Typhoid Fever Workup

  • Author: John L Brusch, MD, FACP; Chief Editor: Burke A Cunha, MD   more...
 
Updated: Sep 21, 2011
 

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 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.[31]
    • 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.[32]
    • 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% and may show positive results 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, 32, 33, 34] (Open Table in a new window)

IncubationWeek 1Week 2Week 3Week 4
Bone marrow aspirate (0.5-1 mL)90% (may decrease after 5 d of antibiotics)
Blood (10-30 mL), stool, or duodenal aspirate culture40%-80%~20%Variable (20%-60%)
Urine25%-30%, timing unpredictable
  • Polymerase chain reaction (PCR):[35, 36] 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.
  • 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,[37] are promising, but the success rates of these assays vary greatly in the literature.
  • Other nonspecific laboratory studies
    • 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 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.[38]
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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.
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Procedures

  • Bone marrow aspiration: The most sensitive method of isolating S typhi is BMA culture (see Lab Studies).
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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, 4 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, 6]

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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).[29]

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Contributor Information and Disclosures
Author

John L Brusch, MD, FACP  Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Thomas Garvey, MD, JD  Primary Care Physician, Burlington Medical Associates; Co-chair, Medical Advisory Committee for the Elimination of Tuberculosis

Thomas Garvey, MD, JD is a member of the following medical societies: American College of Legal Medicine, American College of Physicians, and American Society of Law, Medicine & Ethics

Disclosure: Nothing to disclose.

Roberto Corales, DO  Medical Director, Principal Investigator, AIDS Community Health Center

Roberto Corales, DO is a member of the following medical societies: American Medical Association, American Osteopathic Association, and International AIDS Society

Disclosure: Nothing to disclose.

Steven K Schmitt  MD, Staff Physician, Department of Infectious Disease, Cleveland Clinic

Steven K Schmitt is a member of the following medical societies: Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Martin J Wood, MD †  Former Consulting Staff, Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, UK

Martin J Wood, MD † is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, American Society for Microbiology, Infectious Diseases Society of America, International Society for Infectious Diseases, and Royal College of Physicians

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Richard B Brown, MD, FACP  Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine

Richard B Brown, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, and Massachusetts Medical Society

Disclosure: Nothing to disclose.

Eleftherios Mylonakis, MD  Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital

Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD  Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

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Life cycle of Salmonella typhi.
Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever[2, 26, 27, 28, 29, 30]
IncubationWeek 1Week 2Week 3Week 4Post
SystemicRecovery 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 feverVery commonaVery common
Acute high feverVery rareb
ChillsAlmost allc
RigorsUncommon
AnorexiaAlmost all
DiaphoresisVery common
Neurologic
MalaiseAlmost allAlmost allTyphoid state (common)
InsomniaVery common
Confusion/deliriumCommondVery common
PsychosisVery rareCommon
CatatoniaVery rare
Frontal headache



(usually mild)



Very common
Meningeal signsRareeRare
ParkinsonismVery rare
Ear, nose, and throat
Coated tongueVery common
Sore throatf
Pulmonary
Mild coughCommon
Bronchitic coughCommon
RalesCommon
PneumoniaRare (lobar)RareCommon



(basal)



Cardiovascular
Dicrotic pulseRareCommon
MyocarditisRare
PericarditisExtremely rareg
ThrombophlebitisVery rare
Gastrointestinal
ConstipationVery commonCommon
DiarrheaRareCommon (pea soup)
Bloating with tympanyVery common (84%)[30]
Diffuse mild abdominal painVery common
Sharp right lower quadrant painRare
Gastrointestinal hemorrhageVery rare; usually traceVery common
intestinal perforationRare
HepatosplenomegalyCommon
JaundiceCommon
Gallbladder painVery rare
Urogenital
Urinary retentionCommon
HematuriaRare
Renal painRare
Musculoskeletal
MyalgiasVery rare
ArthralgiasVery rare
Rheumatologic
Arthritis (large joint)Extremely rare
Dermatologic
Rose spotsRare
Miscellaneous
Abscess (anywhere)Extremely rareExtremely rareExtremely 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.



Table 2. Sensitivities of Cultures[2, 32, 33, 34]
IncubationWeek 1Week 2Week 3Week 4
Bone marrow aspirate (0.5-1 mL)90% (may decrease after 5 d of antibiotics)
Blood (10-30 mL), stool, or duodenal aspirate culture40%-80%~20%Variable (20%-60%)
Urine25%-30%, timing unpredictable
Table 3. Antibiotic Recommendations by Origin and Severity
LocationSeverityFirst-Line AntibioticsSecond-Line Antibiotics
South Asia, East Asia[45]



[48, 40]



UncomplicatedCefixime POAzithromycin PO
ComplicatedCeftriaxone IV or



Cefotaxime IV



Aztreonam IV or



Imipenem IV



Eastern Europe, Middle East, sub-Saharan Africa, South America[46, 49] UncomplicatedCiprofloxacin PO or



Ofloxacin PO



Cefixime PO or



Amoxicillin PO or



TMP-SMZ PO



or Azithromycin PO



ComplicatedCiprofloxacin IV or



Ofloxacin IV



Ceftriaxone IV or



Cefotaxime IV or



Ampicillin IV



or



TMP-SMZ IV



Unknown geographic origin or Southeast Asia[50, 45]



[48, 40, 46, 49]



UncomplicatedCefixime PO plus



Ciprofloxacin PO or



Ofloxacin PO



Azithromycin PO*
ComplicatedCeftriaxone IV or



Cefotaxime IV, plus



Ciprofloxacin IV or



Ofloxacin IV



Aztreonam IV or



Imipenem IV, plus



Ciprofloxacin IV



or



Ofloxacin IV



*Note that the combination of azithromycin and fluoroquinolones is not recommended because it may cause QT prolongation and is relatively contraindicated.
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