illness, stool culture results are positive because of bacteria shed through the gallbladder.
Multiple blood cultures (>3) yield a sensitivity of 73%-97%. Large-volume (10-30 mL) blood culture and clot culture may increase the likelihood of detection. [39]
Stool culture alone yields a sensitivity of less than 50%, and urine culture alone is even less sensitive. Cultures of punch-biopsy samples of rose spots reportedly yield a sensitivity of 63% but may remain positive even after administration of antibiotics. 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.
Bone marrow aspiration and blood are cultured in a selective medium (eg, 10% aqueous oxgall) or a nutritious medium (eg, tryptic soy broth) and are incubated at 37°C for at least 7 days. Subcultures are made daily to one selective medium (eg, MacConkey agar) and one inhibitory medium (eg, Salmonella-Shigella agar). Identification of the organism with these conventional culture techniques usually takes 48-72 hours from acquisition.
Table 2. Sensitivities of Cultures [2, 39, 40, 41] (Open Table in a new window)
|
Incubation |
Week 1 |
Week 2 |
Week 3 |
Week 4 |
Bone marrow aspirate (0.5-1 mL) |
|
90% (may decrease after 5 d of antibiotics) |
|||
Blood (10-30 mL), stool, or duodenal aspirate culture |
40%-80% |
~20% |
Variable (20%-60%) |
||
Urine |
|
25%-30%, timing unpredictable |
|||
Polymerase chain reaction
Polymerase chain reaction (PCR) has been used for the diagnosis of typhoid fever with varying success. Nested PCR, which involves two rounds of PCR using two primers with different sequences within the H1-d flagellin gene of S typhi, offers the best sensitivity and specificity. Combining assays of blood and urine, this technique has achieved a sensitivity of 82.7% and reported specificity of 100%. However, no type of PCR is widely available for the clinical diagnosis of typhoid fever. [42, 43]
Specific serologic tests
Assays that identify Salmonella antibodies or antigens support the diagnosis of typhoid fever, but these results should be confirmed with cultures or DNA evidence.
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.
Indirect hemagglutination, indirect fluorescent Vi antibody, and indirect enzyme-linked immunosorbent assay (ELISA) for immunoglobulin M (IgM) and IgG antibodies to S typhi polysaccharide, as well as monoclonal antibodies against S typhi flagellin, [44] are promising, but the success rates of these assays vary greatly in the literature.
In summary, current laboratory tests possess suboptimal sensitivity and specificity. In addition, there are no validated diagnostic methods for detecting asymptomatic carriers. [45]
Other nonspecific laboratory studies
Since the sensitivity of cultures of blood, bone marrow, urine and stool vary with the duration of disease, various nonspecific tests have been studied regarding usefulness in diagnosing typhoid fever.
Most patients with typhoid fever are moderately anemic, have an elevated erythrocyte sedimentation rate (ESR), thrombocytopenia, and relative lymphopenia.
Most also have a slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT) and decreased fibrinogen levels.
Circulating fibrin degradation products commonly rise to levels seen in subclinical disseminated intravascular coagulation (DIC).
Liver transaminase and serum bilirubin values usually rise to twice the reference range.
Mild hyponatremia and hypokalemia are common.
A combination of absolute eosinopenia, elevated aspartate aminotransferase levels, and elevated C-reactive protein levels (>40 mg/L) have been shown to be a positive predictor of S typhi and S paratyphi bacteremia. [46]
A serum alanine amino transferase (ALT)–to–lactate dehydrogenase (LDH) ratio of more than 9:1 appears to be helpful in distinguishing typhoid from viral hepatitis. A ratio of greater than 9:1 supports a diagnosis of acute viral hepatitis, while ratio of less than 9:1 supports typhoid hepatitis. [47]
Imaging Studies
Radiography: Radiography of the kidneys, ureters, and bladder (KUB) is useful if bowel perforation (symptomatic or asymptomatic) is suspected.
CT scanning and MRI: These studies may be warranted to investigate for abscesses in the liver or bones, among other sites.
Procedures
Bone marrow aspiration: The most sensitive method of isolating S typhi is BMA culture (see Lab Studies).
Histologic Findings
The hallmark histologic finding in typhoid fever is infiltration of tissues by macrophages (typhoid cells) that contain bacteria, erythrocytes, and degenerated lymphocytes. Aggregates of these macrophages are called typhoid nodules, which are found most commonly in the intestine, mesenteric lymph nodes, spleen, liver, and bone marrow but may be found in the kidneys, testes, and parotid glands. In the intestines, four classic pathologic stages occur in the course of infection: (1) hyperplastic changes, (2) necrosis of the intestinal mucosa, (3) sloughing of the mucosa, and (4) the development of ulcers. The ulcers may perforate into the peritoneal cavity.
In the mesenteric lymph nodes, the sinusoids are enlarged and distended by large collections of macrophages and reticuloendothelial cells. The spleen is enlarged, red, soft, and congested; its serosal surface may have a fibrinous exudate. Microscopically, the red pulp is congested and contains typhoid nodules. The gallbladder is hyperemic and may show evidence of cholecystitis. Liver biopsy specimens from patients with typhoid fever often show cloudy swelling, balloon degeneration with vacuolation of hepatocytes, moderate fatty change, and focal typhoid nodules. Intact typhoid bacilli can be observed at these sites. [2, 4]
Staging
The proper treatment approach to typhoid fever depends on whether the illness is complicated or uncomplicated. Complicated typhoid fever is characterized by melena (3% of all hospitalized patients with typhoid fever), serious abdominal discomfort, intestinal perforation, marked neuropsychiatric symptoms, or other severe manifestations. Depending on the adequacy of diagnosis and treatment, complicated disease may develop in up to 10% of treated patients. Delirium, obtundation, stupor, coma, or shock demands a particularly aggressive approach (see Treatment). [36]
-
Life cycle of Salmonella typhi.
Tables
|
Incubation |
Week 1 |
Week 2 |
Week 3 |
Week 4 |
Post |
Systemic |
Recovery phase or death (15% of untreated cases) |
10%-20% relapse; 3%-4% chronic carriers; long-term neurologic sequelae (extremely rare); gallbladder cancer (RR=167; carriers) |
||||
Stepladder fever pattern or insidious onset fever |
|
Very commona |
Very common |
|||
Acute high fever |
|
Very rareb |
|
|
||
Chills |
|
Almost allc |
||||
Rigors |
|
Uncommon |
||||
Anorexia |
|
Almost all |
||||
Diaphoresis |
|
Very common |
||||
Neurologic |
||||||
Malaise |
|
Almost all |
Almost all |
Typhoid state (common) |
||
Insomnia |
|
|
Very common |
|||
Confusion/delirium |
|
Commond |
Very common |
|||
Psychosis |
|
Very rare |
Common |
|
||
Catatonia |
|
Very rare |
|
|
||
Frontal headache (usually mild) |
|
Very common |
|
|
||
Meningeal signs |
|
Raree |
Rare |
|
||
Parkinsonism |
|
Very rare |
|
|
||
Ear, nose, and throat |
||||||
Coated tongue |
|
Very common |
|
|
||
Sore throatf |
|
|
|
|
||
Pulmonary |
||||||
Mild cough |
|
Common |
|
|
||
Bronchitic cough |
|
Common |
|
|
||
Rales |
|
Common |
|
|
||
Pneumonia |
|
Rare (lobar) |
Rare |
Common (basal) |
||
Cardiovascular |
||||||
Dicrotic pulse |
|
Rare |
Common |
|||
Myocarditis |
|
Rare |
|
|
||
Pericarditis |
|
Extremely rareg |
|
|
||
Thrombophlebitis |
|
|
|
Very rare |
||
Gastrointestinal |
||||||
Constipation |
|
Very common |
Common |
|||
Diarrhea |
|
Rare |
Common (pea soup) |
|||
Bloating with tympany |
|
Very common (84%) [37] |
|
|
||
Diffuse mild abdominal pain |
|
Very common |
|
|
||
Sharp right lower quadrant pain |
|
Rare |
|
|
||
Gastrointestinal hemorrhage |
|
Very rare; usually trace |
Very common |
|||
intestinal perforation |
|
|
|
Rare |
||
Hepatosplenomegaly |
|
Common |
||||
Jaundice |
|
Common |
||||
Gallbladder pain |
|
Very rare |
||||
Urogenital |
||||||
Urinary retention |
|
Common |
||||
Hematuria |
|
Rare |
||||
Renal pain |
|
Rare |
||||
Musculoskeletal |
||||||
Myalgias |
Very rare |
|||||
Arthralgias |
Very rare |
|||||
Rheumatologic |
||||||
Arthritis (large joint) |
Extremely rare |
|||||
Dermatologic |
||||||
Rose spots |
|
Rare |
||||
Miscellaneous |
||||||
Abscess (anywhere) |
|
Extremely rare |
Extremely rare |
Extremely rare |
||
a Very common: Symptoms occur in well over half of cases (approximately 65%-95%). b Very rare: Symptoms occur in less than 5% of cases. c Almost all: Symptoms occur in almost all cases. d Common: Symptoms occur in 35%-65% of cases. e Rare: Symptoms occur in 5%-35% of cases. f Blank cells: No mention of the symptom at that phase was found in the literature. g Extremely rare: Symptoms have been described in occasional case reports. |
||||||
|
Incubation |
Week 1 |
Week 2 |
Week 3 |
Week 4 |
Bone marrow aspirate (0.5-1 mL) |
|
90% (may decrease after 5 d of antibiotics) |
|||
Blood (10-30 mL), stool, or duodenal aspirate culture |
40%-80% |
~20% |
Variable (20%-60%) |
||
Urine |
|
25%-30%, timing unpredictable |
|||
