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Info re: Dengue Fever

Dengue Fever

Background: Dengue has been called the most important mosquito-transmitted viral disease in terms of morbidity and mortality. Dengue fever is a benign acute febrile syndrome occurring in tropical regions. In a small proportion of cases, the virus causes increased vascular permeability that leads to a bleeding diathesis or disseminated intravascular coagulation (DIC) known as dengue hemorrhagic fever (DHF). Secondary infection by a different dengue virus serotype has been confirmed as an important risk factor for the development of DHF. In 20-30% of DHF cases, the patient develops shock, known as the dengue shock syndrome (DSS). Worldwide, children younger than 15 years comprise 90% of DHF subjects; however, in the Americas, DHF occurs in both adults and children.
Dengue is a homonym for the African ki denga pepo, which appeared in English literature during an 1827-28 Caribbean outbreak. The first definite clinical report of dengue is attributed to Benjamin Rush in 1789, but the viral etiology and its mode of transmission via mosquitos were not established until the early 20th century.
Pathophysiology: Dengue viral infections frequently are not apparent. Classic dengue primarily occurs in nonimmune, nonindigenous adults and children. Symptoms begin after a 5- to 10-day incubation period. DHF/DSS usually occurs during a second dengue infection in persons with preexisting actively or passively (maternally) acquired immunity to a heterologous dengue virus serotype. Illness begins abruptly with a minor stage of 2-4 days' duration followed by rapid deterioration. Increased vascular permeability, bleeding, and possible DIC may be mediated by circulating dengue antigen-antibody complexes, activation of complement, and release of vasoactive amines. In the process of immune elimination of infected cells, proteases and lymphokines may be released and activate complement coagulation cascades and vascular permeability factors.
Frequency:
• In the US: Between 1990 and 1992, reports of 10 imported cases of dengue fever were published. While still rare, this is a dramatic increase from 1 case reported during the period from 1987 to 1989; this probably results from increases in air travel and an exotic vector that has adapted to cold climates. Cases along the Texas-Mexico border have been cited recently.
• Internationally: Dengue virus causes about 100 million cases of acute febrile disease annually, including more than 500,000 reported cases of DHF/DSS. Currently, dengue is endemic in 112 countries. The world's largest known epidemic of DHF/DSS occurred in Cuba in 1981, with more than 116,000 persons hospitalized and as many as 11,000 cases reported in a single day. Current outbreaks can be monitored via the ProMed listserve by contacting owner-promed@promedmail.org.
Mortality/Morbidity:
• Treated DHF/DSS is associated with a 3% mortality rate.
• Untreated DHF/DSS is associated with a 50% mortality rate.
Race: Ethnicity is nonspecific, but the disease's distribution is geographically determined. Fewer cases have been reported in the black population than in other races.
Sex: No predilection is known; however, fewer cases of DHF/DSS have been reported in men than in women.
Age: All ages are susceptible. In endemic areas, a high prevalence of immunity in adults may limit outbreaks to children.

CLINICAL

History:
• Fever
o Abrupt onset, rising to 39.5-41.4°C
o Accompanied by frontal or retro-orbital headache
o Lasts 1-7 days, then defervesces for 1-2 days
o Biphasic, recurring with second rash but not as high
• Rash
o Initial rash transient, generalized, macular, and blanching; occurs in first 1-2 days of fever
o Second rash occurring within 1-2 days of defervescence, lasting 1-5 days
o Second rash morbilliform, maculopapular, sparing palms and soles
o Occasionally desquamates
• Bone pain
o Absent in DHF/DSS
o After onset of fever
o Increases in severity
o Not associated with fractures
o May last several weeks
o Most common in legs, joints, and lumbar spine
• Miscellaneous symptoms
o Nausea and vomiting
o Cutaneous hyperesthesia
o Taste aberrations
o Anorexia
o Abdominal pain (severe in DHF/DSS)
Physical:
• Fever
• Signs of intravascular volume depletion
o Hypotension with narrowed pulse pressure (see Picture 1)
o Delayed capillary refill (see Picture 2)
• Hemorrhagic manifestations
o Positive tourniquet test
o Petechiae, purpura, epistaxis, gum bleeding, GI bleeding, menorrhagia
• Rash
• Hepatomegaly (inconsistent)
• Generalized lymphadenopathy
Causes:
• Dengue virus types 1-4
o Aedes aegypti mosquito vector
o Human-mosquito-human cycle
o Found in tropical regions, especially Southeast Asia

DIFFERENTIALS
Hepatitis
Malaria
Meningitis
Pediatrics, Bacteremia and Sepsis
Pediatrics, Meningitis and Encephalitis
Tick-Borne Diseases, Rocky Mountain Spotted Fever
Yellow Fever

Other Problems to be Considered:
Leptospirosis
Rickettsioses
River viruses
Scrub typhus
Typhoid
Viral infections (eg, influenza, chikungunya, Mayaro fever, Rift Valley fever, West Nile, Sindbis, and Ross River)

WORKUP

Lab Studies:
• Isolation of virus in serum and detection of immunoglobulins (IgM and IgG) by enzyme-linked immunosorbent assay (ELISA) antibody capture, monoclonal antibody, or hemagglutination
• Complete blood count
o Hemoconcentration (hematocrit increased 20%)
o Thrombocytopenia (platelet count <100 x 109/L)
o Leukopenia
• Chemistry panel
o Electrolyte imbalances
o Acidemia
o Elevated BUN
• Liver function tests
o Elevated transaminases
o Hypoproteinemia
• Guaiac test for occult blood in stool
• DIC panel, as indicated
Imaging Studies:
• Chest x-ray
o Bronchopneumonia
o Pleural effusion
• Head CT scan without contrast
o For altered level of consciousness
o Intracranial bleeding
o Cerebral edema
Other Tests:
• Electrocardiogram
o Nonspecific changes may be effects of fever, electrolyte disturbances, tachycardia, or medications.
o Usefulness of these changes as a marker of cardiac involvement is unclear

TREATMENT

Prehospital Care:
• Initiate supportive therapy
o Intravenous (IV) crystalloids, as needed to keep systolic blood pressure above 90 mm Hg
o O2, empirically
Emergency Department Care:
• Supportive therapy
o IV access, O2, and monitoring are helpful.
o IV crystalloids may be necessary for hypotension; central line may be needed.
o Correct electrolyte abnormalities and acidemia.
• Implement therapy for DIC if indicated.
• Corticosteroids are not helpful.
• No antiviral therapy is available.
Consultations:
• Infectious disease
• Travel clinic, if available

MEDICATION

No specific medications are indicated for direct treatment of the dengue virus infection.

FOLLOW - UP

Further Inpatient Care:
• Admit to ICU if hypotensive or in DIC, otherwise admit to medicine ward.
o Patient may require a central line.
o Patient may require an arterial line.
o Patient may require blood components.
Deterrence/Prevention:
• Reduce A aegypti vector populations.
• Reduce exposure to A aegypti.
o Use insect repellent.
o Sleep under a mosquito net in affected areas.
o Wear protective clothing.
• Vaccines against all 4 serotypes are currently under development. While this is challenging due to the complex immune response, vaccines may ultimately be the most effective control strategy, since vector control programs have been largely unsuccessful and of only short-term local benefit.
Complications:
• Complications are rare but may include the following:
o Brain damage from prolonged shock or intracranial hemorrhage
o Myocarditis
o Encephalopathy
o Liver failure
Prognosis:
• Morens states that the rapid clinical response to aggressive fluids and electrolytes in even moribund children with DHF/DSS "is among the most dramatic events in clinical medicine." Treated promptly, children in shock and coma can wake up and return to near normalcy within hours.
• Convalescence may be prolonged, with weakness and mental depression.
• Continued bone pain, bradycardia, and premature ventricular contractions (PVCs) are common.
• Survival is related directly to early hospitalization and aggressive supportive care.
• Dengue fever is not contagious through person-to-person contact.
Medical/Legal Pitfalls:
• Failure to admit patients for aggressive supportive therapy
• Failure to rule out other possible illnesses and specific therapies
Special Concerns:
• Pediatric deaths associated with dengue viral infection most commonly occur in infants younger than 1 year.

BIBLIOGRAPHY
• Guzman MG, Kouri G: Dengue and dengue hemorrhagic fever in the Americas: lessons and challenges. J Clin Virol 2003 May; 27(1): 1-13[Medline].
• Guzman MG, Kouri G: Dengue: an update. Lancet Infect Dis 2002 Jan; 2(1): 33-42[Medline].
• Halstead SB: Pathogenesis of dengue: challenges to molecular biology. Science 1988 Jan 29; 239(4839): 476-81[Medline].
• Hoeprich PD, Jordan MC, Ronald AR, eds; Halstead SB: Infectious diseases: A treatise of infectious processes. 1994; 919-923.
• Kao CL, King CC, Chao DY, et al: Laboratory diagnosis of dengue virus infection: current and future perspectives in clinical diagnosis and public health. J Microbiol Immunol Infect 2005 Feb; 38(1): 5-16[Medline].
• Kuno G: Review of the factors modulating dengue transmission. Epidemiol Rev 1995; (2): 321-35[Medline].
• Malavige GN, Fernando S, Fernando DJ, et al: Dengue viral infections. Postgrad Med J 2004 Oct; 80(94: 588-601[Medline].
• Mandell GL, Douglas RG Jr, Bennett JE, eds; Monath TP: Principles and practice of infectious disease, 3rd ed. Churchill Livingstone, Inc; 1990: 1248-1251.
• Monath TP: Yellow fever and dengue: The interactions of virus, vector, and host in the re-emergence of epidemic disease . Semin Virol 1994; 5: 133-145.
• Morens DM: Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis 1994 Sep; (3): 500-12[Medline].
• Ray CG, Ryan KJ, ed: Sherris medical microbiology: An introduction to infectious diseases. McGraw-Hill Professional Publishing; 1994: 525-535.
• Stephenson JR: Understanding dengue pathogenesis: implications for vaccine design. Bull World Health Organ 2005 Apr; 83(4): 308-14[Medline].
• Tassniyom S, Vasanawathana S, Chirawatkul A, Rojanasuphot S: Failure of high-dose methylprednisolone in established dengue shock syndrome: a placebo-controlled, double-blind study. Pediatrics 1993 Jul; 92(1): 111-5[Medline].
• World Health Organization: Dengue Haemorrhagic Fever: Diagnosis, Treatment and Control . World Health Org; 1986: 1-2.

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