Disease-a-Month 59 (2013) 410–425

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Viral hemorrhagic fever viruses Robin B. McFee, DO, MPH, FACPM, FAACT

Dengue,1–6 a viral hemorrhagic fever (VHF) virus,7–11 is the most common mosquito-borne illness (Figs. 1 and 2),1,2,4,12–16 and one of the fastest spreading infections worldwide.4,15–20 It is a significant global health concern given there are estimated 3 billion people who live in areas where dengue virus can be transmitted.5,14–21 Some suggest nearly half of the entire global population is at risk,18–20 including parts of the United States. Viral hemorrhagic fevers (VHFs) refer to a group of infectious illnesses that are caused by several distinct families of viruses, not surprisingly called the viral hemorrhagic fever viruses that include Ebola, Lassa, dengue, and others. VHFs are distributed worldwide.8–10,22 VHFs are a taxonomically diverse group of viruses capable of causing high morbidity and mortality. In addition to endemic illness worldwide, VHFs remain of considerable interest as possible biological weapons.9,10 Regardless of the pathogen, VHF refers to a severe multisystem syndrome that results primarily in fevers and bleeding risks.1–11,23–25 Some form of hematological event secondary to microvascular damage and changes in vascular permeability can occur, along with other symptoms. Inherent with VHFs, the overall vascular system is affected, resulting at times in severe dysregulation of coagulation; depending upon the underlying viral illness, a variety in severity of bleeding can occur from petechiae to circulatory collapse.5,8–10,27 Some VHF viruses cause primarily relatively mild illnesses, others cause a broad range (dengue), and yet others result in life-threatening disease (Ebola).9,10 Most VHFs are considered biosafety level 4 (BSL-4) pathogens—the highest level of security and threat, usually associated with pathogens for which there is no treatment and/or preventive measure. Exceptions to BSL-4 are dengue and yellow fever. VHF viruses belong to four distinct families (Table 1): arenaviruses, filoviruses, bunyaviruses, and flaviviruses that share the following common features8,9,21,22,24:

   

RNA viruses enveloped in a lipid coat. Survival is dependent upon a host (animal or insect) i.e., a natural reservoir. Geographically restricted to regions populated by their respective host species. Humans are not the natural reservoir. Humans become infected through contact with infected hosts. Of note, in some cases, humans can transmit the virus via a variety of mechanisms. Human outbreaks occur sporadically and cannot be predicted. In rare cases, other pathogens can cause a hemorrhagic fever, for example scrub typhus.

0011-5029/$ - see front matter & 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.disamonth.2013.10.003

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Fig. 1. TEM micrograph of dengue virions (dark circles) from CDC images.1,2

The clinical presentation—signs and symptoms associated with VHFs—vary by virus and host characteristics, but initial presentation can include fever usually above 100.41F, significant fatigue, muscle involvement (pain, weakness), and exhaustion.3–5,9,21,23,28 A variety of rashes are possible with VHF. For example, the maculopapular rash in Marburg disease (Fig. 2). It is a nonpruritic maculopapular rash that can resemble the rash of measles (Fig. 3) and may occur in up to 50% of patients infected with the Ebola or Marburg viruses within the first week of illness.27,29 The rash is more common in light-colored skin and desquamates on resolution (Fig. 7). Ocular manifestations can also be associated with hemorrhagic fever viruses (Figs. 4 and 5) and range from conjunctival injection to subconjunctival hemorrhage, in this case associated with Bolivian hemorrhagic fever virus (Fig. 5).10 Evidence of bleeding is variable, again depending upon the pathogen and host (dengue), severity can be affected by a variety of contributing factors, including whether this was a primary infection or reinfection with different strain of DV. Patients with severe cases of VHF often show signs of bleeding under the skin (Fig. 6), in internal organs, or in various orifices— mouth, eyes, ears, or rectum. Severely ill patients may experience circulatory collapse,

Fig. 2. Marburg VHF exanthem.

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Table 1 Viral hemorrhagic fever virus families and examples of member viruses.

 Arenaviruses

  

○ Lassa fever ○ Argentine hemorrhagic fever ○ Bolivian hemorrhagic fever Flaviviridae ○ Yellow fever ○ Dengue fever Bunyaviridae ○ Crimean–Congo fever Filoviruses ○ Marburg and Ebola hemorrhagic fevers

multisystem organ failure (renal failure is not rare), shock, nervous system malfunction, coma, delirium, and seizures and may ultimately die.3–6,9,21

Dengue fever virus (DV) Dengue3–6,21–29 is a Flavivirus8–12,21,22 and member of the family Flaviridiae, along with West Nile virus, yellow fever virus, and tick-borne encephalitis virus, all of which are single-stranded RNA viruses enclosed in a protein capsid, which is enclosed in a host cell membrane-derived envelope. Dengue, like other Flaviviruses, has a positive single-stranded RNA genome packed inside a core protein, surrounded by an icosahedral scaffold, encapsulated by a lipid envelope.12,13,15,30–34 Its 11-kb genome functions similar to mRNA. It encodes a polyprotein, which with translation gets cleaved into structural proteins (C, prM/M, and E), and seven nonstructural proteins by viral

Fig. 3. Measles exanthem.

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Fig. 4. Ocular manifestations of VHF.

Fig. 5. Ocular manifestations in Bolivian hemorrhagic fever.

Fig. 6. Crimean–Congo VHF.

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Fig. 7. Aedes mosquito.

or host proteases. Because dengue viral genome can function as mRNA, once viral RNA is delivered into the cell cytoplasm utilizing bioactive vesicles, translation and genome synthesis can occur. There are four serologically distinct dengue viruses. Infection (and recovery) from one of the four serotypes confers lifelong immunity to the same serotype and only partial, temporary cross immunity to the other types; subsequent infection by another serotype may in fact increase the risk of severe dengue illness.

Epidemiology Dengue is a systemic viral infection that utilizes a mosquito vector (Fig. 8)—Aedes.1–7 The spectrum of illness associated with dengue ranges from asymptomatic to life threatening and fatal. While there are a range of estimates in terms of the populations at risk and magnitude of illness, the true burden remains unknown.16–21 Initially dengue infections occurred as epidemics, but population and ecological changes have influenced the global incidence. The World Health Organization (WHO)21 estimates approximately 200 million cases globally per year, of which 200,000–500,000 are dengue hemorrhagic (DHF) or dengue shock syndrome (DSS), which carry a mortality rate 1–5%, mostly involving children under 15 years of age. There are an estimated 500,000 hospitalizations and over 20,000 deaths. These numbers may not accurately reflect the true impact of the disease, given some regions have good public health infrastructure and others are resource limited. Moreover, a recent study utilizing case data, cartography, and complex mathematical modeling, published in the April 24, 2013 edition of Nature, suggests the WHO estimate is significantly lower than the actual number of persons infected globally.19 These researchers estimate 390 million dengue infections in 2010, which was the year studied by the team. Further, they estimate 96 million have some clinical symptomatology. What remains elusive is the actual number of persons infected who have asymptomatic disease. Beyond the importance of this number to epidemiological studies is the fact that persons with little or mild clinical disease are a

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Fig. 8. Changing epidemiology in the Americas.

potentially large reservoir of virus; an uninfected mosquito becomes infected by biting someone with dengue virus, and thus making it possible to transmit the disease. Dengue is endemic in over 100 countries, including the Americas and American Tropics (Figs. 9 and 10). Although pre-1970 only nine countries experienced severe dengue, WHO considers Europe to be at risk for an outbreak. In the last 20 years, there has been a dramatic increase in disease penetration in South America and the Caribbean (Figs. 8 and 9). In 2010, local transmission of dengue occurred in France.1,16–21,35–40 Found in tropical and subtropical climates, mostly urban and semi-urban areas, infected humans are the carriers/multipliers of the virus—serving as a source for uninfected mosquitoes. Aedes aegypti, Aedes albopictus, and Aedes polynesiensis mosquitoes bite a viremic person, after an incubation period of 8–10 days (Table 2), they can transmit the virus for the insect’s lifespan, which is approximately 1 month.18–20,28,37–40 Dengue can also be transmitted via blood, organs, or tissues via transfusion or transplant. This includes bone marrow. A needle stick, mucous membrane contact with blood, and maternal–fetal transmission are also possible. Peripartum infections may increase the chance of symptomatic disease afflicting the newborn, although the data are limited in terms of the actual number of cases transmitted from mother to newborn. Of concern, the secondary infection effect may place infants at greater risk for dengue if they are infected again in the baby’s 6–12 months. Other than the above, human to human transmission has not been documented.

Fig. 9. Dengue in the Caribbean.

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Fig. 10. Rash on legs due to dengue fever; image from eMedicine.com, 2009. (Photo courtesy of Duane Gubler, PhD.)

Imported cases—from Portugal to other European nations—occurred in 2012. Of note, there is an upward trend in dengue incidence among hospitalized patients in the US. One of the factors is the substantial number of travelers who enter the US from tropical and subtropical regions. Worrisome is the fact that the mosquito vector has spread to at least 26 states, making the risk for dengue and dengue hemorrhagic fever a potential public health threat for the US. With climate change, and more regions becoming habitable for Aedes and other mosquitoes, dengue and other mosquito-borne illnesses are expected to spread.18–20,28,37–40 The natural reservoirs are humans. Not surprising, the distribution is similar to that of malaria worldwide. Severe dengue is a leading cause of illness and death in children across certain Asian and South American countries. Access to proper healthcare can decrease the fatality rate to below 1%; it is much higher untreated. Outbreaks are not uncommon, and pose a challenge given the mainstay of treatment is symptomatic and supportive care—labor and resource intensive interventions— and that there is no antiviral specifically for this virus. A study recently published in the Proceedings of the National Academy of Sciences (PNAS) revealed mosquitoes that spread dengue fever tap into the domestic networks of humans. The data from Iquitos, Peru, shows that the trail of the most rapid transmission of human infections Table 2 Incubation periods of VHF viruses. Virus family

Arenaviridae Arenavirus

Disease (virus)

Natural distribution

Usual source of Incubation human infection (days)

Lassa fever Argentine HF (Junin) Bolivian HF (Machupo) Brazilian HF (Sabia) Venezuelan HF (Guanarito)

Africa South South South South

Rodent Rodent Rodent Rodent Rodent

5–16 7–14 9–15 7–14 7–14

Mosquito Tick

2–5 3–12

Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome

Africa Europe, Asia, and Africa Asia, Europe, and worldwide

Rodent

9–35

Marburg and Ebola

Africa

Unknown

3–16

Bunyaviridae Phlebovirus Rift valley fever Nairovirus Crimean–Congo HF Hantavirus Filoviridae Filovirus Flaviviridae

America America America America

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does not lead through large, public gathering places, as might be expected, but from house-tohouse, as people visit nearby friends and relatives.1 A 2009 outbreak of dengue in Iquitos killed at least 24 people and drove almost 1000 sufferers to the hospital, where cots had to be set up in stairwells and hallways to handle the flood of patients. A city of 400,000 located deep in the Amazonian rain forest, Iquitos is essentially an island, only accessible by boat or plane. The city has high unemployment, and the housing is often substandard. Water is stored in open containers in crowded homes that lack airconditioning or even window screens. These factors make the homes havens for A. aegypti mosquitoes (Fig. 7), the primary vector for the dengue virus. These mosquitoes feast almost exclusively on human blood, bite during the day, and have a limited flight range of about 100 m. One of the lead investigators from Emory University Vazquez-Prokopec noted “on a global scale, human air travel is known as a driver of dengue virus circulation, but this (study) is the first time we’ve quantified the powerful impact of human movement on the small scale of neighborhoods.” Also known as “break-bone fever,” dengue causes debilitating pain leading to the hospitalization of many sufferers. Severe cases can be fatal. “It is vicious, and rapidly growing as a threat,” Vazquez-Prokopec says. During the last 50 years, the incidence of dengue has increased 30-fold. Dengue is ubiquitous in the tropics. Asia represents 70% of the global burden, within which India alone represents approximately 50% of the cases. The Americas represent 14% of the global burden, with approximately 50% of those cases occurring in Brazil and Mexico. The study published in Nature suggests there are more cases in Africa than prior estimates suggested, representing 16% of worldwide dengue. Rain, high temperatures, and being located close to urban centers increase the risk of infection, not a coincidence that ecology plays a key role in mosquito population. Not surprisingly, the researchers note that climate and population migration are key factors in predicting the penetration of dengue globally. As if 100 million cases do not suggest enough of a global threat, nearly 400 million underscores the immediate need to develop vaccines, and antivirals, as well as improved attempts to reduce the mosquito population globally. Dengue is not the only major public health infection spread by mosquitoes.5 Consider West Nile virus in the United States and malaria worldwide. Interestingly, it is not just people but the globalized trade in materials as well; bamboo plants have been shown to carry the mosquito. As with any vector control approach, standing water should be removed, as well as some well known sites that harbor mosquitoes, such as used tires, water storage tanks, even flowerpot trays, and birdbaths. For the latter, garden supply stores sell a variety of agitators, solar or battery powered, that can keep birdbaths and backyard ponds from becoming standing water sources and mosquito breeding sites. Within the last few years, Europe experienced its first sustained outbreak of dengue since the 1920s, with approximately 2000 people infected in Madeira, Portugal. In the United States, there have been several outbreaks, Hawaii in 2001 and South Florida in 2009 and 2010. During 2009 and 2010, dengue fever emerged for the first time in decades in the contiguous United States, when an outbreak in the Florida Keys led to 93 cases.1 As of June 2013, the Lao People’s Democratic Republic recorded over 10,000 cases, which is seven times more than the number for cases during the same timeframe in 2012. Among those who died to date, most were children. Not surprisingly, the rainy season is associated with increased cases, given the attraction for mosquitoes. Vector control is critical to reduce the risk of transmission—internationally and in the United States. Given that the Aedes mosquito resides nearly year round in several Southeastern states, in addition to the travelers returning from dengue endemic regions and a susceptible population, the conditions exist for more outbreaks in the United States and North America. Of concern from a disease-containment perspective is that dengue was not a reportable infection until 2009 in the US. According to the CDC, infection rates were 3–8%. According to a study in GeoSentinel

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among surveillance network clinics, dengue was the top cause of febrile, systemic illness afflicting those returning from the Caribbean, South America, South Central, and Southeast Asia. While malaria is the most common cause of hospitalization as a travel-related illness among persons who return to the US from the tropics, in some studies, dengue was the second most common among febrile travelers who were in dengue endemic areas, based upon serological testing. It is worth repeating the importance of a thorough travel history, which given the magnitude of this global infection, can help make the diagnosis in a timely manner. Of note, a person can become infected from the bite of just one infected mosquito. It is important to use mosquito repellent and avoid times when mosquitoes are prevalent—early morning, several hours after daybreak, late afternoon, and early evening are times when the risk of being bitten are the highest. Mosquitoes may feed/bite anytime during the day, but it is less likely than at predawn and dusk. Interestingly, Aedes mosquitoes live indoors, found in cool, dark places such as bathrooms and closets, under the bed, behind curtains. Travelers should be cautioned, if planning to work/visit in mosquito environments, they should make certain that there are intact screens for windows and doors, air-conditioning instead of open windows, and repellents such as DEET. Although often out of the purview of tourists, the use of insecticides to decrease the mosquito population can be an effective preventive measure. The key is to avoid being in environments heavily populated by mosquitoes.

Clinical Presentation Dengue is a systemic viral infection that utilizes a mosquito vector—Aedes. The spectrum of illness associated with dengue ranges from asymptomatic to life threatening and fatal. Dengue is characterized by the following:



   

Early onset (few days) ○ High fever ○ HA/muscle aches/stomach pains ○ Fatigue ○ Diarrhea/bloody diarrhea ○ Vomiting blood ○ Sore throat/red, itchy eyes ○ Hiccups Febrile illnesses—typically 4 1011F Hematuria and other heme-dyscrasias Relative bradycardia Constitutional symptoms

A severe flu-like illness, with fever that lasts 2–7 days also occurs. When the fever declines other symptoms may develop. Severe dengue is a potentially deadly complication where plasma leaking/capillaries become permeable, allowing fluid escape from blood vessels, leading to ascites, pleural effusion/respiratory distress, and organ failure. Vomiting blood, severe headache, petechiae, easy bruising, bleeding from nose or gums, and internal bleeding may occur as well as joint, muscle, or bone pain. Pulse temperature dissociation, sometimes referred to as relative bradycardia, where heart rate may not increase as predicted with fever, may also occur. Circulatory collapse can rapidly progress to shock or death without prompt, supportive care. There are two common clinical syndromes.4,6,9,10,21,23–28,30–34 1. Dengue hemorrhagic fever (break-bone fever) (DHF) is an acute febrile disease characterized by sudden onset, fever, intense headache, myalgia, retro-orbital pain, arthralgias, and anorexia, and GI conditions can also occur. A maculopapular rash may appear as the fever subsides. With this form, death is uncommon.

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2. Dengue shock syndrome (DSS) is the most severe form and is characterized by hypovolemia, a variety of bleeding manifestations that range from cutaneous to internal. Relative bradycardia and shock are possible, and the mortality rate is 10% or more. Aggressive, early supportive care including rehydration and attention to blood loss is critical. Dengue fever and DHF/DSS have some commonalities—viremia lasting 5–8 days, fever of 2–7 days, headache, myalgia, bone/joint pain, and rash. Leukopenia is possible. Thrombocytopenia and cutaneous hemorrhage can be observed in varying degrees. Break-bone fever—bone/joint pain that can be incapacitating—is also seen commonly in adults. Abnormal hemostasis can be profound. Clinical signs and symptoms of dengue4,6,9,10,21 Diagnosis As global infections start emerging as domestic challenges to the United States, inquiring patients about their travel and occupation, which often involves business travel, becomes critical to emergency medicine and primary care physicians—the front line of health care. The challenge of competing demands in health care, including time per patient, may act as a barrier, but we are in an era where emerging infections against the backdrop of globalization with a growing magnitude in travel-associated infections (TAI) justify the effort. A viral hemorrhagic fever should be considered in any person who presents with a severe febrile illness and clinical evidence of vascular involvement—hypotension, petechiae, easy bleeding, facial/chest flushing, and nondependent edema and has traveled to a region where VHFs are known to occur. Dengue should therefore be considered as part of the differential diagnosis for patients who have traveled to the tropics and subtropics in the 2 weeks prior to the onset of symptoms. This takes into account the incubation period (Table 2) which, though typically is 4–7 days, can be as short as 3 days or upward of 14 days. Of note, mild febrile infection with dengue may not be identified as such. This is owing to the fact that many persons infected with dengue for the initial time often have mild febrile illness or are asymptomatic. As discussed earlier, subsequent infections with dengue are usually associated with severe disease. According to the WHO, dengue fever (DF) is defined as an acute febrile illness AND two or more of the following additional signs and symptoms:

      

Headache Retro-orbital pain Muscle aches Joint pain (can be severe e.g., “Break-Bone Fever”) Rash (Figs. 2 and 7) Hemorrhagic manifestation (mild to outright circulatory collapse) (Figs. 4–6) Leukopenia

The rash of dengue appears as the fever subsides and usually lasts 2–4 days. It is estimated over 50% of patients have an early transient rash and mild hemorrhagic signs, There is often a long convalescent period for those with mild dengue.4,9,10,21 The rash can be macular or maculopapular and generalized (Figs. 2 and 7). In some cases, it may look very similar to the rash associated with measles (Fig. 3). The rash can be confluent with small patches of unaffected skin. The rash may become scaly and pruritic.27 An index of suspicion, thorough history, including travel and occupational, along with physical examination are important. The range of “look-alike” etiologies should be recognized, early-stage rashes can pose a clinical challenge. Consider the study conducted in Brazil involving children with exanthema (with or without fever) who presented to the emergency department

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of a hospital in a dengue endemic region. Among study participants, a protocol exam and thorough history were carried out as well as collection of blood samples that were subjected to a wide variety of serology and other studies. The results were not surprising; dengue virus (DV) was detected in nearly 78% of the children. Herpes virus type 6 (8.4%), and parvovirus (2.8%) were the second and third most commonly identified viruses in the study respectively. No positive serology was noted for measles, rubella, or toxoplasmosis. Among children infected with DV, the most common clinical manifestations included fever, itching, prostration, and myalgia. The tourniquet test was positive in nearly 60% of the confirmed DV cases. Other signs and symptoms include nausea, vomiting, and flushed skin—the latter occurring during the first 24–48 h. Dengue hemorrhagic fever affects an estimated 1% of DF patients, often as the fever subsides (  3–8 days after onset), which makes this period a caution zone for close observation. DHF can be fatal. As noted before, but worth repeating, subsequent dengue infection with a different strain than that of the initial infection is frequently associated with more severe disease. DHF is distinguished from DF by evidence of increased vascular permeability, plasma leakage, and bleeding. According to the WHO, DHF is associated with the following: 1. 2. 3. 4.

Fever or history of fever lasting 2–7 days Hemorrhagic manifestation1 Thrombocytopenia ( r100,000 cells/mm3) Evidence of plasma leakage including hemoconcentration (an increase in hematocrit Z 20% above the age average or a decrease in hematocrit Z 20% after fluid replacement 5. Pleural effusion 6. Ascites 7. Hypoproteinemia

Of note, thrombocytopenia alone does not diagnose DHF. Dengue shock syndrome (DSS) is potentially fatal, and according to WHO is defined in a patient with signs and symptoms consistent with (DHF) AND hypotension and narrow pulse pressure (r 20 mm) OR frank shock/circulatory collapse.

Testing Definitive diagnosis relies on specific virological diagnosis—detection of viremia or IgM.9 Precautions should be observed in collecting, handling, transporting, and processing samples from suspected VHFF patients. A case presumptively considered to be DF, DHF, or DSS can be confirmed using a serum specimen and testing as follows2,4,5,7–10,21,38: 1. Detection of dengue virus genomic sequence 2. Detection of dengue virus antigens (nonstructural protein 1; NS1 antigen) 3. Serologic testing for IgM anti-dengue virus Of note, detection of dengue virus genomes or NS1 antigen is utilized in the acute febrile stage of illness (r 5 days after the onset of symptoms). Testing for IgM anti-dengue virus is most primarily 4 5 days after the onset of fever. 1 The Tourniquet Test (Rumpel–Leede Capillary-Fragility Test or Capillary-Fragility Test) included in item 2, along with hemorrhagic manifestation, is still in use, and some studies demonstrate good utility. However it is not the primary test as noted in previous WHO guidance. Nevertheless, it may still have bedside utility, is safe, and is easy to perform. Apply a blood pressure cuff (raising the pressure between systolic and diastolic blood pressure for 5 min) or a tourniquet. Upon removal of cuff/tourniquet there should be evidence of petechiae/ecchymosis. A negative tourniquet test does not exclude a diagnosis of DHF. The sphygmomanometer is more effective than the tourniquet.

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Dengue can be isolated in cell culture derived from serum, cerebrospinal fluid (CSF), or tissue specimens. However, dengue virus genomes can be readily identified by reverse transcriptase polymerase chain reaction (RT-PCR) from CSF, plasma, serum, or autopsy tissue specimens. There are immunoassays available to detect the NS1 antigen, which is found in blood during the viremia stage. Dengue antigens can be detected in tissue by immunofluorescence and immunohistochemical analysis. In patients with acute illness, serological testing for dengue is carried out for IgM anti-dengue virus; this should become positive usually after 5 days from the onset of symptom(s). Laboratory confirmation also includes seroconversion from negative to positive IgM antidengue virus from specimens obtained from acute phase ( o5 days after fever begins) to convalescent phase (4 5 days post symptom/s onset), along with a Z 4  rise in reciprocal IgG anti-dengue virus titer or hemagglutination inhibition titer to dengue virus antigens in serum obtained from acute and convalescent phase or IgM anti-dengue virus detected in CSF. Of note, IgM anti-dengue virus in a solitary serum sample is suggestive of probably recent dengue infection whereas IgG anti-dengue virus in a single sample can indicate either recent or past dengue infection. It is important to recognize dengue virus antibodies can cross-react with antibodies from other Flaviviruses including West Nile, yellow fever, and Japanese encephalitis viruses, especially when using only antibody testing (IgM or IgG anti-dengue) from a single sample. Also, prior vaccination or infection with another flavivirus may also result in false-positive IgG or IgM anti-dengue. Dengue vaccine status23–25,30–34 To date, there are no FDA-approved vaccines to prevent the four strains of dengue. Several companies are performing Phase I and Phase II studies, with limited clinical trials. Chimeric Yellow Fever–dengue virus (CY-TDV), a live attenuated tetravalent vaccine, has progressed to Phase III studies. There are several other approaches to a dengue vaccine, including other live attenuated vaccines and subunit, DNA, and purified inactivated vaccines. Other approaches such as virus-vectored approaches are in preclinical stages as well. There have been significant barriers to developing a successful vaccine. There remains a need to better understand the impact on non-humans. To date, a well-defined animal disease model is needed. Normal mice, for example, do not display significant viremia or disease when infected with human DV isolates. Challenges are based upon a variety of unknowns including the full nature of dengue. There are four serotypes of dengue virus—DENV 1–4. Multiple dengue viruses can coexist in endemic regions. Infection by one serotype will confer long-term protection only against reinfection by the same serotype, but only short-term protection against secondary infection by any of the remaining three heterologous serotypes. Thus, by necessity, dengue vaccines must address DENV 1–4, i.e., a quadrivalent vaccine. Dengue viremia poses an interesting clinical quandary; in endemic regions where the majority of the population has demonstrable neutralizing antibodies to the four serotypes, viremia still can occur in some of these members upon subsequent mosquito bite from an infected vector. Why some individuals develop subsequent clinical illness remain unknown; individual genetic background, the interval between primary and repeat infection, sequence of infection by serotype, and the underlying immune response may contribute to this phenomenon.12,13,30–34 Another challenge is the mechanism of protective immunity,13 which is not completely understood. Studies suggest antibody-mediated DENV neutralization as a protective mechanism. What is not well known is the quantity of neutralizing antibody required for protective immunity. The role of other immune system mechanisms, including that of cytotoxic T-cell responses, requires additional studies. Complicating the development of an effective dengue vaccine13,30–34 is the paradoxically deleterious effect of immune enhancement in the pathogenesis. Severe disease is most commonly observed in secondary infection with a heterologous strain of DENV. Antibody-

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dependent enhancement may be the primary mechanism for immunopathogenesis. DENV antibodies can contribute to neutralization or enhancement of infection; antibody specificity, affinity, titer, and epitope access have been suggested by studies to play an important role. The potential risks posed by enhancing the immune response make it critical to develop a vaccine that covers all four known DENV serotypes. Recently Sanofi Pasteur (Sanofi) Pharmaceuticals released data from its first clinical trial (Phase IIb) on a recombinant, live attenuated, tetravalent dengue vaccine conducted in Thailand.34 Initial reports seemed promising from a safety perspective. However a recent article published in Lancet revealed that the vaccine was 30% effective; most notably because it failed to protect against one of the four dengue strains—the prevalent strain in Thailand. The clinical trial (Phase II) involved children (age range 4–11 years). According to the study, of the 4002 participants, 2669 received the vaccine—it was administered in three doses over a 12-month period with a control group of 1333, and 3367 were included in the primary analysis. There were 134 confirmed dengue infections noted in the study. While Sanofi continues to study the vaccine trying to determine why it did not protect against one strain, their study did reveal a safe vaccine was possible; something that has been elusive for decades. During the 2 years of follow-up after the initial dose, there were no safety signals reported. Larger-scale Phase III vaccine studies that have 31,000 participants are underway in multiple Asian and South American countries. Results are expected in 2014. The National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health (NIH), developed dengue virus and completed Phase I study, which was conducted in Baltimore, MD; Burlington, VT; and Washington, DC. The trial commenced in July 2010 and was reported in the January 2013 issue of Journal of Infectious Diseases. In this study, the Johns Hopkins researchers tested a single dose of each of the four versions of the investigational dengue vaccine a live attenuated vaccine—TetraVax-DV. Each of the four vaccines tested in the study included different mixes of component viruses. The initial participants included persons not previously exposed to dengue or related viruses such as yellow fever and West Nile viruses. They were randomized into four groups of 20 volunteers who received a single 0.5-ml subcutaneous tetravalent combination and eight received a placebo. Participants were monitored for fever and other dengue-related symptoms. The results seem promising for early phase vaccine; all four candidate tetravalent vaccines induced antibody responses against each of the virus combinations. An antibody response resulted after the first dose. It was also found to be safe; no participants experienced fever or dengue-like severe symptoms. Of note, 90% of white vaccinees experienced a vaccine-related rash, while African American vaccinees had significantly fewer rashes. Studies in Cuba and Haiti suggest that Black persons may have a degree of inherent protection for dengue. Of note, 97% of white vaccines developed antibodies. The exact mechanism in racial difference in terms of antibody response and rash is needed. This vaccine TV003 will be tested in Brazil and Thailand to determine its ability to evoke an immune response.

Other vaccine strategies Virus-vectored vaccines There are vaccines using replication deficient adenovirus vaccine vector and single cycle Venezuelan equine encephalitis virus vaccine vector. West Nile virus particles vaccine vector and measles virus vaccine vector are also under study to integrate various dengue component proteins. To date these remain under study. Adenovirus vaccine vectors have a large insert capacity, efficient deliver, high expression of antigens in a broad array of cells, and a documented record of safety in humans. Purified inactivated virus vaccines, live attenuated viruses, recombinant subunit vaccines, and DNA viruses VLP vaccines as well as live attenuated virus (LAV), virus-like particles (VLPs), and plasmid vectors are being researched. Although beyond the scope of this article,

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each approach has advantages and faces barriers to success. For example, non-living vaccines can offer the advantage of better suitability for immunocompromised individuals—not a insignificant subpopulation considering HIV-infected patients, cancer patients undergoing chemotherapy and rheumatology, as well as transplant patients on immunosuppressive therapy.13

Treatment Dengue-infected patients often require close attention as changes in clinical status will govern the symptomatic and supportive care needed.4,5,8–10,21 To date there are no antiviral medications that demonstrate clinical benefit against dengue. Dehydration as well as shock is possible, so strict attention to hemodynamics and fluid balance is critical. Bed rest is also important. Fever can be treated with acetaminophen. Other symptoms, such as joint pain, which can be severe, as well as headaches, eye pain, and muscle pain may require aggressive pain management, including narcotics. Given the risk of bleeding from this hemorrhagic fever virus, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided as these, and combination products containing them, are anticoagulants. Be mindful of signs/symptoms of DHF and DSS as the fever starts to abate. An acute change from fever to hypothermia, severe abdominal pain, vomiting, bleeding, shortness of breath/difficulty breathing, or altered mental status are potential medical emergencies; these patients belong in the hospital. Fluid resuscitation for patients with DHF/DSS can enhance outcomes. The monitoring of vital signs, fluid balance, hematocrit, and platelet count are critical in guiding treatment. The management of bleeding includes administration of fresh frozen plasma (FFP), clotting factor concentrates, and platelets and aggressive monitoring/treatment of DIC. Multi-organ system support may be necessary. Concomitant infections, including malaria, should be considered given the ecology and vector-borne risks associated with dengue can coexist with other vector-borne pathogens. Strict adherence to infection control, including personal protective equipment, is recommended.

Conclusion With nearly half the world’s population at risk, dengue is a significant public health threat worldwide. It is a rapidly spreading infectious disease, and in the absence of a currently available vaccine, this viral hemorrhagic fever virus is likely to continue as a global health challenge. With the prevalence of mosquitoes capable of transmitting the virus now well established in the United States, the number of cases in North America is likely to increase significantly owing to population movement, global trade, and climate change. Although travel-related illness remains underdiagnosed and global infections are no longer relegated to distant lands, medical education is lagging in terms of training current and future health care professionals about dengue and other emerging pathogens. Clearly the development of effective vaccines and antivirals that can prevent and treat dengue as well as other viral hemorrhagic fevers is critical. In the interim, vector control, rapid diagnosis, and timely reporting to public health authorities, with aggressive symptomatic and supportive care, are critically important to control DF. The World Health Organization and the Centers for Disease Control regularly update the information—diagnosis, epidemiology, treatment, and new interventions, on dengue, viral hemorrhagic fever viruses, and other emerging threats. The health care professional is encouraged to check these sites as well as their regional public health departments for updates on changing local infection patterns. Moreover it is important that we promote increased training, enhancing the clinical skills among current professionals and trainees in the diagnosis of dengue and other travel-related illnesses.

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References 1. Vazquez-Prokopec G, Kitron Uriel. Tracking the spread of dengue fever: domestic networks drive rapid transmission of human infection. 〈http://www.labspaces.net/126448/Tracking_the_spread_of_dengue_fever__Domestic_networks_ drive_rapid_transmission_of_human_infection_〉; 2013 Accessed 08.03.13. 2. Dengue TEM micrograph from 〈www.cdc.gov〉; accessed July 2013. 3. Simmons CP, Farrar JJ, van Vinh Chau N, Wills B. Dengue. N Engl J Med. 2012;366(15):1423–1432. 4. Tomashek KM. Dengue Fever & Dengue Hemorrhagic Fever. Chapter 3. Infectious Diseases Related to Travel. Atlanta, Georgia: Yellow Book; 2012. 5. Morens DM, Fauci AS. Dengue and hemorrhagic fever: a potential threat to public health in the United States. J Am Med Assoc. 2008;299(2):214–216. 6. Isada CM, Kasten BL, Goldman MP, eds. Infectious Diseases Handbook. 5th ed. Ohio: Lexi-Comp Publishing; 2003:109 7. CDC Fact Sheet—Viral Hemorrhagic Fever Viruses. 〈http://www.cdc.gov〉; accessed 08.03.13. 8. Viral Hemorrhagic Fevers Fact Sheet. Centers for Disease Control and Prevention (CDC). 〈www.CDC.gov〉; accessed 08.03.13. 9. Bankoff J, Thompson T. Hemorrhagic Fever. In: McFee RB, Leikin JB, eds. Toxico-Terrorism. New York, New York: McGraw Hill; 2007:383–391. 10. Peters CJ. Bioterrorism: viral hemorrhagic fever. In: 6th ed. Mandell GL, Bennett JE, Dolin R, eds. Mandell Douglas and Bennett’s Principles and Practice of Infectious Diseases, vol 2. Philadelphia, PA: Elsevier Churchill Livingston; 2005: 3626–3629. 11. Peters CJ, Zaki SR, Rollin PE. Viral hemorrhagic fevers. In: Fekety R, ed. Atlas of Infectious Diseases, Volume VIII. Philadelphia, PA: Churchill, Livingstone; 1997:10.1–10.26. 12. Noisakran S, Onlamoon N, Songprakhon P, Hsiao HM, et al. Cells in dengue virus infection in vivo. Adv Virol. 2010. (ID 164878). 13. Schmitz J, Roehrig J, Barrett A, Hombach J. Next generation dengue vaccines: a review of candidates in preclinical development. Vaccine. 2011;29(42):7276–7284. 14. Brown E. Scientists map dengue, estimate 390 million infections per year LA Times April 08, 2013. 〈http://articles. latimes.com/print/2013/apr/08/science/la-sci-sn-global-dengue-cases-estimated〉; accessed 07.22.13. 15. Guzman MG, Kouri G, Diaz M, et al. Dengue, one of the great emerging health challenges of the 21st century. Expert Rev Vaccines. 2004;3(5):511–520. 16. Beatty ME, Letson GW, Margolis HS. Estimating the global burden of dengue. Am J Trop Med Hyg. 2009;81(suppl): 231. 17. Van Kleef E, Bambrick H, Hales S. The geographic distribution of dengue fever and the potential influence of global climate change. TropIKA.net 〈http://journal.tropkia.net/scielo.pho?script=sci_arttext&pid=S2078-8606201000500 0001&Ing=en&nrm=iso〉. 18. Hirschler B. Experts triple estimate of world dengue fever infections Reuters Apr 7, 2013. 〈http://www.reuters.com/ assets/print?aid=USBRE93608620130407〉; accessed 07.22.13. 19. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature. 2013;496(7446):504–507. 20. Brady OJ. Refining the global spatial limits of dengue virus transmission by evidence based consensus. PLoS Negl Trop Dis. 2012;6(8):e1760. 21. World Health Organization (WHO) Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control 〈www.who. org〉; accessed July 2013. 22. Chambers TJ, Hahn CS, Galler R, Rice CM. Flavivirus genome organization, expression and replication. Ann Rev Microbiol. 1990;44:649–688. 23. Durbin AP, Whitehead SS. Dengue vaccine candidates in development. Curr Top Microbiol Immunol. 2010;338: 129–143. 24. Swaminathan S, Batra G, Khanna N. Dengue vaccines: state of the art. Expert Opin Ther Patient. 2010;20(6):819–835. 25. Guzman MG. Dengue vaccines: new developments. Drugs Future. 2011;36:45–62. 26. Murphy BR, Whitehead SS. Immune response to dengue virus and prospects for a vaccine. Annu Rev Immunol. 2011;29:587–619. 27. Campagna DS, Miagostovich MP, Siqueira MM, daCunha RV. Etiology of exanthema in children in a dengue endemic area. J Pediatr (Rio J). 2006;82(5):354–358. 28. Wilder-smith A, Schwartz E. Dengue in travelers. N Engl J Med. 2005;353(9):924–932. 29. Martini GA, Knauff HG, Schmidt HA, Mayer G, Baltzer G. A hitherto unknown infectious disease contracted from monkeys. German Med Mon. 1968;13(10):457–470. 30. Hunsperger EA, Yoksan S, Buchy P, et al. Evaluation of Commercially available anti-Dengue virus immunoglobulin M tests. Emerg Infect Dis. 2009;15(3):436–440. 31. Sabchareon A, Wallace D, Sirivicayakul C, et al. Protective efficacy of the recombinant, live attenuated, CY tetravalent dengue vaccine in Thai schoolchildren: a random controlled phase 2b trial. Lancet. 2012;380(9853):1559–1567. 32. Dengue Vaccine Research—WHO 〈http://www.who.int/vaccine_research/diseases/dengue/dengue_vaccines/en/ index.html〉; accessed 07.22.13. 33. NIH-developed candidate dengue vaccine shows promise in early stage trial. 〈http://nih.gov/news/health/jan2013/ niaid-23.htm〉; 2013 Accessed 07.24.13. 34. Lagrange C. Reuters Sanofi starts dengue vaccine production to keep lead over rivals 〈http://news.yahoo.com/ sanofi-starts-dengue-vaccine-production-keep -lead-over-11335836〉; accessed 07.24.13. 35. Tatem AJ, Hay SI, Rogers DJ. Global traffic and disease vector dispersal. Proc Natl Acad Sci U S A. 2006;103(16): 6242–6247. 36. 〈http:/www.nc.cdc.gov/travel/yellowbook/2012〉; accessed 07.22.13.

R.B. McFee / Disease-a-Month 59 (2013) 410–425

425

37. Clark G, Gubler D. Dengue Fever, CDC Traveler’s Information on Dengue Fever, Centers for Disease Control. 〈www. cdc.gov〉. 38. Cobelens FG, Groen J, Osterhaus AD, et al. Incidence and risk factors of probable dengue virus infection among Dutch travelers to Asia. Trop Med Int Health. 2002;7(4):331–338. 39. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med. 2006;354(2):119–130. 40. Jelinek T, Dobler G, Holscher M, et al. Prevalence of infection with dengue virus among international travelers. Arch Intern Med. 1997;157(20):2367–2370.