No information reported for this week.

B. The Johns Hopkins Hospital. Information provided by Dr. May Arroyo, Department of Pathology.

Case presentation: A sexually active 28 year old male with no significant past medical history presented with a four day history of fever (104^o F), frontal headache, eye pain aggravated by eye movement, and musculo-skeletal pain. In addition, he reported a non-pruritic rash on his arms and torso of one day duration. Travel history was significant for recent arrival from a one week trip to a Caribbean island. On physical exam, the patient was febrile (102^oF) with lymphadenopathy, a blanching diffuse maculopapular rash, and a small number of petechiae on the arms. Laboratory findings included a white blood cell count of 3,500 cells/mm3, and a platelet count of 105,100. The patient was symptomatically treated and discharged to home. Serologies were pending at the time of discharge.

Organisms: The serum of the patient tested positive for dengue IgM and negative for dengue IgG. Dengue virus is the etiologic agent of dengue fever and a member of the Flaviviridae family of RNA viruses. Four serologically related dengue viruses have been identified (types 1-4). Infection with one serotype confers immunity to that homologous serotype but not to the other types. Dengue virus infects cells of the mononuclear phagocyte lineage. Viral infection and replication has been shown to be enhanced in the presence of antibody against other heterotypes or subneutralizing concentrations of homotypic antibody, presumably by enhancing the penetration of virions via FcR-mediated uptake of antibody-coated viral particles (1,2). The virus somehow escapes lysosomal breakdown and escapes into the cytosol where viral replication proceeds. This phenomenon (antibody-enhanced viral infection) explains the enhanced disease severity with repeated infection (see below). Since multiple serotypes are now endemic within a particular region of the world, the more severe complications of dengue fever have become more common.

Dengue virus is endemic in the tropical and subtropical regions of the world. The virus is transmitted through the bite of an infected member of the Aedes family of mosquitoes including Aedes aegypti (the vector of yellow fever) and A. albopictus. A aegypti is generally found in urban settings, where it feeds during the daytime, and prefers breeding in freshwater collections such as in discarded tires, flower pots, cans, and buckets.

Clinical presentation: Symptoms develop after an incubation period of 3 to 15 days, and are characterized by abrupt onset of fever, accompanied by frontal headache, retroorbital pain, nausea, vomiting, chills, back pain, myalgias, arthralgias (hence the name "breakbone" fever), and generalized lymphadenopathy. A blanching maculopapular or scarlatiniform rash generally appears on the 2nd through 5th day of the fever. Neurologic complicatious include encephalopathy, peripheral mononeuropathy polyneuritis, and Bell's palsy. Laboratory findings include leukopenia, thrombocytopenia, and mild elevation of liver enzymes. Recovery occurs within one week, although some patients develop depression (hence the name "brakeheart" fever). This self-limiting disease is referred to as "classic" dengue fever and generally afflicts individuals following primary infection (2, 3). A more severe disease occurs in individuals living in an endemic region, generally children, following a second infection with a different serological dengue virus. These patients may develop dengue hemorrhagic fever (DHF) or dengue shock syndrome. DHF begins with an acute onset of fever and "classic" symptoms but progresses to hemorrhagic manifestations defined by a positive tourniquet test, thrombocytopenia (less than 100,00 platelets), and hemoconcentration (a greater than 20% increase in hematocrit) (2, 3). Increase in vascular permeability, hypovolemia, and coagulopathy may progress to shock. CNS complications are more common in DHF than in classic dengue. Mortality rates range from 2 to 10 %. Dengue hemorrhagic fever or dengue shock syndrome is also seen in children under 1 year of age with primary infection who are born to dengue-immune mothers. Interestingly, dengue hemorrhagic fever or dengue shock syndrome have not been shown to occur in individuals with a third or fourth dengue infection (2, 3).

Laboratory diagnosis: The gold standard for diagnosis consists of isolation of the virus from sera taken during the acute febrile phase. Various mosquito cell lines are now available for culture and isolation. Detection employs indirect immunofluorescence antibody test. The traditional method for the diagnosis of dengue virus consisted of a hemagglutination inhibition assay. This test required comparison of antibody titers in acute versus convalescent sera. The assay evaluates the ability of antiviral antibodies in the sera to inhibit virus antigen-dependent hemagglutination (3). A fourfold rise or greater in antibody titer is diagnostic of an acute infection. The ELISA assay has replaced the use of this older test. Anti-dengue IgM can be detected within 5 days after the onset of symptoms in both primary and secondary infections, and may remain elevated for as many as 90 days (3). Anti-dengue IgG appears within 2 days in secondary infections, and by day 14 in primary infections. A company by the name of PanBio has released a 5 minute immunochromatographic test (Dengue Fever Test) for the detection of dengue IgM and IgG antibodies. Distinction between primary and secondary infections can be made by IgM/IgG ratios.

Treatment: Treatment is mainly supportive and includes bed rest, antipyretics, analgesics, and fluids.

Epidemiology: Dengue fever is endemic in the Caribbean, Central and South America, Africa, and Southeast Asia. Outbreaks have also been reported in Mexico and Southern Texas. Cases of dengue importation by travelers visiting endemic areas have been reported. A small outbreak of Dengue fever occurred among a small group of tourists from Maryland and Pennsylvania after returning from a one week trip to the British Islands in 1996 (4).

References:

(1) Halstead, S.B. Pathogenesis of Dengue: Challenges to molecular biology. Science 239:476;1988.

(2) Ramirez-Ronda, C.H., and Garcia, C.D. Dengue in the Western Hemisphere. Inf. Dis. Clin. of North Amer. 8:107;1994.

(3) Henchal, E.A., and Putnak, J.R. The Dengue Viruses. Clin. Micro. Rev. 3:376;1990.

(4) Karp, B.E. Dengue fever: A risk to travelers. Maryland Med. J. 46:299;1997.