Atypical Dengue Fever Mimicking Typhoid Fever in a College Student Traveler
Article Outline
To the Editor:
Dengue virus belongs to the family flaviviridae, a group of approximately 70 viruses, of which 30—6 commonly—have been associated with human disease. These are: dengue, yellow fever, West Nile encephalitis, St. Louis encephalitis, Japanese encephalitis, and tick-borne encephalitis. All are single-stranded RNA viruses that share common envelope proteins; which produces significant cross-reactivity.
Dengue virus has 4 subtypes, and infection with one subtype produces lifelong immunity to that subtype only. Subsequent reinfection with a second serotype has been implicated as a risk factor for increased disease severity and progression to dengue hemorrhagic fever and dengue shock syndrome. Serotype 3 is now the dominant strain currently circulating in Brazil.
Dengue fever is transmitted by mosquito vector, usually Aedes aegypti, although other Aedes species are potential vectors. A. aegypti has a worldwide distribution throughout most of the tropical and subtropical world, from 30° north to 20° south latitude. Dengue fever is largely a disease of urban centers, as the Aedes mosquito has adapted well to the city environment, with the dense human population providing stagnant fresh water supplies for mosquito breeding.
Humans are the reservoir of dengue fever. After biting an infected host, the mosquito remains infective for the rest of its life (average 2-8 weeks), potentially infecting multiple victims.1, 2
The World Health Organization estimates 50-100 million cases per year. The Pan American Health Organization reported 760,846 cases in 2007. Brazil alone had approximately 345,000 cases in 2006, and an average of 280,000 cases per year from 1981-2006. The rates of disease progression to dengue hemorrhagic fever range from 0.02% to 2%, with death rates of ∼10%.3
Dengue fever classically starts abruptly after a short 2-3 day incubation period, with fever, severe headache, malaise/fatigue, and severe arthralgia, that is, “break bone” fever. Headache and retro-orbital pain are characteristic, and fever is sometimes preceded by facial swelling. Fevers to 40.6°C (105°F) can occur for 5-7 days, accompanied by relative bradycardia. Patients then defervesce, only to have fever typically return days later (biphasic illness), that is, a “camelback fever” curve.1, 2, 4, 5, 6, 7
Bone marrow suppression is common, manifested by leukopenia and thrombocytopenia. Atypical lymphocytes are a constant feature of dengue fever. Serum transaminases are mildly elevated, and serum transaminases have a high negative predictive value arguing against the diagnosis of dengue fever.1, 2
Dengue fever can be diagnosed by demonstrating elevated dengue IgM (immunoglobulin M) enzyme-linked immunosorbent assay titers. Also diagnostic are convalescent titers demonstrating a 4-fold increase in IgG dengue titers.
Case Report
A 20-year-old woman was admitted to the hospital with a 1-week history of fever, evanescent truncal rash, nausea/vomiting, and diarrhea. The patient had just returned from a 3-week vacation in Brazil. Her symptoms began with a low-grade fever, a mild headache, and myalgia.
Over the next 3 days she developed temperatures to 39.4°C (103°F), and she returned to the Emergency Department for evaluation. She denied sore throat, stiff neck, cough, or skin rash. Her only medications were acetaminophen and ibuprofen for the myalgia. She reported recent travel to Brazil, where she had stayed in an apartment in Rio de Janeiro and had multiple mosquito bites. She denied any ill contacts, and denied eating any undercooked foods or unpasteurized dairy products. She was a college student in a long-term monogamous relationship. She did not smoke, drink alcohol, or use illicit drugs.
On physical examination, the patient was a well-appearing woman in no distress. At that time, she was afebrile. The sclerae were not icteric, and there was no conjunctival suffusion. The neck was supple, and the pharynx was without erythema or exudates. A questionable evanescent truncal rash was present. The cardiac examination was normal, and the lungs were clear. The abdomen was soft, with mild right upper quadrant tenderness to deep palpation.
Laboratory studies revealed a white blood cell count of 3.4 K/mm3 (PMNs = 32%, lymphoctes = 39%, monocytes = 17%, and atypical lymphocytes = 10%). The patient was not anemic, and her platelet count was 38 K/mm3. The erythrocyte sedimentation rate was 10 mm/h, and C-reactive protein was 5.97 (n < 3 mg/L). The laboratory tests were unremarkable except for mildly elevated transaminases, with a SGOT = 121 IU/L (n = 13-39 IU/L) and SGPT = 67 IU/L (n = 4-36 IU/L). The serum ferritin level was highly elevated at 1017 ng/mL (n = 10-187 ng/mL); serum amylase was normal and serum lipase was slightly elevated at 60 u/dL (n = 5-51 u/dL). Hepatitis A, B, C, and E virus serologies were negative. Chest radiograph was normal, and an abdominal sonogram revealed some perihepatic ascites. Computed tomography of the abdomen and pelvis revealed perihepatic ascites and periportal edema with gall bladder wall enhancement.
The patient became afebrile, and her gastrointestinal symptoms gradually subsided. Blood, urine, and stool cultures were negative. Malaria smears were negative, and her serum lactate dehydrogenase was normal. Her serum transaminases slowly normalized. Epstein-Barr virus (EBV) VCA titers were elevated (IgM = 1:158 and IgG). Cytomegalovirus titers were negative. Brucella, Q fever, and ehrlichiosis titers were negative. Yellow fever and febrile agglutinins also were negative. Dengue fever serology was positive, with an elevated IgM titer of 9.95 IU and an elevated IgG titer of 9.78 IU. Repeat dengue titers 1 month later revealed an elevated IgM titer of 7.51 IU and elevated IgG titer of 8.57 IU.
Discussion
Dengue fever is in the differential diagnosis in fevers in returning travelers from endemic dengue fever areas.1, 2, 8, 9 In adults, the differential diagnosis of fever in a returning traveler without localizing signs is most commonly limited to malaria or typhoid fever.10 Our patient initially complained of a mild headache and myalgias, unusual for mild dengue fever. She had an evanescent truncal rash, which was atypical for resembling the rash of EBV infectious mononucleosis (IM) dengue fever. Consistent with the diagnosis of dengue fever was nausea, vomiting, and mild epigastric pain.
Dengue is a biphasic illness whose fever is characterized by a “camelback” pattern with relative bradycardia.4, 5, 6, 7 When the patient was seen by the Infectious Disease service on her second hospital admission, her clinical presentation was primarily gastrointestinal, that is, typhoid fever consistent with another diagnostic consideration because she was a college student, was EBV IM. Her laboratory abnormalities included leukopenia, lymphocytosis, atypical lymphocytes, thrombocytopenia, and mildly elevated serum transaminases. Her mononucleosis spot test was negative; viral EBV VCA IgM titer was slightly elevated (1:158), raising the possibility of EBV IM, a reasonable diagnostic consideration in a young adult college student. However, the patient was not prominently fatigued and did not have bilateral posterior cervical adenopathy or splenomegaly typical of EBV IM. Because of her travel to Brazil, dengue titers were ordered and subsequently reported as positive. Her minimally elevated EBV IgM titer is best explained on the basis of cross-reactivity with dengue fever.
This case is instructive in reminding clinicians that dengue fever is an emerging infectious disease in the Americas and should be suspected, particularly in travelers returning from Brazil.3, 8, 9 The classic presentation of dengue fever is readily diagnosed clinically.1, 2 This case lacked the classic features of dengue, making diagnosis difficult. Typhoid fever and EBV IM were the most likely diagnostic possibilities. The most important nonspecific laboratory clues suggesting the diagnosis of dengue fever were leukopenia, lymphocytosis, atypical lymphocytes, and thrombocytopenia accompanied by mild elevations of the serum transaminases. Because the patient was a college student, the possibility of EBV IM was considered given her leukopenia, atypical lymphocytosis, and increased serum transaminases and evanescent truncal rash (Table). Because of her recent visit to Brazil, the diagnosis of dengue fever was entertained, prompting specific testing for dengue fever. In view of the recent increase in prevalence of dengue fever, clinicians should suspect dengue fever, particularly in travelers returning from Brazil who may present in a non-classic guise.
Table. Differential Diagnosis of Dengue Fever
| Clinical Findings | Dengue Fever | Malaria | Typhoid Fever | EBV Infectious Mononucleosis |
|---|---|---|---|---|
| Symptoms | ||||
 Apathetic affect | − | − | + | − |
| Severe headache | + | + | ± | − |
| Malaise/fatigue | ± | +⁎ | + | + |
| N/V/D | + | − | ± | − |
| Signs | ||||
| Relative bradycardia | + | − | + | − |
| Camelback (biphasic) fever | + | − | − | − |
| Conjunctival suffusion | + | − | − | − |
| Bilateral posterior cervical adenopathy | − | − | − | + |
| Hepatosplenomegaly | − | + | + | + |
| Truncal rash | +† | − | ±‡ | ± |
| Laboratory tests | ||||
| WBC count | ||||
| No/mild leukopenia | − | + | + | + |
| Moderate/severe leukopenia | + | − | − | − |
| Atypical lymphocytes | + | + | − | + |
| Thrombocytopenia | + | + | − | ± |
| Increased LDH | − | + | − | − |
⁎Between malarial paroxysms. |
†Characteristic scarlatinaform/sandpaper truncal rash. |
‡If present, rose spots. |
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Funding: None.
Conflict of Interest: The contributing authors do not have any conflict of interest in regard to this article.
Authorship: All authors had access to the data and played an important role in writing this manuscript.
PII: S0002-9343(08)01178-9
doi:10.1016/j.amjmed.2008.11.009
Published by Elsevier Inc.
