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1.  The relationship of interacting immunological components in dengue pathogenesis 
Virology Journal  2009;6:211.
The World Health Organization (WHO) estimates that there are over 50 million cases of dengue fever reported annually and approximately 2.5 billion people are at risk. Mild dengue fever presents with headache, fever, rash, myalgia, osteogenic pain, and lethargy. Severe disease can manifest as dengue shock syndrome (DSS) or dengue hemorrhagic fever (DHF). Symptoms of DSS/DHF are leukopenia, low blood volume and pressure encephalitis, cold and sweaty skin, gastrointestinal bleeding, and spontaneous bleeding from gums and nose. Currently, there are no therapeutics available beyond supportive care and untreated complicated dengue fever can have a 50% mortality rate. According to WHO DSS/DHF is the leading cause of childhood mortality in some Asian countries. Dendritic cells are professional antigen presenting cells that are primary targets in a dengue infection. Dengue binds to Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN). DC-SIGN has a high affinity for ICAM3 which is expressed in activating T-cells. Previous studies have demonstrated an altered T-cell phenotype expressed in dengue infected patients that could be potentially mediated by dengue-infected DCs.
Dengue is enhanced by three interacting components of the immune system. Dengue begins by infecting dendritic cells which in immature dendritic cells is mediated by DC-SIGN. In mature dendritic cells, antibodies can enhance dengue infection via Fc receptors. Downstream of dendritic cells T-cells become activated and generate the very cytokines implicated in vascular leak and shock in addition to activating effector cells. Both the virus and the antibodies are involved in release of complement and anaphylatoxins which can cause or exacerbate DHF/DSS. These systems are inextricable and strongly associated with dengue pathogenesis.
PMCID: PMC2789730  PMID: 19941667
2.  A case presentation of a fatal dengue myocarditis showing evidence for dengue virus-induced lesion 
Dengue is a prevalent arthropod-borne viral disease in tropical and subtropical areas of the globe. Dengue clinical manifestations include asymptomatic infections; undifferentiated fever; dengue fever, which is characterized by fever, headache, retroorbital pain, myalgia, and arthralgia; and a severe form of the disease denominated dengue haemorrhagic fever/dengue shock syndrome, characterized by haemoconcentration, thrombocytopenia, and bleeding tendency. However, atypical manifestations, such as liver, central nervous system, and cardiac involvement, have been increasingly reported. We report an atypical and rare presentation of dengue disease marked by a dramatic and fatal cardiogenic shock due to acute myocarditis. Histopathological analysis of heart tissue showed several multifocal areas of muscle necrosis and intense interstitial oedema associated with clusters of virus particles inside the cardiomyocytes and in the interstitial space, providing evidence of a possible direct action of dengue virus on myocardium.
PMCID: PMC3821802  PMID: 24222821
Acute heart failure; acute myocarditis; cardiogenic shock; dengue fever
3.  Acute gingival bleeding as a complication of dengue hemorrhagic fever 
Dengue fever is mosquito borne disease caused by dengue virus (DENV) of Flaviviridae family. The clinical manifestations range from fever to severe hemorrhage, shock and death. Here, we report a case of 20-year-old male patient undergoing orthodontic treatment presenting with acute gingival bleeding with a history of fever, weakness, backache, retro orbital pain and ecchymosis over his right arm. The hematological investigations revealed anemia, thrombocytopenia and positive dengue non-structural protein-1 antigen and also positive immunoglobulin M and immunoglobulin G antibodies for DENV. Patient was diagnosed as a case of dengue hemorrhagic fever and was immediately referred for appropriate management. This case report emphasizes the importance of taking correct and thorough medical history.
PMCID: PMC3800419  PMID: 24174736
Acute gingival bleeding; dengue fever; hemorrhage; thrombocytopenia
4.  Evaluation of the Traditional and Revised WHO Classifications of Dengue Disease Severity 
Dengue is a major public health problem worldwide and continues to increase in incidence. Dengue virus (DENV) infection leads to a range of outcomes, including subclinical infection, undifferentiated febrile illness, Dengue Fever (DF), life-threatening syndromes with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. The long-standing World Health Organization (WHO) dengue classification and management scheme was recently revised, replacing DF, Dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS) with Dengue without Warning Signs, Dengue with Warning Signs (abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, increasing hematocrit with decreasing platelets) and Severe Dengue (SD; dengue with severe plasma leakage, severe bleeding, or organ failure). We evaluated the traditional and revised classification schemes against clinical intervention levels to determine how each captures disease severity using data from five years (2005–2010) of a hospital-based study of pediatric dengue in Managua, Nicaragua. Laboratory-confirmed dengue cases (n = 544) were categorized using both classification schemes and by level of care (I–III). Category I was out-patient care, Category II was in-patient care that did not meet criteria for Category III, which included ICU admission, ventilation, administration of inotropic drugs, or organ failure. Sensitivity and specificity to capture Category III care for DHF/DSS were 39.0% and 75.5%, respectively; sensitivity and specificity for SD were 92.1% and 78.5%, respectively. In this data set, DENV-2 was found to be significantly associated with DHF/DSS; however, this association was not observed with the revised classification. Among dengue-confirmed cases, the revised WHO classification for severe dengue appears to have higher sensitivity and specificity to identify cases in need of heightened care, although it is no longer as specific for a particular pathogenic entity as was the traditional schema.
Author Summary
Dengue is a mosquito-transmitted viral disease that is a major public health problem worldwide. Dengue virus (DENV) infection leads to Dengue Fever (DF) and a spectrum of life-threatening syndromes with fluid loss and hypotensive shock or other severe manifestations. Recently, the traditional World Health Organization (WHO) dengue classification scheme (classic DF, Dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS)) was replaced with Dengue without Warning Signs, Dengue with Warning Signs and Severe Dengue (SD). Using data from 544 laboratory-confirmed dengue cases recruited over five years of a hospital-based study of pediatric dengue in Managua, Nicaragua, we evaluated the traditional and revised classification schemes against clinical intervention levels (I–III) to determine how each captures disease severity. The sensitivity and specificity to capture Category III care for DHF/DSS were 39.0% and 75.5%, respectively, and for SD were 92.1% and 78.5%, respectively. Interestingly, DENV-2 was significantly associated with DHF/DSS; however, this association was not observed with the revised classification. This study indicates that among dengue-confirmed cases, the revised WHO classification appears to have higher sensitivity and specificity for identifying cases in need of heightened care, although it is no longer as specific for a particular pathogenic entity as was the traditional schema.
PMCID: PMC3210746  PMID: 22087348
5.  Travel-related Dengue Virus Infection, the Netherlands, 2006–2007 
Emerging Infectious Diseases  2011;17(5):821-828.
To assess the incidence of and risk factors for clinical and subclinical dengue virus (DENV) infection, we prospectively studied 1,207 adult short-term travelers from the Netherlands to dengue-endemic areas. Participants donated blood samples for serologic testing before and after travel. Blood samples were tested for antibodies against DENV. Seroconversion occurred in 14 (1.2%) travelers at risk. The incidence rate was 14.6 per 1,000 person-months. The incidence rate was significantly higher for travel during the rainy months. Dengue-like illness occurred in 5 of the 14 travelers who seroconverted. Seroconversion was significantly related to fever, retro-orbital pain, myalgia, arthralgia, and skin rash. The risk for DENV infection for short-term travelers to dengue-endemic areas is substantial. The incidence rate for this study is comparable with that in 2 other serology-based prospective studies conducted in the 1990s.
PMCID: PMC3321765  PMID: 21529390
Dengue; epidemiology; risk factors; prospective study; viruses; the Netherlands; vector-borne infections; travelers; viruses; research
6.  Dengue Fever, Hawaii, 2001–2002 
Emerging Infectious Diseases  2005;11(5):742-749.
Autochthonous dengue infections were last reported in Hawaii in 1944. In September 2001, the Hawaii Department of Health was notified of an unusual febrile illness in a resident with no travel history; dengue fever was confirmed. During the investigation, 1,644 persons with locally acquired denguelike illness were evaluated, and 122 (7%) laboratory-positive dengue infections were identified; dengue virus serotype 1 was isolated from 15 patients. No cases of dengue hemorrhagic fever or shock syndrome were reported. In 3 instances autochthonous infections were linked to a person who reported denguelike illness after travel to French Polynesia. Phylogenetic analyses showed the Hawaiian isolates were closely associated with contemporaneous isolates from Tahiti. Aedes albopictus was present in all communities surveyed on Oahu, Maui, Molokai, and Kauai; no Ae. aegypti were found. This outbreak underscores the importance of maintaining surveillance and control of potential disease vectors even in the absence of an imminent disease threat.
PMCID: PMC3320380  PMID: 15890132
Arboviruses; dengue fever; emerging infectious diseases; hemorrhagic fever; vector-borne diseases
7.  Dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient: the first case report 
Dengue infection, a mosquito-borne infectious disease in tropical and subtropical areas, has recently become an emerging global disease. The clinical course of dengue infection may be unfavorable in immunocompromised patients. In this report, we present a 16-year old female patient with acute myeloid leukemia who received allogeneic peripheral blood stem cell transplant five months prior to presentation. She was hospitalized at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, due to fever, headache, and myalgia for one day. During hospitalization, she developed capillary leakage syndrome and progressive thrombocytopenia. A diagnosis of dengue hemorrhagic fever was made and confirmed by positive dengue serology and polymerase chain reaction testing. She made a full recovery 14 days after hospitalization. Our case possibly acquired dengue virus from infected mosquitoes while visiting her relatives four days before her present illness. In conclusion, this is the first reported case of dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient. In addition, we review all previous reports of dengue infection in organ transplant recipients.
PMCID: PMC3892570  PMID: 24470881
dengue; dengue hemorrhagic fever; stem cell transplantation; bone marrow transplantation.
8.  Enhancing Surveillance for Arboviral Infections in the Arizona Border Region 
To enhance arboviral surveillance and laboratory capacity to establish a surveillance baseline for the emerging threat of Dengue fever in the Arizona-Mexico border region.
West Nile Virus (WNV) and dengue virus (DENV) are both arboviruses which are transmitted to humans by an infected mosquito bite during blood-meal feeding. The clinical presentations of non-neuroinvasive WNV and dengue fever are similar, and symptoms may include acute onset of high fever, headache, myalgia, arthralgia, nausea, vomiting, and often a maculopapular rash. More serious manifestations of these viruses include fatal encephalitis and meningitis in WNV patients and fatal hemorrhagic disease in dengue patients. Over the last decade, WNV has spread rapidly across North America, reaching Arizona in 2004, and has become a significant cause of human illness since that time. Even though dengue has been described as primarily a disease of the tropics and sub-tropical areas, there is a small but significant risk for dengue outbreaks in the continental United States as evidenced by surveillance efforts in Texas that identified local dengue transmission in 2005. In recent years, outbreaks of dengue have occurred in Mexico border states, most notably Sonora in 2010. That same year, Arizona had the highest incidence of WNV cases in the U.S. including number of neuroinvasive disease cases, total cases, and number of deaths per state. The emergence of DENV and WNV as important public health problems maybe have been due to non-effective mosquito control, global demographic changes (urbanization and population growth), increased air travel, and inadequate surveillance.
Vector mapping: Mapping techniques will be utilized to visually depict Aedes aegypti populations captured from previous seasonal public health environmental vector trapping programs.
Laboratory capacity: Multi-state laboratory training by CDC Dengue Branch was held in October 2012.
Surveillance: The WNV cases that present to medical services for WNV testing and reported to public health officials are the most severe nueroinvasive cases. Much less is understood about the non-neuroinvasive cases with often present with non-descript symptoms.
Vector mapping: Comparative densities of Ae. aegypti with academic partners of the Entomology and Public Health conducting a study capturing Ae. aegypti may help to enhance environmental programs.
Laboratory Capacity: The laboratory training will cover conventional serological methods as well as recently FDA cleared molecular RT-PCR. Participants will include public health laboratory personnel working in molecular and serology diagnostics and other binational partners.
Surveillance: A convenient seroprevalence study at sentinel-hospital site of symptomatic patients presenting in Arizona border hospital sites will be performed to better understand circulating levels of arboviral infections.
Appropriate and timely response to surveillance data is the key to identification human and animal disease associated with WNV, DENV, and other arboviruses. The mosquito vector Ae. aegypti is well established widespread and thriving in Arizona yet there is no autochthonous transmission of DENV identified to date. The results from this study will identify gaps and potential prevention and control measures for emerging infectious diseases including WNV and DENV in Arizona.
PMCID: PMC3692884
Dengue; Surveillance; Emerging infections; Dengue fever; Arboviral
9.  Dengue Hemorrhagic Fever: the sensitivity and specificity of the WHO definition in identifying severe dengue cases in Thailand, 1994-2005 
Dengue virus infection causes a spectrum of clinical manifestations, usually classified according to the World Health Organization (WHO) guidelines into dengue fever (DF) and dengue hemorrhagic fever (DHF). Its ability to categorize severe dengue illness has recently been questioned.
We evaluated dengue case definitions in a prospective study at a pediatric hospital in Bangkok from 1994-2005. One thousand and thirteen children were enrolled within the first three days of fever and followed with standardized data collection. Cases were classified based on application of the strict WHO criteria. All dengue virus infections were laboratory confirmed. We retrospectively grouped patients based on whether they received significant intervention based on the fluid replacement and/or requirements for blood transfusion.
Fifty eight percent (85/150), 15% (40/264), and 12% (73/599) of DHF, DF and other febrile illnesses (OFI) cases, respectively, received significant intervention. Sixty-eight percent of dengue cases requiring intervention met strict WHO criteria for DHF. In contrast, only 1% of OFI cases met WHO criteria for DHF. Plasma leakage and thrombocytopenia were the two components contributing to the specificity of the WHO case definition and identified dengue cases that required intervention. Hemorrhagic tendency did not reliably differentiate DF and DHF. In DF cases, thrombocytopenia and bleeding were associated with severity.
Dengue illness is heterogeneous in severity, and severe clinical features occurred in patients that were not characterized as DHF. The WHO case definition of DHF demonstrates 62% sensitivity and 92% specificity in identifying dengue illness requiring intervention without the need for laboratory confirmation of dengue virus infection in endemic areas.
PMCID: PMC2853952  PMID: 20205587
dengue hemorrhagic fever; dengue fever; WHO clinical guidelines; plasma leakage; clinical severity
10.  Hypokalemic quadriparesis: An unusual manifestation of dengue fever 
Dengue is the most important mosquito-borne, arboviral infection found in tropical and sub-tropical climates. Clinical presentation varies from a severe flu-like illness to a potentially lethal dengue hemorrhagic fever. Dengue has been regarded as a nonneurotropic virus. However, there are reports describing neurological involvements in dengue virus infection. The neurological involvement in dengue virus infection includes encephalitis, acute disseminated encephalomyelitis, transverse myelitis, and Guillain-Barre syndrome. The neurological spectrum of dengue patients has been limited because of small number of case reports, paucity of imaging, and neurophysiologic studies. There are only a few isolated case reports and case series documenting acute pure motor quadriparesis in dengue fever. We report acute pure motor reversible quadriparesis due to hypokalemia. Clinicians in the endemic area should be aware of such association of acute pure motor reversible quadriparesis with dengue fever
PMCID: PMC3361784  PMID: 22690057
Dengue fever; flaccid paralysis; hypokalemia; quadriparesis
11.  Factors Predicting Severe Dengue in Patients with Dengue Fever 
Dengue virus (DENV) affects over half the world’s population in 112 countries, and dengue fever (DF) is the second largest arthropod borne infectious global hazard after malaria with complications like Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS), accounting for significant morbidity and mortality world-over. Pakistan is significantly affected with DENV infection and to-date no study identifying risk factors associated with development of severe complications of DF has been done.
997 confirmed cases of DF were collected from a tertiary care hospital in Lahore, Pakistan and their clinical and biochemical data were collected. Univariate, multivariate and logistics regression analysis was performed to identify risk factors associated with development of DHF and DSS.
Bleeding OR 70.7 (CI 38.4–129.9), deranged liver function test OR 1.9 (CI 0.97–0.99), presence of urinary red blood cells OR 1.4 (95%CI 0.179–0.900) and presence of urinary protein OR 1.1 (95%CI 0.191–0.974) were related to development of DHF and DSS.
Severe Dengue, like DHF and DSS can be predicted by the presence of clinical and biochemical factors like signs of bleeding, deranged liver function test, presence of urinary red blood cells and urinary protein; so that the patients at high risk for complication be identified early and started on treatment timely.
Predictors of severe dengue are identified in this study but further large scale multi-centered studies are needed for better interpretation.
PMCID: PMC3591277  PMID: 23505602
12.  Demographic and Clinico-Epidemiological Features of Dengue Fever in Faisalabad, Pakistan 
PLoS ONE  2014;9(3):e89868.
This cross-sectional study was carried out to explore the epidemiological and clinical features of dengue fever in Faisalabad, Pakistan during 2011 and 2012. During the study period, anti-dengue IgM positive cases were reported in the post-monsoon period during the months of August–December. Certain hotspots for the dengue infection were identified in the city that coincide with the clusters of densely populated urban regions of the city. Out of total 299 IgM positive patients (male 218 and female 81); there were 239 dengue fever (DF) and 60 dengue hemorrhagic fever (DHF) patients. There was decrease in the median age of dengue patients from 31 years in 2011 to 21.5 years in 2012 (p<0.001). Abdominal pain was seen in 35% DHF patients followed by nausea in 28.3%, epistaxis in 25% and rash in 20% patients (p<0.05). Patients reported to be suffering from high-grade fever for an average of 8.83 days in DHF as compared to 5.82 days in DF before being hospitalized. Co-morbidities were found to be risk factor for the development of DHF in dengue patients. Clinical and laboratory features of dengue cases studied could be used for the early identification of patients at risk of severe dengue fever.
PMCID: PMC3940608  PMID: 24595236
13.  Dengue fever mimicking acute appendicitis: A case report☆ 
Dengue fever is an acute viral disease, which usually presents as a mild febrile illness. Patients with severe disease present with dengue haemorrhagic fever or dengue toxic shock syndrome. Rarely, it presents with abdominal symptoms mimicking acute appendicitis. We present a case of a male patient presenting with right iliac fossa pain and suspected acute appendicitis that was later diagnosed with dengue fever following a negative appendicectomy.
A 13-year old male patient presented with fever, localized right-sided abdominal pain and vomiting. Abdominal ultrasound was not helpful and appendicectomy was performed due to worsening abdominal signs and an elevated temperature. A normal appendix with enlarged mesenteric nodes was found at surgery. Complete blood count showed thrombocytopenia with leucopenia. Dengue fever was now suspected and confirmed by IgM enzyme-linked immunosorbent assay against dengue virus.
This unusual presentation of dengue fever mimicking acute appendicitis should be suspected during viral outbreaks and in patients with atypical symptoms and cytopenias on blood evaluation in order to prevent unnecessary surgery.
This case highlights the occurrence of abdominal symptoms and complications that may accompany dengue fever. Early recognition of dengue fever mimicking acute appendicitis will avoid non-therapeutic operation and the diagnosis may be aided by blood investigations indicating a leucopenia, which is uncommon in patients with suppurative acute appendicitis.
PMCID: PMC3825978  PMID: 24096347
Dengue fever; Acute appendicitis; Acute abdomen; Leucopenia
14.  Dengue: a new challenge for neurology 
Neurology International  2012;4(3):e15.
Dengue infection is a leading cause of illness and death in tropical and subtropical regions of the world. Forty percent of the world's population currently lives in these areas. The clinical picture resulting from dengue infection can range from relatively minor to catastrophic hemorrhagic fever. Recently, reports have increased of neurological manifestations. Neuropathogenesis seems to be related to direct nervous system viral invasion, autoimmune reaction, metabolic and hemorrhagic disturbance. Neurological manifestations include encephalitis, encephalopathy, meningitis, Guillain-Barré syndrome, myelitis, acute disseminated encephalomyelitis, polyneuropathy, mononeuropathy, and cerebromeningeal hemorrhage. The development of neurological symptoms in patients with positive Immunoglobulin M (IgM) dengue serology suggests a means of diagnosing the neurological complications associated with dengue. Viral antigens, specific IgM antibodies, and the intrathecal synthesis of dengue antibodies have been successfully detected in cerebrospinal fluid. However, despite diagnostic advancements, the treatment of neurological dengue is problematic. The launch of a dengue vaccine is expected to be beneficial.
PMCID: PMC3555217  PMID: 23355928
dengue; neurological manifestations; treatment.
15.  Acute renal failure due to rhabdomyolysis following dengue viral infection: a case report 
With more than one-third of the world’s population living in areas at risk for transmission, dengue fever is a leading cause of illness and death in the tropics and subtropics. Despite the high incidence of dengue fever, rhabdomyolysis leading to acute renal failure is an extremely rare complication of dengue fever. Only a few such cases have been reported in the literature.
Case presentation
We describe the case of a 42-year-old, previously healthy Sri Lankan Sinhalese man who developed acute renal failure due to rhabdomyolysis following dengue virus infection. He was transferred to our institution with a five-day history of fever, headache, myalgia, impaired level of consciousness, and reduced urinary output. He was hemodynamically stable and did not have evidence of plasma leakage. His serology for dengue immunoglobulin M and immunoglobulin G was positive, and biochemical investigations disclosed evidence of rhabdomyolysis and acute renal failure. He was treated with induced alkaline diuresis and hemodialysis, and he experienced an uncomplicated recovery.
The occurrence of acute renal failure significantly increases the mortality of patients with dengue fever. Therefore, early diagnosis and early management are crucial in rhabdomyolysis complicating dengue fever to prevent established acute renal failure. It should be kept in mind that the threshold for suspecting rhabdomyolysis is very low in dengue fever. Creatinine phosphokinase levels should routinely be measured in all patients with severe dengue fever for early detection of rhabdomyolysis to prevent acute renal failure.
PMCID: PMC3750229  PMID: 23889764
Dengue fever; Myositis; Rhabdomyolysis; Acute renal failure
16.  The revised WHO dengue case classification: does the system need to be modified? 
There has been considerable debate regarding the value of both the 1997 and 2009 World Health Organization (WHO) dengue case classification criteria for its diagnosis and management. Differentiation between classic dengue fever (DF) and dengue haemorrhagic fever (DHF) or severe dengue is a key aspect of dengue case classification. The geographic expansion of dengue and its increased incidence in older age groups have contributed to the limited applicability of the 1997 case definitions. Clinical experience of dengue suggests that the illness presents as a spectrum of disease instead of distinct phases. However, despite the rigid grouping of dengue into DF, DHF and dengue shock syndrome (DSS), overlap between the different manifestations has often been observed, which has affected clinical management and triage of patients. The findings of the DENCO study evaluating the 1997 case definitions formed the basis of the revised 2009 WHO case definitions, which classified the illness into dengue with and without warning signs and severe dengue. Although the revised scheme is more sensitive to the diagnosis of severe dengue, and beneficial to triage and case management, there remain issues with its applicability. It is considered by many to be too broad, requiring more specific definition of warning signs. Quantitative research into the predictive value of these warning signs on patient outcomes and the cost-effectiveness of the new classification system is required to ascertain whether the new classification system requires further modification, or whether elements of both classification systems can be combined.
PMCID: PMC3381438  PMID: 22668448
Dengue; Classification; Diagnosis; World Health Organization
17.  Dengue viruses – an overview 
Infection Ecology & Epidemiology  2013;3:10.3402/iee.v3i0.19839.
Dengue viruses (DENVs) cause the most common arthropod-borne viral disease in man with 50–100 million infections per year. Because of the lack of a vaccine and antiviral drugs, the sole measure of control is limiting the Aedes mosquito vectors. DENV infection can be asymptomatic or a self-limited, acute febrile disease ranging in severity. The classical form of dengue fever (DF) is characterized by high fever, headache, stomach ache, rash, myalgia, and arthralgia. Severe dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) are accompanied by thrombocytopenia, vascular leakage, and hypotension. DSS, which can be fatal, is characterized by systemic shock. Despite intensive research, the underlying mechanisms causing severe dengue is still not well understood partly due to the lack of appropriate animal models of infection and disease. However, even though it is clear that both viral and host factors play important roles in the course of infection, a fundamental knowledge gap still remains to be filled regarding host cell tropism, crucial host immune response mechanisms, and viral markers for virulence.
PMCID: PMC3759171  PMID: 24003364
dengue virus; dengue fever; dengue hemorrhagic fever; dengue shock syndrome; flavivirus; vector-borne virus; arbovirus
18.  Serotype and genotype analysis of dengue virus by sequencing followed by phylogenetic analysis using samples from three mini outbreaks-2007-2009 in Pakistan 
BMC Microbiology  2011;11:200.
Since the first reported outbreak of dengue hemorrhagic fever in Pakistan, several mini outbreaks have erupted in the region. Dengue virus serotype 3 (DEN-3) was first documented in 2005 outbreak in Karachi. Reports show that serotype 3 is prevalent in Lahore since 2008. Serotype 2 (DEN-2) is the major circulating serotype in Pakistan as it is documented since 1994. We have conducted a detailed study of three outbreaks of dengue virus infection that occurred in years 2007, 2008 and 2009 in Lahore by using molecular techniques such as PCR and nucleotide sequencing of the C-prM gene junction of Dengue virus.
Through the analysis of 114 serum samples collected over the period of three years (2007-2009), total 20 patients were found to be infected with dengue virus. In year 2007, four were positive for serotype 2 and one sample was positive for serotype DEN-3. In 2008, five samples had concurrent infection with serotypes DEN-2 and DEN-3 while three samples were infected only with serotype DEN-2. In year 2009, one sample had concurrent infection with serotypes DEN-2 and DEN-3 while six were positive for serotype DEN-2 only.
Our study showed that serotype DEN-2 was dominant in positive samples of dengue virus infection collected during the period of three years (2007-2009). The other serotype present was serotype DEN-3. Genotypes of serotype DEN-2 and serotype DEN-3 were subtype IV and subtype III, respectively.
PMCID: PMC3180347  PMID: 21906394
19.  Acute Febrile Illness Surveillance in a Tertiary Hospital Emergency Department: Comparison of Influenza and Dengue Virus Infections 
In 2009, an increased proportion of suspected dengue cases reported to the surveillance system in Puerto Rico were laboratory negative. As a result, enhanced acute febrile illness (AFI) surveillance was initiated in a tertiary care hospital. Patients with fever of unknown origin for 2–7 days duration were tested for Leptospira, enteroviruses, influenza, and dengue virus. Among the 284 enrolled patients, 31 dengue, 136 influenza, and 3 enterovirus cases were confirmed. Nearly half (48%) of the confirmed dengue cases met clinical criteria for influenza. Dengue patients were more likely than influenza patients to have hemorrhage (81% versus 26%), rash (39% versus 9%), and a positive tourniquet test (52% versus 18%). Mean platelet and white blood cell count were lower among dengue patients. Clinical diagnosis can be particularly difficult when outbreaks of other AFI occur during dengue season. A complete blood count and tourniquet test may be useful to differentiate dengue from other AFIs.
PMCID: PMC3592528  PMID: 23382160
20.  Paralytic squint due to abducens nerve palsy : a rare consequence of dengue fever 
BMC Infectious Diseases  2012;12:156.
Dengue fever is an endemic illness in the tropics with early and post infectious complications affecting multiple systems. Though neurological sequelae including mononeuropathy, encephalopathy, transverse myelitis, polyradiculopathy, Guillain-Barre syndrome , optic neuropathy and oculomotor neuropathy have been reported in medical literature, the abducens nerve despite its notoriety in cranial neuropathies in a multitude of condition due to its long intracranial course had not been to date reported to manifest with lateral rectus paralysis following dengue.
Case presentation
A previously well 29 year old male with serologically confirmed dengue hemorrhagic fever developed symptomatic right lateral rectus palsy during the critical phase of the illness, which persisted into convalescence and post convalescence with proven deficit on Hess screen. Alternate etiologies were excluded by imaging, serology and electrophysiology.
The authors detail the first reported case of abducens nerve palsy complicating dengue fever in a previously healthy male from Sri Lanka. In a tropical country with endemic dengue infections, dengue related abducens neuropathy may be considered as a differential diagnosis in cases of acquired lateral rectus palsy after dengue fever.
PMCID: PMC3437196  PMID: 22799448
Dengue fever; Squint; Abducens palsy
21.  Competitive inhibitor of cellular alpha-glucosidases protects mice from lethal dengue virus infection 
Antiviral research  2011;92(2):369-371.
Dengue virus infection causes diseases in people, ranging from the acute febrile illness Dengue fever, to life-threatening Dengue Hemorrhagic Fever/Dengue Shock Syndrome. We previously reported that a host cellular α-glucosidases I and II inhibitor, imino sugar CM-10-18, potently inhibited dengue virus replication in cultured cells, and significantly reduced viremia in dengue virus infected AG129 mice. In this report we show that CM-10-18 also significantly protects mice from death and/or disease progress in two mouse models of lethal dengue virus infection. Our results thus provide a strong support for the development of CM-10-18 or its derivatives as antiviral agents to treat server dengue virus infections.
PMCID: PMC3209657  PMID: 21854808
glucosidase inhibitor; dengue virus; lethal infection mouse model
22.  Temporal Dynamics of the Transcriptional Response to Dengue Virus Infection in Nicaraguan Children 
Dengue is the most prevalent mosquito-borne human illness worldwide. The ability to predict disease severity during the earliest days of the illness is a long-sought, but unachieved goal.
We examined human genome-wide transcript abundance patterns in daily peripheral blood mononuclear cell (PBMC) samples from 41 children hospitalized with dengue virus (DENV) infection in Nicaragua, as well as 8 healthy control subjects. Nine patients had primary dengue fever (DF1), 11 had dengue fever with serologic evidence of prior DENV infection, i.e., secondary dengue fever (DF2), 12 had dengue hemorrhagic fever (DHF), and 9 had dengue shock syndrome (DSS). We identified 2,092 genes for which transcript abundance differed significantly between patients on days 3–6 of fever and healthy subjects (FDR<1%). Prior DENV infection explained the greatest amount of variation in gene expression among patients. The number of differentially expressed genes was greatest on fever day 3 in patients with DF1, while the number in patients with DF2 or DHF/DSS was greatest on day 5. Genes associated with the mitotic cell cycle and B cell differentiation were expressed at higher levels, and genes associated with signal transduction and cell adhesion were expressed at lower levels, in patients versus healthy controls. On fever day 3, a set of interferon-stimulated gene transcripts was less abundant in patients who subsequently developed DSS than in other patient groups (p<0.05, ranksum). Patients who later developed DSS also had higher levels of transcripts on day 3 associated with mitochondrial function (p<0.01, ranksum). These day 3 transcript abundance findings were not evident on subsequent fever days.
In conclusion, we identified differences in the timing and magnitude of human gene transcript abundance changes in DENV patients that were associated with serologic evidence of prior infection and with disease severity. Some of these differential features may predict the outcome of DENV infection.
Author Summary
Infection with dengue virus (DENV) causes dengue fever, the most prevalent mosquito-borne illness of humans worldwide. Tens of millions of cases occur annually; up to 500,000 patients develop additional life-threatening complications, including hemorrhage and shock. The clinical course of the disease evolves rapidly, making it difficult to identify patients at risk for severe disease and suggesting that biological events associated with the development of severe disease may be short-lived. We examined gene expression patterns in the blood of children hospitalized with DENV infection, and found that patients with differences in disease severity and history of previous DENV infection shared a common set of gene expression features, but the timing and magnitude of these features differed. In our study, prior DENV infection explained the greatest amount of variation in gene expression among patients. We discovered features of gene expression on day 3 that were associated with subsequent disease severity—features that were not apparent on subsequent days, emphasizing the importance of looking at temporal patterns of gene expression in acute infection.
PMCID: PMC3527342  PMID: 23285306
23.  T-Cell Immunity to Infection with Dengue Virus in Humans 
Dengue virus (DENV) is the etiologic agent of dengue fever, the most significant mosquito-borne viral disease in humans. Up to 400 million DENV infections occur every year, and severity can range from asymptomatic to an acute self-limiting febrile illness. In a small proportion of patients, the disease can exacerbate and progress to dengue hemorrhagic fever and/or dengue shock syndrome, characterized by severe vascular leakage, thrombocytopenia, and hemorrhagic manifestations. A unique challenge in vaccine development against DENV is the high degree of sequence variation, characteristically associated with RNA viruses. This is of particular relevance in the case of DENV since infection with one DENV serotype (primary infection) presumably affords life-long serotype-specific immunity but only partial and temporary immunity to other serotypes in secondary infection settings. The role of T cells in DENV infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing to severe disease. Our recent study has suggested an HLA-linked protective role for T cells. Herein, we will discuss the role of T cells in protection and pathogenesis from severe disease as well as the implications for vaccine design.
PMCID: PMC3945531  PMID: 24639680
DENV; T cells; protection; pathogenesis; HLA; vaccines
Indian Journal of Dermatology  2010;55(1):68-78.
Dengue viral infections are one of the most important mosquito-borne diseases in the world. Presently dengue is endemic in 112 countries in the world. It has been estimated that almost 100 million cases of dengue fever and half a million cases of dengue hemorrhagic fever (DHF) occur worldwide. An increasing proportion of DHF is in children less than 15 years of age, especially in South East and South Asia. The unique structure of the dengue virus and the pathophysiologic responses of the host, different serotypes, and favorable conditions for vector breeding have led to the virulence and spread of the infections. The manifestations of dengue infections are protean from being asymptomatic to undifferentiated fever, severe dengue infections, and unusual complications. Early recognition and prompt initiation of appropriate supportive treatment are often delayed resulting in unnecessarily high morbidity and mortality. Attempts are underway for the development of a vaccine for preventing the burden of this neglected disease. This review outlines the epidemiology, clinical features, pathophysiologic mechanisms, management, and control of dengue infections.
PMCID: PMC2856379  PMID: 20418983
Dengue; epidemiology; clinical features; treatment
25.  Rhabdomyolysis and Dengue Fever: A Case Report and Literature Review 
Case Reports in Medicine  2013;2013:101058.
The medical literature contains only a few reports of rhabdomyolysis occurring in patients with dengue fever. We report the case of a 25-year-old Jamaican man who was admitted to a private hospital four days after the onset of an acute febrile illness with fever, myalgia, and generalized weakness. Dengue fever was confirmed with a positive test for the dengue antigen, nonstructural protein 1. He remained well and was discharged on day 6 of his illness. On day 8, he started to pass red urine and was subsequently admitted to the University Hospital of the West Indies. On admission he was found to have myoglobinuria and an elevated creatine phosphokinase (CPK) of 325,600 U/L, leading to a diagnosis of rhabdomyolysis. Dengue IgM was positive. He was treated with aggressive hydration and had close monitoring of his urine output, creatinine, and CPK levels. His hospital course was uneventful without the development of acute renal failure and he was discharged after 14 days in hospital, with a CPK level of 2463 U/L. This case highlights that severe rhabdomyolysis may occur in patients with dengue fever and that early and aggressive treatment may prevent severe complications such as acute renal failure and death.
PMCID: PMC3568885  PMID: 23424589

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