International EM: Treating the World Traveler

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Typhoid and paratyphoid fevers are caused by Salmonella typhi and Salmonella paratyphi A,B and C. These organisms are distributed worldwide, but are most common in areas of poor sanitation and personal hygiene…

Treating the World Traveler
Typhoid and paratyphoid fevers are caused by Salmonella typhi and Salmonella paratyphi A,B and C. These organisms are distributed worldwide, but are most common in areas of poor sanitation and personal hygiene. In 1909 Sir William Osler estimated an incidence of 500,000 cases a year with 40,000 annual deaths in the US due to Typhoid fever. Although Typhoid fever is now rare in the US it is conservatively estimated that there are at least 12.5 million cases worldwide annually. Of these, 62% occur in Asia, 35% in Africa and up to 5% of patients will die from infection. Many of the challenges in controlling this illness are related to public health, but increasing resistance to chloramphenicol introduces a growing challenge to treatment, especially in the developing world. Emerging laboratory techniques may make the diagnosis of this illness easier.

Salmonella typhi and Salmonella paratyphi A,B and C are all anaerobic,Gram negative, flagellated bacilli. All possess an antigenic structure comprised of a lipopolysaccharide somatic surface antigen (O) and a flagellar antigen (H). S. typhi and S. paratyphi C usually possess a polysaccharide surface antigen (Vi) that coats the O antigen, protecting it from antibody attack.


Salmonella typhi and Salmonella paratyphi A and B only infect humans, almost exclusively by ingestion through the fecal-oral route. Infectivity is dose dependent. Contaminated food, water, milk, shellfish, food handlers, and flies all assist in the transmission of Salmonella species. Gastric acidity is protective, but any condition that decreases gastric acidity can increase the risk of infection. Salmonella are extremely hardy and can survive for weeks in dust, water, and in freezing and arid climates.


The initial ingestion of S.Typhi is followed by incubation of the organism in various tissues. Gastric acidity can protect against infection. After ingestion, S. Typhi multiplies in the lumen of the bowel, at which time stool cultures will be positive, although the patient will not yet be ill. Penetration through the intestinal mucosa follows, as organisms travel to the mesenteric lymph nodes, and then via the thoracic duct to the bloodstream (primary bacteremia). Organisms then infect the liver, spleen, and reticuloendothelial system, which marks the end of incubation period. Further multiplication and then massive release into the bloodstream (secondary bacteremia) is heralded by the onset of clinical symptoms. The secondary bacteremia results in the infection of multiple organs, and all organ systems can be infected.

Clinical Manifestations
The incubation period of typhoid fever varies from several days to greater than 3 weeks, averaging around 14 days. First week: Non specific symptoms, malaise, anorexia, gradually worsening fever, occasionally chills, headache, upper respiratory symptoms, cough, and hearing loss. Patients are often constipated in the first week.

Second week: Continued fever (relative bradycardia), toxic appearing, diarrhea, vomiting. Rose spots, 2-4 mm pink papules visible on the torso of fair-skinned individuals are seen in about 50% of patients. Abdominal pain and distension with hepatosplenomegaly may be present. Third week: Patient becomes increasingly toxic with high fever, delirium or coma the so-called “Typhoid state.” Diarrhea may have a  pea soup appearance. Multiplication of S. Typhi in Peyers patches of the small bowel may result in small bowel hemorrhage or perforation and peritonitis. Sepsis, anemia, leukopenia, pneumonia and myocarditis may also occur. Death may occur in untreated patients in the 3rd week of illness, usually from GI perforation, anemia, toxemia or occasionally meningitis. If the patient survives through the 4th week of illness and GI complications do not occur, fever, toxemia and abdominal symptoms abate over a few days.


Complications of Typhoid fever are numerous, and can occur at any time during the illness, even after a seemingly benign illness. Complications may be the presenting symptom or sign rather than the picture of typhoid fever. Complications include small bowel perforation, GI hemorrhage, hemolytic anemia (common in patients with G6PD deficiency), typhoid pneumonia, meningitis, glomerulonephritis, acute renal failure, nephrotic syndrome, arthritis, osteomyelitis, orchitis, hepatitis, acute cholecystitis, and parotitis. Abscesses may occur virtually anywhere in the body as late complication, most commonly in the liver, spleen, brain, breast and bone. Deep venous thrombosis and Guillane-Barre syndrome have been reported in association with Typhoid fever.


Diagnosis of typhoid fever is made by way of clinical suspicion, serologic studies, and culture techniques.  Unfortunately, the features of typhoid fever tend to be nonspecific, and a number of other causes need to be considered when encountering febrile illnesses.  Particularly in the tropics, malaria is one entity that can mimic this presentation.  Tuberculosis, brucellosis can mimic typhoid. Other illnesses to consider in the differential diagnosis of typhoid fever include malaria, dengue fever, endocarditis, brucellosis, tuberculosis, typhus, visceral leishmaniasis and other lymphoproliferative disorders.

Nonspecific hematologic and biochemical findings can lend support for the diagnosis. Leukopenia is common.  There is often a modest degree of hyponatremia, as well as a mild transaminitis.

In the initial workup of typhoid fever, blood, urine and stool cultures should be obtained, and repeated at least once if negative.  Stool and urine are most commonly positive in the second and third week of illness.  Blood cultures are most commonly positive early in the course of the disease.   The sensitivity of blood cultures ranges from 40-80% in most series.  It is reduced by prior antibiotic therapy and with inadequate blood volume when inoculating broth medium.  It can be increased by repeat cultures over time.  Buffy coat concentration and culture has been shown to increase sensitivity. 


Standard stool cultures have a sensitivity of only 30-40% when done by rectal swab.  Because of irregular shedding, it may be necessary to perform multiple stool cultures to make a diagnosis using this technique.  In addition to stool cultures, the diagnosis can be achieved by culturing intestinal contents that are collected on a duodenal string.  Sensitivities using this technique are reported to be 60-80%. 

Urine cultures are positive in the minority of patients, with a sensitivity of only 5-10%.  This positivity rate increased with coinfection with Schistosoma haematobium, whose association with typhoid fever has long been recognized. 

Although not commonly used for diagnosis, the organism has been reportedly cultured from CSF, peritoneal fluid, tonsils, lymph nodes, and tonsils.

The most successful culture technique is using samples obtained from bone marrow via needle aspiration.  These cultures approach a 90% sensitivity, even in patients already on antibiotic therapy.  It is usually not necessary to resort to this method to achieve a diagnosis. 

If bone arrow cultures are not obtainable, then a combination of culturing blood (8-15 mL), mononuclear cell buffy coat fractions, intestinal secretions, and stool, will together identify 85-90% of patients with typhoid fever. 

Serologic studies have been one of the standard diagnostic tools for decades, although they remain imperfect.  The Widal test, using the O, H, or Vi antigens, can offer support for the diagnosis of typhoid when there is a fourfold rise in antibody titer. 

However the test suffers from a low sensitivity and specificity.  Although not the most accurate tool, the Widal test remains simple and widespread in use in developing countries.  There are commercially available slide agglutination tests using the Widal technique, which is useful in some settings where more advanced diagnostic methods are not available.

The most advanced method to achieve diagnosis is using the polymerase chain reaction (PCR), using fragments of the flagellin gene (H1-d).  The sensitivity of this test approaches 100%, but is limited by its lack of availability in most clinical settings, even in developed countries.

Treatment and Prevention

Successful treatment requires rapid diagnosis, antibiotic administration, and supportive care.  With prompt treatment, mortality rates have been reduced from 10-15% to 1-4%. 

Chloramphenicol is the antibiotic most widely used worldwide for treating typhoid fever.  Tetracyclines and aminoglycosides are not effective against S. tyhi, although they may demonstrate in vitro activity.  Ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole have been successfully used to treat this entity.  However, in the past decade, flouroquinolones and third generation cephalosporins have been shown to be as effective as choramphenicol, and in the developed world have largely become the antibiotics of choice. 

In the past ten to fifteen years, outbreaks of multidrug-resistant typhoid fever (MDRTF) have been increasingly reported.  These generally include resistance to choramphenicol, trimethoprim-sulfamethoxasole, and ampicillin.  MDRTF is now endemic in Africa, Asia, Latin America, China, and India. 

Patients with MDRTF tend to have a more difficult course of illness and a higher mortality than those patients who have infections susceptible to the usual first line antibiotics (7-16% vs. 1-4%). 

In addition to antibiotic therapy and supportive care, studies have clearly demonstrated that corticosteroid administration reduces mortality in patients with severe typhoid fever.  It does not appear to increase the incidence of complications, relapse rate, or induction of a carrier state among those treated.

Prevention of typhoid fever is achieved with public health measures including clean water supplies, proper food preparation and refrigeration, as well as appropriate sanitation and personal hygiene. Treatment of chronic carriers, especially food handlers or those with schistosomal coinfection is also important.

TYPHOID FEVER//the basics
-Obtain a travel history
-Incubation period is 3-21 days
-Non-specific symptoms first week, toxic appearance second week
-On physical exam look for fever with relative bradycardia, Rose spots
-Diagnosis made by clinical suspicion, serologic testing and cultures
-Treatment is with fluoroquinolones, 3rd generation cephalosporins
-Always consider malaria in the differential diagnosis of a sick patient with a travel history
Essentials of Tropical Infectious Diseases, edited by R. Guerrant, D. Walker, P. Weller;  Chapter 15, Typhoid Fever, by Thong P. Le, Stephen L. Hoffman.  Churchill Livingston, 2001.


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