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Another Disease for the Differential

Roberts, James R. MD

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doi: 10.1097/01.EEM.0000459713.42409.66
    The Asian tiger mosquito can transmit dengue, which is not that uncommon in febrile patients returning from many countries, but often the diagnosis is not considered. Dengue is mainly a clinical diagnosis, but malaria and Ebola must also be considered. And chikungunya is also now appearing in the United States, and must be added to the differential. Common findings with dengue are leukopenia, thrombocytopenia, and elevated liver enzymes. Only a fever is present in the early stages, so it's an easy diagnosis to miss, especially if you do not get a travel history. Most patients do well, but this is a rather lengthy annoying disease, and there is no specific treatment.

    Emergency clinicians rarely had to worry about exotic or foreign endemic illnesses, but the recent Ebola outbreak, as well as the sporadic presentation of tropical or foreign diseases in travelers, has changed all this. Last month I discussed an infectious disease never thought to be important in the United States, chikungunya. This mosquito-transmitted viral illness has accounted for sporadic outbreaks in the lower United States, but it's quite prevalent in Africa, Asia, and now even the Caribbean. Chikungunya is generally benign, but is an annoying febrile illness that can be associated with long-term arthralgias and, most importantly, be mistaken for other illnesses. Chikungunya remains largely a clinical diagnosis, but exotic lab tests can prove it.

    Similarly, dengue fever is one of those diseases that one heard about in medical school and quickly forgot. Unfortunately, dengue has an expanding global footprint, with little progress in its control over the past decade. Patients with dengue may be seen in any ED in the United States, and every emergency clinician should consider it under the right circumstances. In reality, a febrile illness in a recent traveler is associated with a relatively high incidence of a once-exotic, now rather common, viral illness.


    Simmons CP, Farrar JJ, et al.

    New Engl J Med


    Dengue has a large global burden, affecting many millions of individuals each year in 100 countries. It is the world's most prevalent mosquito-borne viral disease, surpassing malaria in some countries. Analysis of data from more than 17,000 ill travelers in the GeoSentinel Surveillance Network found that dengue accounted for an amazing 10 percent of post-travel systemic febrile illnesses, second only to malaria. Mononucleosis related to Epstein-Barr virus or cytomegalovirus, rickettsial infections, and typhoid or paratyphoid fever were the next most common defined causes of systemic febrile illnesses in this study.

    Dengue was the most frequently identified cause of systemic febrile illness among travelers returning from Southeast Asia (32%), the Caribbean (24%), South Central Asia (14%), and South America (14%). It is only slightly less common than malaria among travelers returning from Central America. Amazingly, almost 100 million cases of dengue are diagnosed worldwide per year.

    Dengue is a self-limited systemic viral infection that can be transmitted between humans by mosquitos. The primary vector is the urban-adapted Aedes aegypti mosquito, a bug that has become widely distributed across many latitudes. A secondary vector, the Aedes albopictus mosquito (Asian tiger mosquito), has markedly expanded the spread of dengue. Infections in the United States would most likely be seen in travelers from Mexico or the Caribbean, but the disease is also present in South America, Africa, and Southeast Asia.

    Dengue is quite endemic in Puerto Rico, a popular American vacation destination. Many cases are asymptomatic, but dengue virus infections can present with a wide range of clinical manifestations, including a mild febrile illness to a rare life-threatening shock syndrome with multi-organ dysfunction. The mainstay of dengue prevention is vector control through various activities targeting the control of mosquitoes and removal of their breeding sites.

    The diagnosis should be considered in any patient who develops a fever within 14 days of even a brief trip to the tropics or subtropics. Fortunately, dengue can essentially be excluded as the cause of symptoms in a traveler who develops illness more than 14 days after returning from a dengue-endemic country. Dengue is caused by an RNA virus (types 1-4), but there is only minimal cross-protection among the four serotypes. Individuals living in an area of endemic dengue can be infected with up to four dengue serotypes in a lifetime. Many cases are asymptomatic, but there is a wide variety of clinical manifestations. Dengue used to be characterized by two types, dengue and dengue hemorrhagic fever. Currently the disease is characterized as dengue and severe dengue only.

    Of course, the differential diagnosis is broad, including measles, rubella, influenza, and other viral infections. Other diseases that may fall into this category in a recent traveler are typhoid, malaria, leptospirosis, and rickettsial disease. Severe dengue manifests as hypovolemic shock, respiratory distress, severe bleeding, and various organ impairment.

    Patients will develop symptoms from three to seven days following exposure to the infecting mosquito. There are generally three phases: first, a rather prolonged initial febrile phase, then a phase where the disease is manifested in various organs, and then spontaneous recovery. As with many viral illnesses, the initial phase is characterized by a high fever with accompanying headache, abdominal pain, vomiting, myalgias, joint pains, and often a transient macular rash. This is similar to many other diseases, including malaria, influenza, and chikungunya. The severe muscle pains have been termed breakbone fever. One may see mild hemorrhagic manifestation such as petechiae and bruising at venous puncture sites. Common laboratory findings include a mild to moderate thrombocytopenia and leucopenia. An elevation in hepatic aminotransferase levels is also common. The febrile stage lasts about four to seven days, and most patients recover without complications.

    Less fortunate patients with dengue shock syndrome experience a systemic vascular leak developing at the time of fever defervescence. Patients demonstrate hemoconcentration, hypoproteinemia, plural effusions, and ascites, and can develop outright hypovolemic shock. Plasma leakage with increased vascular permeability is a pathophysiologic feature of severe dengue. Clinically evident bleeding also occurs during this period, and a moderate to severe thrombocytopenia is a characteristic tipoff. The main bleeding sites are the skin and nose, and bleeding is usually minor. Physical findings of dengue are nonspecific, perhaps a macular or maculopapular rash as well as lymphadenopathy, hepatomegaly, and conjunctival injection. From a clinical standpoint, the hemorrhagic manifestations of a dengue infection are often classic, and can suggest a diagnosis. Bleeding into the skin is characterized by increased vascular fragility, platelet dysfunction, and thrombocytopenia. Very characteristic is a hematoma around a puncture site.


    The diagnosis of acute dengue is mainly a clinical call. A variety of sophisticated viral and antibody studies will establish the diagnosis, but no effective antiviral agents currently exist to treat dengue infections. Patients can generally be treated at home if they can tolerate oral fluids. Obviously, patients with complicated illness or any signs of shock should be promptly fluid-resuscitated in an intensive care environment. Platelet concentrates, fresh frozen plasma, and cryoprecipitate are rarely needed, but may be depending on coagulation abnormalities. An ongoing search for a preventable vaccine is being pursued.

    Comment: Early in its onset, particularly when there is just a fever and some associated systemic complaints, the diagnosis would be impossible to make, and would likely not be considered in a U.S. ED. Ebola has taught us that the days are long gone when one can miss asking about a travel history in the ED. Any travel to a foreign country in the past two weeks changes the ED evaluation and thinking process. Malaria is still one of the most common travel-related illnesses presenting in the United States, but dengue is also clearly fair game.

    I actually missed a patient with dengue who returned from Costa Rica with a fever, muscle aches, headache, a slight elevation in liver enzymes, and slightly low platelets. I was clueless about the cause, and thought perhaps this was the first sign of HIV. I didn't even zero in on the travel history. About six days later, the patient called me and told me he had been diagnosed with dengue. His course was relatively benign, but I should have been tipped off by the elevated liver enzymes and thrombocytopenia, and at least called for an ID consultation in the ED. I now know that leukopenia, thrombocytopenia, and elevation in liver enzymes are characteristic laboratory findings. So much for so-called useless lab tests in someone with a seemingly run-of-the-mill virus infection.

    Missing the diagnosis on the first visit is of little consequence to the outcome, but a focus on dengue can negate the search for other problems including CT scan, lumbar punctures, and blood cultures. You might see a second visit from the same patient because the fever lasts four to seven days, upping your suspicions that the initial diagnosis was wrong. With influenza season here, it is likely that a case of dengue will be diagnosed as the flu, perhaps another reason to get a routine CBC, LFTs, and a viral influenza analysis on febrile patients. The key, once again, is travel history.

    Fever and systemic complaints in a traveler to foreign countries have become more of a challenge in the United States. Of course, Ebola is a main concern, but malaria is still not uncommon in returning patients. Now add chikungunya and dengue to the list. A malaria smear is easily performed in the ED, but ferreting out other febrile illnesses is quite a task these days. Maybe share the burden with your ID consultant.

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    Principal Symptoms of Dengue

    • High fever and at least two of the following:
    • Severe headache
    • Severe eye pain (behind the eyes)
    • Joint pain
    • Muscle and/or bone pain (breakbone fever)
    • Rash
    • Mild bleeding (e.g., nose or gum bleed, petechiae, or easy bruising)
    • n Low white cell count, thrombocytopenia, elevated liver enzymes

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