CLINICAL VIGNETTE

Typhoid Fever

Yvette Scott, M.D., and Ali Towfigh, M.D.

Case Report

A 61-year-old gentleman with a past medical history of gastroesophageal reflux disease and hyperlipi-demia presented to urgent care after returning from a 7-month stay in the Philippines. He complained of intermittent fevers, rash, nausea, diarrhea and headache which started approximately 5 to 6 months after his arrival to the Philippines. He admitted to occasional rectal bleeding with his episodes of diarrhea, along with vague abdominal discomfort and infrequent bouts of non-bloody emesis. He also reported at times feeling somewhat confused. He denied having respiratory or cardiac symptoms. The patient was hospitalized in the Philippines when his symptoms initially started and reports being diag-nosed with typhoid fever, which required intravenous fluid resuscitation and "antibiotics" (although he did not know which antibiotic he was given). The symptoms subsequently improved. However, after returning home a couple of weeks later, the above aforementioned symptoms recurred. The patient denied receiving any vaccinations prior to his travel.

On presentation, most of the history was obtained from the patient's wife due to the patient's state of being slightly confused. He was not ill-appearing and was alert and oriented to person, place and time but appeared apathetic. He was afebrile and hemody-namically stable. His examination was significant for a salmon-colored maculopapular rash located on his bilateral flank area, abdomen and bilateral axilla. The cardiac, pulmonary and abdominal examinations were within normal limits with no hepatomegaly. Computed tomographic scan of the head was normal. Pertinent laboratory results were as follows: sodium 126 mmol/L, potassium 3.19 mmol/L, chloride 92 mmol/L, carbon dioxide 19.7 mmol/L, magnesium

1.5 mmol/L, aspartate aminotransferase 100 U/L, alanine aminotransferase 125 U/L with a negative hepatitis panel. Given the electrolyte abnormalities, the patient was admitted to the hospital and was provided supportive care. During the first 24 hours of hospitalization, the patient became febrile and hemodynamically decompensated which required transfer to the intensive care unit. The patient was empirically started on ceftriaxone and flagyl after obtaining blood, urine and stool cultures. Urinalysis, chest x-ray, and abdominal ultrasonography were unremark-able. Blood cultures returned positive for Salmonella typhi, sensitive to ciprofloxacin and ceftriaxone, but resistant to amoxicillin and trimethoprim-sulfamethoxazole. Urine and stool cultures were negative. The ceftriaxone and flagyl was then switched to ciprofloxacin and the patient was discharged home once electrolytes normalized and patient was in stable condition. On follow-up outpa-tient visit, the patient reported complete resolution of his symptoms and return to his usual state of health.

Discussion

Typhoid fever is a systemic infection caused by the bacterium Salmonella typhi. Largely a disease of unsanitary conditions, most of the cases can be found in developing countries.¹ Typhoid fever is usually contracted by ingestion of water or food contaminated by the fecal matter or urine of a person excreting S typhi. According to global estimates, there are at least 21 million new cases of typhoid fever each year, resulting in 200,000 deaths.² In the United States, up to two-thirds of typhoid fever cases are travel-related, with those traveling to Southeast Asia being at 3 times higher risk than those visiting South America and 8 times higher than those visiting the Caribbean.³ This case illustrates one such traveler, who presented with a relapse after presumably being treated for typhoid fever.

Relapse occurs in 5% to 10% of patients, usually 2 to 3 weeks after resolution of fever.¹ The relapse is usually milder than the original episode, and the antibiotic susceptibility of the organism obtained during the original episode is usually the same as of the original isolate. Antibiotics most commonly used to treat typhoid include chloramphenicol, trimetho-prim-sulfamethoxazole, amoxicillin, third-generation cephalosporins, azithromycin, and fluoroquinolones. Relapse rates vary amongst these agents, with fluoro-quinolones having the lowest relapse rates and chlo-ramphenicol, the highest.¹ Furthermore, resistance is a significant problem for the previously designated first-line agents for treatment of typhoid, namely chloramphenicol, amoxicillin, and trimethoprim-sulfamethoxazole, as was the case in the patient described. Multidrug-resistant strains of S typhi are common in areas of Asia, and some of these even demonstrate reduced susceptibility to fluoro-quinolones. Nonetheless, there is strong evidence to suggest that fluoroquinolones are the most effective drugs for treatment of typhoid fever.¹ Published data indicate that fluoroquinolones are more rapidly effec-tive and produce lower rates of stool carriage than both chloramphenicol and trimethoprim-sulfamethox-azole.¹ However, these traditional first-line agents, including amoxicillin, remain appropriate for treat-ment of typhoid fever in regions where the disease is still fully susceptible to these drugs, and where fluo-roquinolones are not readily accessible or affordable. These drugs remain relatively inexpensive, widely available, and rarely associated with side effects.

Clinical manifestations and severity of typhoid fever vary. Though fever and gastrointestinal symptoms are typically expected, many patients may have a nonspe-cific illness not recognized clinically as typhoid fever.¹ The patient described in this case did have a recent history of typhoid fever and was therefore diagnosed with less difficulty, but this is not often the case. The differential diagnosis of typhoid fever is extensive and includes endocarditis, malaria, deep abscesses, encephalitis, influenza, infectious mononu-cleosis, lymphoproliferative disease, and connective-tissue disease. Given the myriad nonspecific symptoms and signs associated with typhoid fever, and the low incidence in developed countries such as the United States, elicitation of a travel history is crucial. Clinical manifestations of typhoid fever include fever, malaise, nausea, anorexia, headache, and myalgia. The patient may have constipation or diarrhea. Physical signs can include a tender abdomen, hepatomegaly, and splenomegaly. Rose spots, erythematous maculopapular lesions occurring typically on the chest and abdomen, have been reported in 5% to 30% of cases.¹ There may also be a history of intermittent confusion with one study reporting an incidence as high as 73%.⁴ Laboratory values may be consistent with electrolyte abnormali-ties typically caused by vomiting, diarrhea, and/or anorexia, and liver enzyme elevations of 2 to 3 times the upper limit of normal. Complications can occur in 10% to 15% of cases.¹ These include gastrointestinal bleeding (most common), intestinal perforation, encephalopathy, and shock, to name a few. Blood cultures are the standard method of diagnosis, being positive in 60% to 80% of cases.¹ Bone marrow culture is more sensitive, even in patients treated with antibiotics for several days. Stool cultures are positive in only 30% of patients with typhoid fever, but should nonetheless be obtained.

To prevent typhoid fever in U.S. patients traveling abroad, oral and injectable typhoid vaccines are avail-able. A recent Center for Disease Control study of typhoid fever patients in the U.S. found that in those cases related to travel, only 4% reported receiving typhoid vaccination,² which is exemplified by the patient in this case. The report concluded that typhoid vaccine should be considered even in those planning short-term travel to high-risk areas. Both forms of the vaccine have been shown to protect 50% to 80% of recipients, with adverse reactions being reported as rare.² Given that the vaccine does not confer immunity to 100% of recipients, typhoid fever should still be considered in vaccinated individuals returning from endemic regions.

Typhoid fever remains a disease of developing coun-tries where sanitary conditions are poor. In the United States, the majority of reported cases are related to travel to these endemic areas. Most of these cases can be prevented by administration of typhoid vaccine prior to travel. Once infected, patients may present with a variety of nonspecific symptoms and signs suggestive of a whole host of other possibilities. Thus, a travel history is an invaluable tool in diag-nosis of typhoid fever. Rapid diagnosis and treatment with effective antibiotics may help improve outcomes though relapse rates can be significant depending on the antibiotic chosen. Choice of antibiotic depends on culture susceptibility results. In cases where no culture is available, knowledge of the likely suscepti-bility given available global data may be helpful. Nonetheless, fluoroquinolones have proven to currently be the most effective drugs for treatment of typhoid fever.

REFERENCES

1. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Engl J Med. 2002; 347(22):1770-82.

2. Technical Information on Typhoid Fever, (Feb 2004). Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/typhoidfever_g.htm. Accessed April 20, 2005.

3. Mathieu JJ, Henning KJ, Bell E, Frieden TR. Typhoid fever in New York City, 1980 through 1990. Arch Intern Med. 1994 Aug;154(15):1713.

4. Ali G, Rashid S, Kamli MA, Shah PA, Allaqaband GQ. Spectrum of neuropsychiatric complications in 791 cases of typhoid fever. Trop Med Int Health. 1997 Apr;2(4):314-318.

Originally submitted on May 27, 2005