Current estimates suggest up to 100 million infections with dengue occur worldwide each year, and the dengue viruses (and subsequent dengue hemorrhagic fever [DHF]) are now arguably the most important arthropod-borne viruses from a medical and public health perspective.53 Both epidemic and endemic transmission of dengue viruses is maintained through a human-mosquito-human cycle involving mosquitoes of the genus Aedes. Humans become infected after being bitten by an infected female Aedes mosquito, and viremia in humans begins toward the end of a 4- to 6-day incubation period. This viremia persists until fever resolves, which is typically 3 to 7 days’ duration. An uninfected Aedes mosquito may acquire the virus after feeding during a period of viremia. The worldwide incidence of dengue and DHF has been increasing in the past several decades, largely the result of human behaviors such as population growth, poorly planned urbanization (overcrowding, poor water distribution, and poor sanitation), modern transportation, changing lifestyles, such as increased reliance on plastic containers and tires (which increase standing water and thereby supporting mosquito breeding), and most importantly, the lack of effective mosquito control.
The typical clinical manifestations of dengue range from self-limited dengue fever to dengue hemorrhagic fever with shock syndrome.54-57 Symptoms typically develop between 4 and 7 days after the bite of an infected mosquito, although the incubation period may extend to 14 days. Dengue can be excluded as the cause of symptoms in a traveler developing an illness more than 14 days after returning from a dengue-endemic country. The syndromes associated with dengue include dengue fever (classic dengue), dengue with hemorrhagic manifestations, and DHF, the most serious and lethal form of dengue.54-57 Classic dengue fever is an acute febrile illness with headache, retroorbital pain, and myalgias and malaise with severe joint pain (“break-bone fever”). The fever lasts 5 to 7 days but a minority of patients display a biphasic (“saddleback”) fever curve, with the second febrile phase lasting 1 to 2 days.54-57 The febrile period may also be followed by a period of marked fatigue that can last for days to weeks, especially in adults.
Hemorrhagic manifestations occur commonly in patients with classic dengue fever, and in rare cases can be life threatening. In some case series, up to 60% of children with dengue fever experience some hemorrhagic symptoms while only 25% of adults may have the same manifestations. The main bleeding sites are the skin and nose, with gastrointestinal bleeding being uncommon. This clinical presentation needs to be differentiated from DHF. DHF is the most serious manifestation of dengue virus infection and can be associated with circulatory failure and shock.54-57 The four cardinal features of DHF, as defined by the World Health Organization (WHO), include increased vascular permeability (plasma leakage syndrome as defined by a hemoconcentration [20% or greater rise in hematocrit]), pleural effusion, or ascites, marked thrombocytopenia, fever lasting up to a week, and spontaneous bleeding.58 The physical examination in patients with dengue is generally nonspecific. The frequencies of fever and rash are noted above. Injection of the conjunctiva, pharyngeal erythema, lymphadenopathy, and hepatomegaly are present in up to half of patients. The rash is typically macular or maculopapular and may be associated with pruritus. Laboratory findings include leukopenia, thrombocytopenia, and elevated liver enzymes.54,57,59 The gold standard for diagnosis is confirmation by serology. Confirmation of acute dengue virus infection is most frequently accomplished using serology.54,57,59
The treatment of dengue is supportive.54,57,59 Patients with dengue fever should be cautioned to maintain intake of oral fluid to avoid dehydration. Fever and myalgias can be managed with acetaminophen. The most important measure to assist the patient with suspected dengue fever is to carefully evaluate the patient for impending complications or early evidence of DHF. Gastrointestinal bleeding, epistaxis, or menorrhagia in patients with DHF can be severe enough to require blood transfusion. Significant internal bleeding may occur and could mask the hemoconcentration seen with DHF, and in these cases, aggressive and massive blood product resuscitation is needed. Use of a histamine H2 receptor antagonist or proton pump inhibitor is reasonable in patients with gastrointestinal bleeding, although there is no evidence of benefit. Platelet transfusions have not been shown to be effective at preventing or controlling hemorrhage, but may be warranted in patients with severe thrombocytopenia (<10,000/mm3) and active bleeding. Administration of intravenous vitamin K1 is recommended for patients with severe liver dysfunction or prolonged prothrombin time. Plasma leakage in DHF is important to manage with intravascular volume repletion to prevent or reverse hypovolemic shock. In mild cases, particularly when medical attention is received early, oral rehydration may be sufficient. However, in patients with established intravascular volume loss, intravenous fluid administration is recommended.60 For patients with shock, initial resuscitation with normal saline or Ringer lactate, preferably with 5% dextrose, is recommended, either as an infusion over the first hour or as a bolus for patients in profound shock based on World Health Organization recommendations. A second infusion of an equal volume is recommended in patients who remain in shock. A debate as to whether crystalloids or colloids should be used for volume replacement in critically ill patients with DHF currently exists. One large randomized double-blind comparison of three fluids for initial resuscitation of 512 Vietnamese children with dengue shock syndrome was performed.60 Three hundred eighty-three patients with moderate shock were assigned to Ringer lactate or one of two different colloid solutions: 6% dextran 70 or 6% hydroxyethyl starch. One hundred twenty-nine patients with severe shock were randomized to receive one of the two colloids. The treatment regimen closely followed the WHO protocol above, with 15 mL/kg administered over the first hour and 10 mL/kg over the second hour. The trial established that Ringer lactate was a safe, effective, and inexpensive alternative in initial resuscitation of patients with moderate shock. In patients with severe shock, dextran and starch performed similarly, although dextran was associated with more hypersensitivity reactions. In addition, more recent studies evaluating starch-based colloid infusions suggest worse outcomes in sepsis, and thus may need to be avoided.
Other adjuvant therapies have included steroids, although several trials have demonstrated that corticosteroids are no more effective than placebo in reducing death, need for blood transfusion, or serious complications in DHF.54,57,59 Other modalities, including intravenous immunoglobulins, pentoxifylline, and activated factor VII, have also been proposed for use but data continue to be very limited.54,57,59
The hemorrhagic fever viruses include wide number of geographically distributed viruses found worldwide, including Ebola and Marburg viruses, Rift Valley fever, Crimean Congo hemorrhagic fever, Lassa fever, yellow fever, and dengue fever.61,62 Ebola and Marburg viruses are in the family Filoviridae. Although any of the many VHF can cause severe disease in a traveler, Marburg and Ebola virus serve as a classic template for VHFs and will be largely discussed here. Marburg virus has a single species while Ebola has four different species that vary in virulence in humans. Transmission appears to occur through contact with nonhuman primates and infected individuals.62,63 Settings for transmission have occurred in vaccine workers handling primate products, nonhuman primate food consumption, nosocomial transmission, and laboratory worker exposure. The use of VHF in bioterrorism has also been postulated, largely based on its high contagiousness in aerosolized primate models.64 The exact reservoir for the virus was initially felt to be with wild primates, but recently bats have been labeled as the reservoir, passing the infection onto nonhuman primates in the wild. The clinical manifestations of both Marburg and Ebola virus are similar in presentation and pathophysiology, with morality being the only major difference between them. Initial incubation period after exposure to the virus is 5 to 7 days, with clinical disease beginning with the onset of fever, chills, malaise, severe headache, nausea, vomiting, diarrhea, and abdominal pain.65-67 Disease onset is abrupt, and over the next few days, symptoms and signs worsen to include prostration, stupor, and hypotension. Shortly thereafter, impaired coagulation occurs with increased conjunctival and soft tissue bleeding. In some cases, more massive hemorrhage can occur in the gastrointestinal and urinary tract, and in rare instances, alveolar hemorrhage can occur.65-67 The onset of maculopapular rash on the arms and trunk also appears classic and may be a very distinctive sign. Along with the bleeding and hypotension, multiorgan failure occurs eventually leading to death. Reports of outbreaks and cases have largely occurred in developing countries where critical care resources are more limited, thus experience with mechanical ventilation and the development of ARDS is not well documented. Case fatality rates have reached 80% to 90% in the recent outbreak of Marburg outbreak in Angola, but Ebola case fatality rates appear lower at 50%.62,63 The diagnosis of VHF becomes extremely important in order to initiate supportive care before the onset of shock, alert and involve the public health department, and institute infection control measures.8,61,68 However, diagnosis is difficult outside of the endemic area. VHF should be suspected in cases of an exposed laboratory worker, an acutely ill traveler from an endemic area (ie, central Africa), or in the presence of some classic clinical findings with increasing cases within the community suggesting a bioterror attack. Outside of travel or laboratory exposure, the presence of a high fever, malaise and joint pain, conjunctival bleeding and bruising, confusion, and progression to shock and multiorgan failure should raise suspicion of VHF, particularly if multiple cases are presenting in the community.64 Laboratory diagnosis includes antigen testing by enzyme-linked immunosorbent assay or viral isolation by culture, but these tests are only performed by the CDC currently.8,61,68-71 As no specific therapy is available, patient management includes supportive care, including a lung-protective strategy with low-tidal-volume ventilation if ARDS occurs as part of the disease course.8,61,68-71 In a few cases in a Zaire outbreak in 1995, whole blood with IgG antibodies against Ebola may have improved outcome, although analysis showed these patients were likely to survive anyhow. Although transmission appears to spread by droplet route, airborne precautions are recommended with respiratory protection with an N-95 or PAPR and placement of the patient in a respiratory isolation room.72 Equipment should be dedicated to that individual, and all higher risk procedures should be done with adequate, full PPE. Any suspected case of VHF should immediately involve public health officials and infection control department, as public health interventions and outbreak investigation will be paramount to reduce spread of disease.72 If exposure to an HCW occurs, there is no specific postexposure prophylaxis, and infection control and occupational health should be involved with potential quarantine measures for exposed individuals.
Hantaviruses are part of a larger genus that contains over 20 viral species.73,74 They make up two severe acute febrile illnesses: hemorrhagic fever with renal syndrome (HFRS, found in the Old World) and hantavirus cardiopulmonary syndrome (HPS, found in the New World). Particularly, HPS was classified when cases of severe acute febrile respiratory illness were seen in the Southwestern United States.73,74 In North America, disease was originally reported mostly in the Southwest and California, though more recently, cases have been reported in other parts of the United States, Canada, Europe, China, Chile Argentina, and other parts of South America.75 Cyclical outbreaks tend to occur largely in relation to the rodent population change. Symptoms initially begin with a fever, chills, and myalgias in a prodromal phase. There is a lack of upper respiratory symptoms as disease progresses rapidly to dry cough, respiratory failure, and ARDS, shock, coagulopathy, and arrhythmias. Resolution can also occur rapidly.75,76 Notably, thrombocytopenia with an immunoblast predominant leukocytosis is characteristic of the early cardiopulmonary phase.75 Diagnosis is by serologic testing of IgM in early disease and IgG in later disease through public health laboratories. Clinical contact with rodents in an endemic area with a leukocytosis and thrombocytopenia should aid the diagnosis.77 Treatment is mainly supportive, with extracorporeal membrane oxygenation being used in some case. Ribavirin has been effective in HFRS, but not HPS. Mortality remains at roughly 20%.75,76 Transmission of hantavirus occurs through contact with rodent material when the virus is aerosolized.75,76 This mostly occurs in indoor settings where dead rodent and rodent feces are present. Direct live rodent contact has not been implicated in transmission, and no human-to-human transmission has been documented with HPS. Cases appear mostly to be isolated North America, with a spring to early summer cyclical pattern.75,76 The amount and extent of the exposure change based on the rodent reservoir population. Hantavirus is a reportable disease to public health officials.