The document summarizes current methods for diagnosing dengue virus infection. It discusses the limitations of clinical diagnosis due to non-specific symptoms in early infection. Laboratory diagnostic methods include virus isolation through mosquito inoculation or cell culture, which is sensitive but requires specialized facilities. Reverse-transcriptase PCR detection of viral RNA in blood is now more widely used, as it is rapid, sensitive and specific. Both virus isolation and PCR can detect infection early in the viremic phase. Serological tests detect antibody response and are more useful later in infection or for secondary dengue diagnosis. Improved early diagnosis remains a challenge, especially with development of a dengue vaccine.
Dengue is a rapidly spreading mosquito-borne viral disease that infects an estimated 50 million people annually. Laboratory diagnosis of dengue is important for early detection, confirmation of clinical diagnosis, surveillance, outbreak control, and research. During the acute phase within 5 days of illness, the virus can be detected through virus isolation, nucleic acid detection, or antigen detection (NS1). After the acute phase, antibodies are detected - IgM appears first and indicates a primary infection, while IgG indicates a secondary infection. IgM levels peak at 2 weeks and decline over 2-3 months. IgG levels rise more slowly but persist for months or life. The IgM/IgG ratio can distinguish primary from secondary infection. Patient monitoring
Dengue is a rapidly spreading mosquito-borne viral disease. During the acute phase of infection, up to 5 days after onset of symptoms, the dengue virus can be detected through NS1 antigen detection, virus isolation, or nucleic acid detection. From 3 days to 2 months after symptoms begin, dengue-specific IgM antibodies are detectable and used for diagnosis. IgG antibodies develop later, after 3 weeks, and can be detected for months or life, indicating a past infection. Differentiating primary from secondary dengue infection involves measuring the ratio of IgM to IgG antibodies. Monitoring of platelet counts and hematocrit values during the acute phase aids diagnosis and assessment of severity.
The document summarizes information about dengue virus, including that it is spread by Aedes mosquitoes during the day, there is no vaccine, and symptoms include fever, headaches, joint pain and rash. It describes dengue hemorrhagic fever as a serious condition affecting those previously infected with a different strain, and notes tests for dengue antibodies are performed at Liaquat National Hospital using an immunochromatographic kit called BIAS-3.
Laboratory investigation of dengue in Jeddahhosammadani
The document discusses laboratory diagnosis of dengue hemorrhagic fever. It describes dengue virus characteristics and various diagnostic techniques used including virus isolation, serological tests like ELISA and hemagglutination inhibition, and molecular detection of dengue virus RNA through reverse transcription PCR. It provides details of specific diagnostic tests and procedures used at the Jeddah Regional Laboratory.
The document discusses dengue, its causative virus, transmission cycle, clinical manifestations, diagnosis, and management in children. It describes how the dengue virus is transmitted between humans and mosquitoes, the four serotypes of the virus, and the typical 3 phase clinical course of dengue fever and dengue hemorrhagic fever. It provides guidelines for classifying and managing patients based on symptoms and severity, including outpatient and inpatient treatment and criteria for discharge.
This document provides guidance on evaluating and managing acute febrile illness in returning travelers. It outlines:
1) Common causes of fever in returning travelers, including malaria, dengue, influenza, and enteric fever.
2) Recommendations for obtaining a thorough travel history, physical exam, and diagnostic testing based on the patient's symptoms, risk factors, and travel destinations.
3) Treatment guidelines for various infections based on disease severity and suspected pathogen.
Dengue fever- clinical features,investigations, diagnosis, treatment and prev...DeepakBhosle
This presentation is for medical students and general practitioner It contains detailed account of epidemiology, causation, clinical features, investigations,diagnosis, treatment of dengue fever. contains pictures. useful latest and comprehensive information about Dengue. It also contains dengue case definitions of WHO.It also lists the complications of dengue. It enumerates the warning signs for more severe form of dengue fever. Includes risk factors for dengue shock syndrome and dengue hemorrhagic fever.It includes a list if clinical markers of dengue. Also details about the habits of the dengue vector , aedes aegypti mosquito
This document provides an overview of dengue fever management. It discusses the virus and vector, pathogenesis, clinical manifestations, investigations, severity grading, treatment approaches including fluid management, and discharge criteria. Key points include: dengue is caused by a flavivirus with 4 serotypes transmitted by Aedes aegypti mosquitoes; symptoms range from mild fever to potentially fatal shock; grading disease severity is important to determine management; intravenous fluids and monitoring for warning signs are the main treatment approaches.
Dengue is a rapidly spreading mosquito-borne viral disease that infects an estimated 50 million people annually. Laboratory diagnosis of dengue is important for early detection, confirmation of clinical diagnosis, surveillance, outbreak control, and research. During the acute phase within 5 days of illness, the virus can be detected through virus isolation, nucleic acid detection, or antigen detection (NS1). After the acute phase, antibodies are detected - IgM appears first and indicates a primary infection, while IgG indicates a secondary infection. IgM levels peak at 2 weeks and decline over 2-3 months. IgG levels rise more slowly but persist for months or life. The IgM/IgG ratio can distinguish primary from secondary infection. Patient monitoring
Dengue is a rapidly spreading mosquito-borne viral disease. During the acute phase of infection, up to 5 days after onset of symptoms, the dengue virus can be detected through NS1 antigen detection, virus isolation, or nucleic acid detection. From 3 days to 2 months after symptoms begin, dengue-specific IgM antibodies are detectable and used for diagnosis. IgG antibodies develop later, after 3 weeks, and can be detected for months or life, indicating a past infection. Differentiating primary from secondary dengue infection involves measuring the ratio of IgM to IgG antibodies. Monitoring of platelet counts and hematocrit values during the acute phase aids diagnosis and assessment of severity.
The document summarizes information about dengue virus, including that it is spread by Aedes mosquitoes during the day, there is no vaccine, and symptoms include fever, headaches, joint pain and rash. It describes dengue hemorrhagic fever as a serious condition affecting those previously infected with a different strain, and notes tests for dengue antibodies are performed at Liaquat National Hospital using an immunochromatographic kit called BIAS-3.
Laboratory investigation of dengue in Jeddahhosammadani
The document discusses laboratory diagnosis of dengue hemorrhagic fever. It describes dengue virus characteristics and various diagnostic techniques used including virus isolation, serological tests like ELISA and hemagglutination inhibition, and molecular detection of dengue virus RNA through reverse transcription PCR. It provides details of specific diagnostic tests and procedures used at the Jeddah Regional Laboratory.
The document discusses dengue, its causative virus, transmission cycle, clinical manifestations, diagnosis, and management in children. It describes how the dengue virus is transmitted between humans and mosquitoes, the four serotypes of the virus, and the typical 3 phase clinical course of dengue fever and dengue hemorrhagic fever. It provides guidelines for classifying and managing patients based on symptoms and severity, including outpatient and inpatient treatment and criteria for discharge.
This document provides guidance on evaluating and managing acute febrile illness in returning travelers. It outlines:
1) Common causes of fever in returning travelers, including malaria, dengue, influenza, and enteric fever.
2) Recommendations for obtaining a thorough travel history, physical exam, and diagnostic testing based on the patient's symptoms, risk factors, and travel destinations.
3) Treatment guidelines for various infections based on disease severity and suspected pathogen.
Dengue fever- clinical features,investigations, diagnosis, treatment and prev...DeepakBhosle
This presentation is for medical students and general practitioner It contains detailed account of epidemiology, causation, clinical features, investigations,diagnosis, treatment of dengue fever. contains pictures. useful latest and comprehensive information about Dengue. It also contains dengue case definitions of WHO.It also lists the complications of dengue. It enumerates the warning signs for more severe form of dengue fever. Includes risk factors for dengue shock syndrome and dengue hemorrhagic fever.It includes a list if clinical markers of dengue. Also details about the habits of the dengue vector , aedes aegypti mosquito
This document provides an overview of dengue fever management. It discusses the virus and vector, pathogenesis, clinical manifestations, investigations, severity grading, treatment approaches including fluid management, and discharge criteria. Key points include: dengue is caused by a flavivirus with 4 serotypes transmitted by Aedes aegypti mosquitoes; symptoms range from mild fever to potentially fatal shock; grading disease severity is important to determine management; intravenous fluids and monitoring for warning signs are the main treatment approaches.
This document provides an outline for a presentation on Dengue Fever. It begins with introducing Dengue Fever and its global prevalence. It then covers the pathogenesis, classification (into dengue fever without warning signs, with warning signs, and severe dengue), clinical course over incubation, febrile, critical and recovery phases. The document also discusses assessment, investigations, differential diagnosis, management approaches depending on classification and severity, additional points, and references.
The document summarizes information about dengue fever, including:
1. Dengue fever is caused by the dengue virus and transmitted by Aedes mosquitoes, primarily Aedes aegypti.
2. Aedes aegypti prefers to lay eggs in artificial containers near humans and feeds primarily on people.
3. There are four types of dengue virus; infection with one type usually provides lifelong immunity to that type but only short-term immunity to others, increasing risk of severe illness from a different type in subsequent infections.
This document provides an overview of dengue, including its epidemiology, life cycle, pathogenesis, clinical features, diagnosis, management, prognosis, and prevention. Some key points:
- Dengue is a self-limited viral infection transmitted by mosquitoes that infects 50-100 million people yearly and is a major public health challenge due to lack of vaccines or treatments.
- There are four serotypes of the dengue virus. Infection causes an acute febrile illness that in some cases progresses to severe dengue with plasma leakage and potential complications including shock.
- Diagnosis is based on virus detection, serology, or PCR. Management focuses on supportive care and fluid management. Prevention emphasizes mosquito control
It is about detailed management of dengue and malaria in adults and children with brief review of clinical history and diagnosis.
reference:
-latest WHO and CDC guidelines
-Nelson 21st edition
-Ghai-Essential Paediatrics 9th edition
-Harrison
This document provides information about Dengue fever, including:
1) It describes Dengue fever as the most rapidly spreading mosquito-borne viral disease in the world, caused by the Dengue virus which has 4 serotypes.
2) Symptoms and classifications of Dengue fever are discussed according to the WHO, including dengue fever without hemorrhage, dengue hemorrhagic fever, and dengue shock syndrome.
3) Diagnosis, treatment, prevention and control of Dengue fever and its vectors are summarized, highlighting supportive care, intravenous fluids, monitoring for complications, and the importance of vector control measures.
This document provides an overview of viral hemorrhagic fever (VHF) and focuses on yellow fever. It classifies VHFs and describes their pathogenesis. Yellow fever is caused by a flavivirus transmitted by mosquitoes. It presents with fever, bleeding, liver and kidney damage. Diagnosis involves blood tests showing low platelets and clotting factors. Treatment focuses on supportive care; vaccines can prevent yellow fever.
This document provides information about influenza H1N1 virus:
- It is an RNA virus that causes seasonal flu epidemics and pandemics. There are three main types - A, B, and C. Type A is the most common cause of pandemics.
- The virus undergoes antigenic drift, resulting in seasonal outbreaks, and antigenic shift, resulting in pandemics when a novel subtype emerges that humans have no immunity against.
- H1N1 caused pandemics in 1918, 1957, and 2009. It typically causes respiratory illness but can lead to complications like pneumonia. Early treatment with oseltamivir can reduce severity.
Scrub typhus, also known as bush typhus, is a disease caused by a bacteria called ORIENTIA TSUTSUGAMUSHI.
Scrub typhus is spread to people through bites of infected chiggers (larval mites).
Most cases of scrub typhus occur in rural areas of Southeast Asia, Indonesia, China, Japan, India, and northern Australia. Anyone living in or travelling to areas where scrub typhus is found could get infected
Scrub typhus is not transmitted directly from person to person; it is only transmitted by the bites of vectors
Chiggers are abundant in locales with high relative humidity (60%–85%), low temperature (20°C–30°C), low incidence of sunlight, and a dense substrate-vegetative canopy.
Occupational risk is higher in farmers (aged 50–69 years), females.
The document provides information on Dengue Fever, including that it is caused by a mosquito-borne flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes. It has four serotypes that provide varying levels of immunity. Symptoms include fever, headache, rash and bleeding. Diagnosis involves antibody and viral testing. Severe dengue is classified as dengue hemorrhagic fever or dengue shock syndrome, characterized by bleeding, low platelets and plasma leakage. Monitoring of patients involves serial complete blood counts and hematocrit levels to detect signs of plasma leakage. Proper fluid management and monitoring for bleeding and organ dysfunction is important throughout the illness.
The document discusses HIV/AIDS and cryptococcal meningitis. It provides information on HIV/AIDS including that it is caused by the HIV virus and weakens the immune system. It then discusses cryptococcal meningitis as an opportunistic infection, describing its symptoms. The remainder of the document discusses a case of a 45-year-old male patient admitted with fever, vomiting and headache who is diagnosed with cryptococcal meningitis and treated with antifungal drugs like amphotericin B and fluconazole.
- Dengue fever is a mosquito-borne viral infection caused by any of four dengue virus serotypes. It is a major public health problem in tropical and subtropical parts of the world.
- The disease ranges from a mild fever to potentially lethal dengue hemorrhagic fever. It is transmitted by the bites of infected Aedes mosquitoes, most commonly Aedes aegypti.
- There is no vaccine or antiviral medication available, so treatment is supportive and focused on relieving symptoms. Prevention relies on reducing mosquito habitats and biting exposure through vector control measures.
The document discusses dengue fever in children, including dengue hemorrhagic fever which causes joint and muscle pain and can develop into a severe, potentially deadly infection. It covers the symptoms, diagnosis, and treatment of dengue fever and dengue hemorrhagic fever, noting that supportive care including fluid replacement is the most important treatment and careful monitoring is needed to watch for complications like shock.
A patient presenting with acute febrile illness should be treated with consideration and caution. Most cases will resolve without complication, but identifying the small percentage with potential life-threatening conditions requires careful examination and investigation over time. Making an early diagnosis risks missing unexpected developments, so empirical treatment should not be withheld in severe situations while the illness course is monitored.
Aetiology,pathophysiology and diagnosis of dengue infectionLee Oi Wah
The document discusses dengue virus, which causes dengue fever and dengue hemorrhagic fever. It is transmitted by mosquitoes and has four serotypes. It also causes lifelong immunity to one serotype but temporary cross-immunity. The document covers dengue's pathophysiology, symptoms, classification, diagnosis and surveillance data from Perak from 2002-2007.
Dengue fever has no specific treatment and management is supportive. It is important to monitor for warning signs and complications like dengue hemorrhagic fever. A 3-year-old boy, Master Rahul, presented with fever and was found to have dengue infection based on serology. He developed bleeding complications and was carefully monitored and provided intravenous fluids and recovered well without any long term issues. Prevention efforts focus on eliminating mosquito breeding sites to prevent transmission of the dengue virus.
This document discusses dengue virus, which is transmitted by mosquitoes and causes dengue fever and dengue hemorrhagic fever. It describes the four serotypes of the dengue virus and their modes of transmission. It outlines the signs and symptoms of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. It also discusses laboratory tests for diagnosis and clinical management, including fluid resuscitation protocols. The goal of treatment is to manage fluid levels and output during the critical phase of potential plasma leakage while avoiding fluid overload.
This document provides an overview of dengue fever, including:
1. It describes the dengue virus, its vector Aedes aegypti mosquito, and the disease's pathogenesis and clinical presentations ranging from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome.
2. It outlines the laboratory diagnosis and management approach divided into three groups - outpatient, inpatient, and emergency treatment groups.
3. It discusses treatment approaches for different clinical stages of the disease as well as vector control methods and the status of vaccine development.
The document discusses dengue virus, its transmission and clinical manifestations. Some key points:
- Dengue virus is transmitted by Aedes aegypti mosquitoes and has 4 serotypes. It causes dengue fever and the more severe dengue hemorrhagic fever/dengue shock syndrome.
- The disease progresses through febrile, critical, and recovery phases. During the critical phase, plasma leakage and bleeding can cause shock.
- Symptoms range from mild fever to severe bleeding, organ impairment and shock. Thrombocytopenia is common.
- Diagnosis is based on clinical criteria and confirmed with serology, antigen or PCR testing. There is no vaccine and treatment focuses
This document discusses a case of dengue fever with myocarditis in an 18-year-old male construction worker presenting with fever, headache, and body aches. Initial tests showed mild left ventricular dysfunction which later improved. Dengue IgM was positive, confirming dengue fever with cardiac involvement. Recent studies show that while cardiac complications of dengue are uncommon, myocarditis is the most documented pathology and can present asymptomatically. Echocardiography is useful for diagnosis where sinus bradycardia is often the only ECG finding.
Dengue viral infections are caused by one of four viruses and transmitted by mosquitoes. The disease ranges in severity from asymptomatic to severe and fatal. Most cases are mild, but some develop shock and hemorrhage. Treatment is supportive and focuses on fluid management to resolve shock while preventing fluid overload. Dengue has spread globally and is a major public health problem in over 100 countries.
Dengue fever in children 2019 by Dr KibogoyoGeorgeKibogoyo
This document provides an overview of dengue fever in children. It discusses the epidemiology, transmission, pathophysiology, classification, clinical presentation, investigations, differential diagnosis, management, prognosis, and prevention of dengue fever in children. Some key points include:
- Dengue is caused by one of four serotypes of dengue virus and is transmitted by Aedes mosquitoes.
- It is a major public health problem in many tropical and subtropical countries.
- Clinical presentation varies from mild fever to severe dengue with hemorrhage, plasma leakage, or organ involvement.
- Diagnosis involves IgM/IgG detection, NS1 antigen detection, PCR, or viral isolation from blood samples.
This document provides an outline for a presentation on Dengue Fever. It begins with introducing Dengue Fever and its global prevalence. It then covers the pathogenesis, classification (into dengue fever without warning signs, with warning signs, and severe dengue), clinical course over incubation, febrile, critical and recovery phases. The document also discusses assessment, investigations, differential diagnosis, management approaches depending on classification and severity, additional points, and references.
The document summarizes information about dengue fever, including:
1. Dengue fever is caused by the dengue virus and transmitted by Aedes mosquitoes, primarily Aedes aegypti.
2. Aedes aegypti prefers to lay eggs in artificial containers near humans and feeds primarily on people.
3. There are four types of dengue virus; infection with one type usually provides lifelong immunity to that type but only short-term immunity to others, increasing risk of severe illness from a different type in subsequent infections.
This document provides an overview of dengue, including its epidemiology, life cycle, pathogenesis, clinical features, diagnosis, management, prognosis, and prevention. Some key points:
- Dengue is a self-limited viral infection transmitted by mosquitoes that infects 50-100 million people yearly and is a major public health challenge due to lack of vaccines or treatments.
- There are four serotypes of the dengue virus. Infection causes an acute febrile illness that in some cases progresses to severe dengue with plasma leakage and potential complications including shock.
- Diagnosis is based on virus detection, serology, or PCR. Management focuses on supportive care and fluid management. Prevention emphasizes mosquito control
It is about detailed management of dengue and malaria in adults and children with brief review of clinical history and diagnosis.
reference:
-latest WHO and CDC guidelines
-Nelson 21st edition
-Ghai-Essential Paediatrics 9th edition
-Harrison
This document provides information about Dengue fever, including:
1) It describes Dengue fever as the most rapidly spreading mosquito-borne viral disease in the world, caused by the Dengue virus which has 4 serotypes.
2) Symptoms and classifications of Dengue fever are discussed according to the WHO, including dengue fever without hemorrhage, dengue hemorrhagic fever, and dengue shock syndrome.
3) Diagnosis, treatment, prevention and control of Dengue fever and its vectors are summarized, highlighting supportive care, intravenous fluids, monitoring for complications, and the importance of vector control measures.
This document provides an overview of viral hemorrhagic fever (VHF) and focuses on yellow fever. It classifies VHFs and describes their pathogenesis. Yellow fever is caused by a flavivirus transmitted by mosquitoes. It presents with fever, bleeding, liver and kidney damage. Diagnosis involves blood tests showing low platelets and clotting factors. Treatment focuses on supportive care; vaccines can prevent yellow fever.
This document provides information about influenza H1N1 virus:
- It is an RNA virus that causes seasonal flu epidemics and pandemics. There are three main types - A, B, and C. Type A is the most common cause of pandemics.
- The virus undergoes antigenic drift, resulting in seasonal outbreaks, and antigenic shift, resulting in pandemics when a novel subtype emerges that humans have no immunity against.
- H1N1 caused pandemics in 1918, 1957, and 2009. It typically causes respiratory illness but can lead to complications like pneumonia. Early treatment with oseltamivir can reduce severity.
Scrub typhus, also known as bush typhus, is a disease caused by a bacteria called ORIENTIA TSUTSUGAMUSHI.
Scrub typhus is spread to people through bites of infected chiggers (larval mites).
Most cases of scrub typhus occur in rural areas of Southeast Asia, Indonesia, China, Japan, India, and northern Australia. Anyone living in or travelling to areas where scrub typhus is found could get infected
Scrub typhus is not transmitted directly from person to person; it is only transmitted by the bites of vectors
Chiggers are abundant in locales with high relative humidity (60%–85%), low temperature (20°C–30°C), low incidence of sunlight, and a dense substrate-vegetative canopy.
Occupational risk is higher in farmers (aged 50–69 years), females.
The document provides information on Dengue Fever, including that it is caused by a mosquito-borne flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes. It has four serotypes that provide varying levels of immunity. Symptoms include fever, headache, rash and bleeding. Diagnosis involves antibody and viral testing. Severe dengue is classified as dengue hemorrhagic fever or dengue shock syndrome, characterized by bleeding, low platelets and plasma leakage. Monitoring of patients involves serial complete blood counts and hematocrit levels to detect signs of plasma leakage. Proper fluid management and monitoring for bleeding and organ dysfunction is important throughout the illness.
The document discusses HIV/AIDS and cryptococcal meningitis. It provides information on HIV/AIDS including that it is caused by the HIV virus and weakens the immune system. It then discusses cryptococcal meningitis as an opportunistic infection, describing its symptoms. The remainder of the document discusses a case of a 45-year-old male patient admitted with fever, vomiting and headache who is diagnosed with cryptococcal meningitis and treated with antifungal drugs like amphotericin B and fluconazole.
- Dengue fever is a mosquito-borne viral infection caused by any of four dengue virus serotypes. It is a major public health problem in tropical and subtropical parts of the world.
- The disease ranges from a mild fever to potentially lethal dengue hemorrhagic fever. It is transmitted by the bites of infected Aedes mosquitoes, most commonly Aedes aegypti.
- There is no vaccine or antiviral medication available, so treatment is supportive and focused on relieving symptoms. Prevention relies on reducing mosquito habitats and biting exposure through vector control measures.
The document discusses dengue fever in children, including dengue hemorrhagic fever which causes joint and muscle pain and can develop into a severe, potentially deadly infection. It covers the symptoms, diagnosis, and treatment of dengue fever and dengue hemorrhagic fever, noting that supportive care including fluid replacement is the most important treatment and careful monitoring is needed to watch for complications like shock.
A patient presenting with acute febrile illness should be treated with consideration and caution. Most cases will resolve without complication, but identifying the small percentage with potential life-threatening conditions requires careful examination and investigation over time. Making an early diagnosis risks missing unexpected developments, so empirical treatment should not be withheld in severe situations while the illness course is monitored.
Aetiology,pathophysiology and diagnosis of dengue infectionLee Oi Wah
The document discusses dengue virus, which causes dengue fever and dengue hemorrhagic fever. It is transmitted by mosquitoes and has four serotypes. It also causes lifelong immunity to one serotype but temporary cross-immunity. The document covers dengue's pathophysiology, symptoms, classification, diagnosis and surveillance data from Perak from 2002-2007.
Dengue fever has no specific treatment and management is supportive. It is important to monitor for warning signs and complications like dengue hemorrhagic fever. A 3-year-old boy, Master Rahul, presented with fever and was found to have dengue infection based on serology. He developed bleeding complications and was carefully monitored and provided intravenous fluids and recovered well without any long term issues. Prevention efforts focus on eliminating mosquito breeding sites to prevent transmission of the dengue virus.
This document discusses dengue virus, which is transmitted by mosquitoes and causes dengue fever and dengue hemorrhagic fever. It describes the four serotypes of the dengue virus and their modes of transmission. It outlines the signs and symptoms of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. It also discusses laboratory tests for diagnosis and clinical management, including fluid resuscitation protocols. The goal of treatment is to manage fluid levels and output during the critical phase of potential plasma leakage while avoiding fluid overload.
This document provides an overview of dengue fever, including:
1. It describes the dengue virus, its vector Aedes aegypti mosquito, and the disease's pathogenesis and clinical presentations ranging from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome.
2. It outlines the laboratory diagnosis and management approach divided into three groups - outpatient, inpatient, and emergency treatment groups.
3. It discusses treatment approaches for different clinical stages of the disease as well as vector control methods and the status of vaccine development.
The document discusses dengue virus, its transmission and clinical manifestations. Some key points:
- Dengue virus is transmitted by Aedes aegypti mosquitoes and has 4 serotypes. It causes dengue fever and the more severe dengue hemorrhagic fever/dengue shock syndrome.
- The disease progresses through febrile, critical, and recovery phases. During the critical phase, plasma leakage and bleeding can cause shock.
- Symptoms range from mild fever to severe bleeding, organ impairment and shock. Thrombocytopenia is common.
- Diagnosis is based on clinical criteria and confirmed with serology, antigen or PCR testing. There is no vaccine and treatment focuses
This document discusses a case of dengue fever with myocarditis in an 18-year-old male construction worker presenting with fever, headache, and body aches. Initial tests showed mild left ventricular dysfunction which later improved. Dengue IgM was positive, confirming dengue fever with cardiac involvement. Recent studies show that while cardiac complications of dengue are uncommon, myocarditis is the most documented pathology and can present asymptomatically. Echocardiography is useful for diagnosis where sinus bradycardia is often the only ECG finding.
Dengue viral infections are caused by one of four viruses and transmitted by mosquitoes. The disease ranges in severity from asymptomatic to severe and fatal. Most cases are mild, but some develop shock and hemorrhage. Treatment is supportive and focuses on fluid management to resolve shock while preventing fluid overload. Dengue has spread globally and is a major public health problem in over 100 countries.
Dengue fever in children 2019 by Dr KibogoyoGeorgeKibogoyo
This document provides an overview of dengue fever in children. It discusses the epidemiology, transmission, pathophysiology, classification, clinical presentation, investigations, differential diagnosis, management, prognosis, and prevention of dengue fever in children. Some key points include:
- Dengue is caused by one of four serotypes of dengue virus and is transmitted by Aedes mosquitoes.
- It is a major public health problem in many tropical and subtropical countries.
- Clinical presentation varies from mild fever to severe dengue with hemorrhage, plasma leakage, or organ involvement.
- Diagnosis involves IgM/IgG detection, NS1 antigen detection, PCR, or viral isolation from blood samples.
This study characterized dengue infections in Pakistan by analyzing hematological and serological markers in 154 suspected dengue cases and 146 control patients with other febrile illnesses. NS1 antigen was detected in 55% of dengue cases, IgM antibodies in 30%, and both in 15%. Control groups primarily had malaria (71%) and enteric fever (20%). Hematological markers (platelet count, hematocrit, WBC) measured before and after treatment showed significant differences for platelet count and hematocrit but not WBC count between the groups. Analysis of clinical symptoms and serological/hematological markers helps diagnose dengue, assess prognosis, and inform prevention efforts to reduce morbidity, mortality and spread of the disease.
this presentation deals mainly with dengue as there has been multiple outbreaks in 2015 and etiological factors involved, current scenario in India, preventive and control measures for dengue, recent strains of dengue and recent vaccine trials of dengue vaccine.
This review article discusses autoimmunity in dengue pathogenesis. It suggests that in addition to direct viral effects, immunopathogenesis, including aberrant immune activation and autoantibodies, plays a role in the development of severe dengue disease. Autoantibodies against endothelial cells, platelets, and coagulation molecules induced by dengue virus infection may lead to abnormal activation or dysfunction of these cells and molecules. Molecular mimicry, where dengue virus proteins mimic host proteins, could explain the cross-reactivity of autoantibodies induced during dengue virus infection. Understanding immunopathogenic mechanisms is important for developing a safe and effective dengue vaccine.
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
A Study Of Clinical And Laboratory Profile Of Dengue Fever In AJoe Andelija
This study analyzed the clinical and laboratory profiles of 150 adult patients diagnosed with dengue fever at a hospital in India over 5 months. Most patients were male between the ages of 21-40. The most common symptoms were fever, headache, myalgia, and abdominal pain. Bleeding manifestations occurred in 19% of patients, most commonly melena. Laboratory findings included thrombocytopenia in all patients and elevated hematocrit in 23% of patients. 21% of cases had severe dengue hemorrhagic fever/dengue shock syndrome. The study aims to better understand the characteristics of dengue patients to aid in diagnosis and management.
The document provides information about Dengue Hemorrhagic Fever (DHF), including:
1) DHF is a severe form of dengue virus infection characterized by fever, hemorrhagic phenomena, hepatomegaly and circulatory failure.
2) It is transmitted via the bite of the Aedes aegypti mosquito, which breeds in stagnant water and exhibits daytime biting behavior.
3) There is no vaccine currently available to prevent DHF, and prevention relies on mosquito control to reduce transmission.
Background & objectives: In Odisha, several cases of dengue virus infection were detected for the first time in 2010, the importance of dengue as a serious mosquito-borne viral infection was felt only in 2011 with the reporting of many more positive cases. This retrospective three year study was done to find out the seroprevalence of dengue Igm antibody and to know the predominant serotype of dengue virus among the patients suspected to have dengue virus infection in a tertiary care hospital in southern Odisha, India.
Methods: Blood samples from clinically suspected dengue cases admitted in the Medicine and Paediatrics departments of a tertiary care hospital were collected. These were processed for detection of dengue specific IgM antibody, carried out by the ELISA method. Dengue IgM antibody positive serum samples were tested for serotypic identification.
Results: of the 5102 samples tested, 1074 (21.05 %) were positive for dengue IgM. Maximum numbers of cases were found in 2012. Majority (47.86 %) of cases were detected in the month of September. The most common affected age group was 11 to 20 yr. DENV1 and DENV2 were the detected serotypes.
Interpretation & conclusions: Rapid increase in the dengue cases in 2012 became a public health concern as majority of cases were affecting the young adolescents. Most of the cases were reported in post-monsoon period indicating a need for acceleration of vector control programmes prior to arrival of monsoon.
Key words Dengue virus - IgM antibody - seroprevalence - serotype - vector control
CNS Iinfection dengue, Teaching Slides, Dr M D Mohire, Kolhapur, Maharashtra,...Mahavir Mohire
1) A study of 210 patients with infectious acute encephalitis syndrome (AES) in India found that 62% had a specific etiological diagnosis. The most common causes were herpes virus (12 patients) and Japanese encephalitis virus (8 patients) for neurological AES, and scrub typhus (42 patients) and dengue virus (20 patients) for systemic AES.
2) Using a syndromic approach, neurological AES could be differentiated from systemic AES with 100% specificity based on the absence of myalgia or rash. Thalamic involvement on imaging predicted Japanese encephalitis with 100% specificity for neurological AES cases.
3) Targeted testing and treatment based on the syndromic approach substantially reduced
Dengue is a mosquito-borne viral disease that is widespread in tropical and subtropical regions. It affects nearly 100 million people annually. The disease is caused by the dengue virus, which has four serotypes. It is transmitted by the bite of infected Aedes mosquitoes. There is no vaccine available to prevent dengue. Treatment involves fluid replacement and pain management. Prevention focuses on reducing mosquito habitats and biting through the use of insect repellents, bed nets, and larviciding.
Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired ...bolohanbiatrice
This document discusses the epidemiology, pathogenesis, microbiology, and definitions related to hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) in adults. It notes that HAP and VAP remain important causes of morbidity and mortality despite improvements. Microorganisms enter the lungs through microaspiration or direct contact with contaminated devices/reservoirs. Common pathogens causing HAP and VAP include aerobic gram-negative bacilli and Staphylococcus aureus. Local antimicrobial resistance patterns must be considered for empiric therapy.
National guideline for Dengue (Latest) by DGHSJony Hossain
This document provides an introduction and summary of the 4th Edition 2018 of the National Guideline for Clinical Management of Dengue Syndrome published by the National Malaria Elimination & Aedes Transmitted Disease Control Program of Bangladesh.
The summary includes:
1) It is the 4th edition of Bangladesh's national guideline for clinically managing dengue syndrome.
2) It was published in 2018 by the National Malaria Elimination & Aedes Transmitted Disease Control Program under the Directorate General of Health Services.
3) The guideline was updated based on the latest WHO/SEARO guidelines and provides evidence-based recommendations for the clinical diagnosis and management of dengue to standardize care across Bangladesh.
The information regarding the dengue fever, Introduction, epidemiology, aetiology, symptoms, general management and prevention , along with one example of the journal club.
Dengue fever is caused by dengue virus, which has four serotypes. It is transmitted by the bites of infected Aedes mosquitoes. The document discusses the epidemiology, clinical features, diagnosis, treatment and control of dengue fever. It outlines how to conduct emergency mosquito control operations and treat patients during outbreaks through vector control methods like spraying and reducing breeding sites, and maintaining fluid volume for severe cases in hospitals. The goal is to eliminate infected mosquitoes and break transmission, while providing care to patients.
Dengue fever is caused by dengue virus, which has four serotypes. It is transmitted by the bites of infected Aedes mosquitoes. The document discusses the epidemiology, clinical features, diagnosis, treatment and control of dengue fever. It describes how dengue is controlled through emergency mosquito control measures like insecticide spraying and source reduction, as well as through treatment of patients in hospitals. Personal protective measures, larval source reduction, and integrated vector management strategies are important for long-term prevention and control of dengue transmission.
Diagnosis and management of dengue in children (IAP Infectious Diseases Chapter)Dr Padmesh Vadakepat
This document provides a review and recommendations on the diagnosis and management of dengue in children. It discusses that dengue is endemic in many parts of Asia and the Americas. The virus is transmitted by mosquitoes Aedes aegypti and Aedes albopictus. Dengue classification has changed from dengue fever and dengue hemorrhagic fever to simply dengue, dengue with warning signs, and severe dengue. Diagnosis involves tests for the NS1 antigen, IgG and IgM antibodies. Treatment depends on severity and can involve outpatient, inpatient or emergency care, monitoring for shock and hemorrhage.
Dengue fever is caused by one of four dengue virus serotypes transmitted by Aedes mosquitoes. It is the most common arboviral infection worldwide, infecting 50-100 million people annually. There is no vaccine or antiviral treatment available, so prevention focuses on controlling mosquito populations. Symptoms range from flu-like illness to severe dengue hemorrhagic fever. Secondary infection with a different serotype increases the risk of more severe disease. Diagnosis involves virus isolation, serology to detect antibodies, or RT-PCR. Proper fluid management is critical for treating dengue hemorrhagic fever cases to reduce the risk of death.
This study examined the risk of serious infection in patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD). The study identified 181 RA patients with ILD between 1998-2014. It found that these patients faced a high risk of serious infections requiring hospitalization, with an overall rate of 7.4 infections per 100 person-years. The risk was highest for patients with organizing pneumonia ILD (27.1 per 100 person-years) and lower for nonspecific interstitial pneumonia and usual interstitial pneumonia. Use of high-dose prednisone (>10mg per day) was also linked to greater infection risk. Identifying patients at highest risk could help reduce infection-related morbidity.
Summer is a time for fun in the sun, but the heat and humidity can also wreak havoc on your skin. From itchy rashes to unwanted pigmentation, several skin conditions become more prevalent during these warmer months.
Nano-gold for Cancer Therapy chemistry investigatory projectSIVAVINAYAKPK
chemistry investigatory project
The development of nanogold-based cancer therapy could revolutionize oncology by providing a more targeted, less invasive treatment option. This project contributes to the growing body of research aimed at harnessing nanotechnology for medical applications, paving the way for future clinical trials and potential commercial applications.
Cancer remains one of the leading causes of death worldwide, prompting the need for innovative treatment methods. Nanotechnology offers promising new approaches, including the use of gold nanoparticles (nanogold) for targeted cancer therapy. Nanogold particles possess unique physical and chemical properties that make them suitable for drug delivery, imaging, and photothermal therapy.
DECLARATION OF HELSINKI - History and principlesanaghabharat01
This SlideShare presentation provides a comprehensive overview of the Declaration of Helsinki, a foundational document outlining ethical guidelines for conducting medical research involving human subjects.
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
low birth weight presentation. Low birth weight (LBW) infant is defined as the one whose birth weight is less than 2500g irrespective of their gestational age. Premature birth and low birth weight(LBW) is still a serious problem in newborn. Causing high morbidity and mortality rate worldwide. The nursing care provide to low birth weight babies is crucial in promoting their overall health and development. Through careful assessment, diagnosis,, planning, and evaluation plays a vital role in ensuring these vulnerable infants receive the specialize care they need. In India every third of the infant weight less than 2500g.
Birth period, socioeconomical status, nutritional and intrauterine environment are the factors influencing low birth weight
NAVIGATING THE HORIZONS OF TIME LAPSE EMBRYO MONITORING.pdfRahul Sen
Time-lapse embryo monitoring is an advanced imaging technique used in IVF to continuously observe embryo development. It captures high-resolution images at regular intervals, allowing embryologists to select the most viable embryos for transfer based on detailed growth patterns. This technology enhances embryo selection, potentially increasing pregnancy success rates.
Breast cancer: Post menopausal endocrine therapyDr. Sumit KUMAR
Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
Diagnosis and Staging
The diagnosis of HR+ breast cancer begins with clinical evaluation, imaging, and biopsy. Imaging modalities such as mammography, ultrasound, and MRI help in assessing the extent of the disease. Histopathological examination and immunohistochemical staining of the biopsy sample confirm the diagnosis and hormone receptor status by identifying the presence of estrogen receptors (ER) and progesterone receptors (PR) on the tumor cells.
Staging involves determining the size of the tumor (T), the involvement of regional lymph nodes (N), and the presence of distant metastasis (M). The American Joint Committee on Cancer (AJCC) staging system is commonly used. Accurate staging is critical as it guides treatment decisions.
Treatment Options
Endocrine Therapy
Endocrine therapy is the cornerstone of treatment for HR+ breast cancer in postmenopausal women. The primary goal is to reduce the levels of estrogen or block its effects on cancer cells. Commonly used agents include:
Selective Estrogen Receptor Modulators (SERMs): Tamoxifen is a SERM that binds to estrogen receptors, blocking estrogen from stimulating breast cancer cells. It is effective but may have side effects such as increased risk of endometrial cancer and thromboembolic events.
Aromatase Inhibitors (AIs): These drugs, including anastrozole, letrozole, and exemestane, lower estrogen levels by inhibiting the aromatase enzyme, which converts androgens to estrogen in peripheral tissues. AIs are generally preferred in postmenopausal women due to their efficacy and safety profile compared to tamoxifen.
Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant is a SERD that degrades estrogen receptors and is used in cases where resistance to other endocrine therapies develops.
Combination Therapies
Combining endocrine therapy with other treatments enhances efficacy. Examples include:
Endocrine Therapy with CDK4/6 Inhibitors: Palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors that, when combined with endocrine therapy, significantly improve progression-free survival in advanced HR+ breast cancer.
Endocrine Therapy with mTOR Inhibitors: Everolimus, an mTOR inhibitor, can be added to endocrine therapy for patients who have developed resistance to aromatase inhibitors.
Chemotherapy
Chemotherapy is generally reserved for patients with high-risk features, such as large tumor size, high-grade histology, or extensive lymph node involvement. Regimens often include anthracyclines and taxanes.
Travel Clinic Cardiff: Health Advice for International TravelersNX Healthcare
Travel Clinic Cardiff offers comprehensive travel health services, including vaccinations, travel advice, and preventive care for international travelers. Our expert team ensures you are well-prepared and protected for your journey, providing personalized consultations tailored to your destination. Conveniently located in Cardiff, we help you travel with confidence and peace of mind. Visit us: www.nxhealthcare.co.uk
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
Kosmoderma Academy, a leading institution in the field of dermatology and aesthetics, offers comprehensive courses in cosmetology and trichology. Our specialized courses on PRP (Hair), DR+Growth Factor, GFC, and Qr678 are designed to equip practitioners with advanced skills and knowledge to excel in hair restoration and growth treatments.
2. Expert Rev. Anti Infect. Ther. 10(8), (2012)896
Review
1940s [23], it was not until 1971 that the feasibility of a dengue
vaccine in preventing DHF was studied [10,24]; and based on initial
data [25–29], a vaccine search was initiated, endorsed and discussed
by the SEARO/WHO Research Study Group and experts in the
field [24]. Despite initial optimism [30,31], more than three decades
have passed without a licensed dengue vaccine in the market.
However, current developments are promising and six tetravalent
candidate vaccines are in Phase I–III trials. Optimistically, a
licensed vaccine can be anticipated in the next 5–7 years [32–34].
Meanwhile, apart from vector control, the burden of dengue on
society can also be reduced through appropriate and timely clini-
cal interventions to prevent severe morbidity and mortality. This
relies on early and accurate diagnosis of dengue. Even when a vac-
cine or an antiviral drug becomes available, the need for accurate
diagnosis would not be diminished. Instead, the requirement for
accurate diagnosis could become more demanding, as surveillance
for dengue in vaccinated individuals would be needed to deter-
mine vaccine efficacy and for the early detection of vaccine-escape
mutants. The goal of this review is thus to determine the state of
the art in diagnosis of dengue and identify areas where improve-
ments through research are needed to prepare for the quality of
diagnostics needed in a postvaccination world.
Current status in diagnosis of dengue
Clinical diagnosis
Diagnosis of dengue starts with a clinical suspicion, prompted by
the recognition of a collection of presenting symptoms and signs. In
the early acute febrile phase of illness, dengue patients often present
with a history of sudden onset fever, which is often accompanied
by nausea, aches and pains. Unfortunately, these symptoms are not
unique to dengue and are reported with other febrile illnesses (OFI).
The onset of a maculopapular rash, retro-orbital pain, petechiae or
bleeding nose or gums are more pathognomonic of dengue and
would more probably trigger a differential diagnosis of dengue,
although these symptoms usually appear in the later stages of illness,
nearer the phase of fever defervescence, when plasma leakage occurs
[1].Their usefulness for early diagnosis would thus be more limited.
A list of the commonly reported symptoms is shown in Table 1.
As each of the individual symptoms cannot accurately differenti-
ate dengue from OFIs, an alternative approach to clinical diagnosis
is to use a permutation of a list of symptoms or signs. The WHO
guidelines for dengue are such examples [1,35]. Indeed, when applied
to prospectively recruited patients who presented with acute febrile
illness less than 72 h from fever onset, both the 1997 and 2009WHO
guidelines showed a similar sensitivity of over 95% in young adults,
albeit with poor specificities of less than 40% [12]. Consequently, the
WHO classification schemes can be useful to trigger a suspicion of
dengue. During epidemics, when the prevalence of dengue is high,
cases that fit these definitions could be treated as presumptive dengue
while awaiting other test results. However, they cannot be used for
a confirmatory diagnosis of dengue. Furthermore, caution must be
exercised in places where dengue infection occurs in older adults.
The same study showed that adults who are 56 years of age and older
had greatly reduced sensitivities, from over 95 to 73.7% and 81.6%
for the 1997 and 2009 WHO classification schemes, respectively.
In such cases, the study suggested that leukopenia in patients with
febrile illness should trigger a suspicion of dengue [12].
Besides the WHO classification schemes, others have attempted
to develop diagnostic algorithms for dengue. Tanner et al. used
a data mining approach to identify a group of symptoms and
hematologic measurements to differentiate dengue from OFIs [36].
The resultant algorithm had a sensitivity and specificity of 71.2
and 90.1%, respectively. Another comprehensive multivariable
logistic regression model was also developed and validated for
distinguishing DHF from DF, DHF from DF or OFIs, dengue
from OFIs and severe dengue from nonsevere dengue. The model
was found to have a sensitivity that ranged from 89.2 (dengue
from OFIs) to 79.6% (DHF from DF) [37]. This model also
provides a tool for probability calculation and classification of
patients based on readily available clinical and laboratory data.
However, the usefulness of such algorithms remains to be tested
in different populations with different circulating DENV strains.
An important limitation in the development of useful clinical
approaches to diagnosis of dengue is the lack of standardization
with regard to study design, diagnostic criteria and data collec-
tion [38]. While this is not surprising as these studies were per-
formed by various laboratories in different countries, it limits the
development of diagnostic classification or algorithms that can
be applied internationally. Indeed, the need for more prospective
studies to construct a valid and generalizable algorithm to guide
the differential diagnosis of dengue in endemic countries remains
urgent [38].
Laboratory diagnosis
As clinical diagnosis lacks specificity, a definitive diagnosis of
dengue infection requires laboratory confirmation. A number of
different laboratory tools are available for diagnostic use. A sum-
mary of laboratory diagnostic methods used in dengue infection
is shown in Table 2 and the approximate time from illness onset at
which these diagnostic tests should be used is shown in Figure 1.
Virus isolation
Dengue viremia can be detected from 2 to 3 days prior to the
onset of fever to up to 5.1 and 4.4 days after the onset of the
disease for primary and secondary infection, respectively [39].
During this viremic period, blood, serum or plasma samples can
be used for virus isolation.
Mosquito inoculation remains the most sensitive method for
virus isolation. The isolation rate of the four serotypes of DENV
is in the range of 71.5–84.2% [40]. Various mosquito species
have been found to be useful and sensitive in dengue isolation,
including A. aegypti, A. albopictus and Toxorhynchites splendens,
where both male and female mosquitoes are susceptible [6,41–44].
These mosquitoes are inoculated intrathoracically with serum or
plasma specimens [40–44]. Specimens collected early in the course
of illness have a greater isolation rate (85.3% before day 4 of ill-
ness) than those collected later (65.4% after day 4 of illness) [40].
Furthermore, the isolation rate in patients with primary dengue
(91.0%) was higher than those with secondary dengue (77.6%).
This observation could be due to the interference of crossreactive
Tang & Ooi
3. 897www.expert-reviews.com
Review
antibodies with virus isolation or a faster rate of viral clearance in
patients with secondary DENV infection [39]. Either explanation,
however, suggests that the prevalence of primary or secondary
DENV infection may influence the overall virus isolation [40,45].
Mouse brain inoculation has also been used to isolate and
amplify DENV. Generally, unweaned mice (2–4 days of age)
are inoculated intracerebrally with serum or plasma specimens
and observed daily. Moribund mice are then sacrificed to harvest
the isolate [46,47].
Both mosquito and mouse brain inoculation techniques are
not routinely used in day-to-day diagnosis owing to their highly
specialized technical, safety and facility requirements as well as
high maintenance costs. Instead, virus isolation using cell lines
is more widely used. The most commonly used cell line for
DENV isolation is C6/36, which was derived from A. albopictus.
Alternatively, mammalian cell lines such as Vero, LLC-MK2 or
BHK-21 could also be used, although these offer lower sensitiv-
ity than C6/36 [41,42,48–53]. Besides diagnosis, virus isolation
offers the advantage of providing a virus isolate that may be
characterized during subsequent in vitro studies, such as genome
sequencing, virus neutralization and infection studies.
A successful isolation of DENV on mosquito or cell culture
can be confirmed and serotyped by an immunofluorescence
assay using DENV- and serotype-specific monoclonal antibodies,
respectively [41,53]. Virus isolation is highly specific and has a
theoretical detection limit of a single viable virus, although in
practice, the sensitivity is only approximately 40.5% in cell line-
based virus isolation [54]. It also requires highly trained operators,
a dependence on sample integrity and a short viremia period, thus
providing a narrow window of opportunity from illness onset [54].
Therefore, despite its advantages, this approach is not widely used
in routine diagnostic laboratories.
Viral RNA detection
Reverse transcriptase PCR (RT-PCR) detection of dengue viral
RNA extracted from blood, serum or plasma provides a rapid,
sensitive and specific method for dengue infection confirmation.
Various primers and protocols have been developed, validated and
used in conventional RT-PCR [1,54–61] and real-time RT-PCR,
either using SYBR®
Green as a fluorescent detection marker or
labeled oligonucleotide probes [58,59,62–79]. A technique using a
single reaction mixture at a constant temperature (nucleic acid
Table 1. Symptoms differentiating dengue infection from other febrile illnesses.
Symptoms Den|OFIs p-value Children (<15 years)|adults
(>15 years)
p-value Ref.
Nausea 50.0|28.9%
68.0|49.0%†
51.3|30.5%
<0.00001
<0.05
<0.001
50.2|76.4% <0.001 [12,103,145,146]
Vomitting 16.4|8.4%
16.2|8.5%
57.0–64.0|31.0–46.0%†
70.0|52.0%†
<0.00001
0.03
<0.01
<0.05
50.2|76.4% <0.001 [12,103,145–148]
Retro-orbital pain 26.0|15.9%
26.6|13.5%
10.01§
<0.00001
0.003
0.001
8.7|29.1% <0.001 [12,103,146,148]
Aches/pains 1.4§
<0.0001 20.3|36.4% 0.012 [12,146]
Rash 11.2–41.2|3.0–6.4% <0.003/0.007 NA NA [12,103,134,149]
Tourniquet test positive 34.0|19.0%
42.0|5.0%†
43.0–65.0|21.0–39.0%
1.86§
0.02
<0.01
<0.1
<0.001
NA NA [12,103,134,149]
Leukopenia 3.8 × 103
|7.3 × 103
/µl
4.5 × 103
|8.1 × 103
/μl
<4.5 × 103
/μl: 72.1|11.5%
<0.0001
<0.1
<0.001
NA NA [12,37,103,145]
Thrombocytopenia
(platelet/mm3
)
16|4% (≤100,000)†
16|82%‡
(≤100,000)
66|95%‡
(≤100,000)
14.9|1.5% (≤100,000)
32,000|96,500
163,500|239,000
70,000|104,000¶
NA
NA
<0.01
<0.001
<0.001
<0.0001
NA
NA NA [12,103,145,147,150]
†
Studies perfomed in children younger than 15 years.
‡
Dengue and severe dengue comparison, performed in children younger than 15 years.
§
Risk ratio.
¶
Average.
Den: Confirmed dengue cases; NA: Not applicable; OFI: Other febrile illness.
Diagnosis of dengue: an update
4. Expert Rev. Anti Infect. Ther. 10(8), (2012)898
Review
sequence-based amplification [NASBA]) [80] was found to be
highly sensitive (98.5%) and specific (100%) [81,82]. NASBA may
be highly useful and applicable during outbreak field diagnosis
where thermocyclers are not readily available.
Sensitivity of conventional RT-PCR ranges from 48.4 to
98.2% and has a detection limit of 1–50 plaque forming units
(PFUs) [54–56,59]. These assays employ primers that bind to
known conserved regions of the DENV genome to avoid false
negative findings due to spontaneous mutations expected in
the replication of the RNA viral genome. The use of in silico
methods to develop a cocktail of primers that bind to almost
all DENV with known sequences has also been explored [58],
although validation in a clinical setting remains to be carried
out. The sensitivity of RT-PCR is also highly dependent on the
short window of opportunity that coincides with the viremic
period, which can last up to 8 days from illness onset (Figure 1).
However, RT-PCR is rarely positive in a case of dengue after
6 days from illness onset [1].
Fluorescence-based real-time RT-PCR has a better reported sen-
sitivity (58.9–100%) and detection limit (0.1–3.0 PFUs) owing to
the sensitivity of the fluorescence detector within the thermocycler
[59,62–67,71,74,75,79]. Multiplex RT-PCRs that differentiate DENV
serotypes in a single assay have also been developed [56,59,65,69,76].
The experience with NASBA is more limited compared with
RT-PCR, although a study has shown that
it can be as sensitive as RT-PCR, with a
detection limit of <25 PFUs/ml [81]. RNA
extraction from whole blood may be more
sensitive (90.0%) than serum or plasma
(62.0%) in the same pool of samples [78].
Besides blood samples, RT-PCR can also
be used to detect DENV RNA in tissues,
including formalin-fixed specimens [82].
Although RT-PCR usually requires exper-
tise in molecular techniques and expensive
equipment [83], modified protocols using
fast-ramping thermocyclers can be used
in conjunction with newly trained opera-
tors during emergency settings, such as in
differentiating dengue from SARS during
an outbreak [62], provided a strict standard
operating procedure is followed.
Dengue viral RNA can also be detected
in urine [68,72] and saliva [72] samples using
real-time RT-PCR. In urine, samples
–2 –1 0
Disease
onset
3
Time (Days)
1 2 4 5 6 7 8 9 10 11 20 30 40 60 90
lgM
lgM
lgG
lgG
2* dengue
1* dengue
>90
Viremia
NS1
Virus isolation
Viral RNA detection
Figure 1. Approximate window of detection for dengue diagnostics.
NS1: Non-structural protein 1.
Data taken from [1].
Table 2. Laboratory diagnostics for dengue: sensitivity and specificity.
Category Technique Parameters Ref.
Sensitivity (%) Specificity (%) Detection limit
Viral detection Virus isolation (mosquitoes) 71.5–84.2 100 NA [6,40–42,44]
Virus isolation (mouse intrecerebral inoculation) NA NA NA [46,47]
Virus isolation (cell culture) 40.5 100 ≥1 viable virus [54]
Viral RNA RT-PCR (conventional) 48.4–100 100 1–50 PFUs [54–57]
Viral RNA RT-PCR (real-time detection) 58.9–100 100 0.1–3.0 PFUs [54,57,63–67,79]
Viral RNA RT-PCR (NASBA) 98.5 100 <25 PFUs/ml [81]
Viral antigen detection (NS1 detection) 54.2–93.4 92.5–100 0.2 ng/ml†
[79,91–103,110]
Antibody detection IgM detection 61.5–100 52.0–100 NA [54,102,115,116]
IgG detection 46.3–99.0 80.0–100 NA
Rapid IgM detection (strips) 20.5–97.7 76.6–90.6 NA [115]
Antigen/antibody
combined detection
NS1 and IgM 89.9–92.9 75.0–100 NA [91,100–102]
NS1 and IgM/IgG 93.0 100 NA [101,151]
NA: Not applicable; NASBA: Nucleic acid sequence-based amplification; PFU: Plaque forming unit; RT-PCR: Reverse transcriptase PCR.
†
Data taken from [110].
Tang & Ooi
5. 899www.expert-reviews.com
Review
collected between day 6 and day 16 after illness onset were
found to have higher rates of detection (50–80%) compared
with day 1 to 3 samples (25–50%) [68]. RT-PCR for DENV
in urine may thus extend the window of opportunity for viral
RNA detection compared with blood specimens (up to day 8).
However, the level of viral RNA in urine and saliva samples is low
(1 × 101
–5 × 101
PFUs/ml) compared with the corresponding serum
samples (7.9 × 102
–1.9 × 105
PFUs/ml) [72].
Antigen detection
Dengue NS1 is a highly conserved glycoprotein essential for
DENV viability and is secreted from infected cells as a soluble
hexamer [84,85]. Serum or plasma DENV NS1 level has been found
to correlate with viremia titer and disease severity [86–88]. It can
be found in the peripheral blood circulation for up to 9 days
from illness onset [89–91], but can persist for up to 18 days from
illness onset in some cases [92]. NS1 detection thus offers a larger
window of opportunity for diagnosis of dengue compared with
virus isolation, RT-PCR or NASBA [68,72]. Commercially available
NS1 capture-based detection kits with sensitivities that ranged
from 54.2 to 93.4% have been comprehensively evaluated (Table 2)
[66,79,91,93–103] and found to be able to confirm dengue infection
in serum specimens that were RT-PCR negative and secondary
dengue infection [97]. However, NS1 detection is less sensitive in
secondary dengue infection (67.1–77.3%) compared with primary
dengue cases (94.7–98.3%) [93,94,96,103], probably owing to the
presence of crossreactive anti-NS1 antibodies that impedes the
detection of free NS1 proteins in the serum or plasma [86,89].
Anti-NS1 antibodies can also be used to detect infection in
other sample sources, such as tissues, including liver, lung and
kidney [104], through immunohistochemistry. This could be use-
ful in postmortem studies. Although highly conserved, serotype-
specific NS1 monoclonal antibodies have been raised and applied
for NS1-based dengue serotype identification assays [105–109]. A
study by Puttikhunt et al. has shown an overall sensitivity of 76.5%
and specificity of 100% for diagnosis of dengue while having sero
typing sensitivities of 100% for DENV 1, 3 and 4 and 82.4% for
DENV2 [109]. However, the sensitivity of these tests may differ
with different strains of DENV as the magnitude of NS1 secretion
appears to be strain dependent [110].
Antibody detection (IgM & IgG)
Detection of antidengue antibodies (IgM and IgG) is the most
widely used test in diagnosis of dengue [111].These kits are either in
the form of Ig capture or direct Ig detection and are configured to
detect IgM, IgG or both simultaneously [102,112–115].There are two
versions of these tests: ELISA or strip format (rapid test). While
ELISA provides greater sensitivity, the strip format is amenable
for bedside use [116].
Antibody response in the form of antidengue IgM can be
detected as early as 3–5 days after illness onset. Levels of IgM
continue to increase for approximately 2 weeks thereafter and may
persist for approximately 179 and 139 days following primary and
secondary infection, respectively [117]. Thus, while a single IgM
raises the likelihood that a febrile patient has dengue, a definitive
diagnosis may require the use of paired sera to demonstrate rising
IgM titers.
A multinational and multicenter study of ten IgM kits has
concluded that ELISA-based detection kits have higher sensi-
tivities (61.5–99.0%) compared with the rapid test formats
(20.5–97.7%). The specificities are in the range of 79.9–97.8%
and 76.6–90.6% for ELISA and rapid tests, respectively [115].
Other evaluation studies have also reported similar sensitivities
and specificities [62,102,116]. The wide ranges of these values are
probably due to the timing of sample collection [118].
Early antidengue IgM response (<2 months) has been found to
be crossreactive to all four DENV serotypes [119] and other flavi
viruses [115]. Hence, epidemiological information on the preva-
lence of other flaviviruses would be useful to guide the interpre-
tation of a positive IgM finding. False positives have also been
observed in patients with previous dengue or malaria infection
[116]. However, more efficient algorithms can be developed to
mitigate this problem, as shown by Prince et al. [120].
During primary infection, IgG can only be detected after
10 days from illness onset, making it less useful for early diagno-
sis. However, the rapid increase of IgG levels during secondary
infection (as early as day 4 from illness onset) [1] can be suggestive
of dengue when the ratio of IgM and IgG is used [62,102,115–117].
Dengue neutralizing antibody detection
Neutralizing antibodies inhibit DENV infection and can thus
provide greater specificity in distinguishing antibodies to DENV
from other crossreactive flavivirus antibodies [121,122]. These anti-
bodies can be measured by using plaque reduction neutralizing
tests (PRNTs), first developed by Russell et al. [122] based on the
protocol from Dulbecco et al. [123]. To date, PRNT remains the
most widely used assay for immunity studies [124,125]. However, it
is labor intensive, time consuming and has low throughput [124],
and is therefore not routinely used in dengue diagnostics.
New tests such as the ELISA-based microneutralization test
(ELISA-MN) [126], the fluorescent antibody cell sorter-based
Dendritic Cell-Specific Intercellular adhesion molecule-3-Grab-
bing Non-integrin expressor DC assay [127] and the enzyme-linked
immunosorbent spot microneutralization assay [128] have been
developed to overcome the limitations associated with PRNT.
These new tests have been separately validated, compared and eval-
uated [124,126–130] against PRNT and found to have good agreement
(false-positive rate <10%) in cases with primary DENV infection
[124,130]. However, Putnak et al. reported poor agreement among
the tests in association with vaccination or secondary infection
[124]. This result could have been influenced by the use of different
cell lines or different strains of DENV [129]. Others have suggested
the use of Fcγ receptor (FcγR)-positive cells for these assays since
DENV infects monocytes and DCs that express such receptors
[131,132]. The use of such cells may also provide information on
whether the antibodies were able to neutralize DENV intra
cellularly or whether neutralization was only mediated through
the coligation of FcγRIIB, which inhibits FcγR-mediated phago-
cytosis and hence DENV entry into monocytes [133]. A limited
observation suggests that this could provide greater specificity on
Diagnosis of dengue: an update
6. Expert Rev. Anti Infect. Ther. 10(8), (2012)900
Review
the DENV serotype responsible for the infection [133]. However,
detailed validation is required for all of these assays before they
can be used clinically.
Combined antigen/antibody detection
Given the dynamic nature of the NS1 antigen, antidengue IgM
and IgG antibody levels during the course of acute illness, efforts
have been made to combine all three tests into a single reaction
for ease of use. Some of these have been evaluated and shown to
have promising diagnostic sensitivity (89–93%) and specificity
(75.0–100%) [91,100–102,134].
Advances in rapid diagnostic tools
While rapid bedside diagnosis formats are available for antigen
or antibody detection or both simultaneously, the sensitivities
and specificities of the available tests have been uniformly lower
than the equivalent laboratory-based assays. A complete review of
these assays is provided elsewhere [102,118]. These limitations may
be due to the use of the lateral flow dipstick approach. The new
lab-on-a-chip platform could offer a way to improve the perfor-
mance of these bedside diagnostic tools [135–137]. This platform
makes use of a number of new technologies; some in combina-
tion, such as microfluidics [135–137] and grating couplers [137] to
improve multiplexing, accommodate better mixing of reagents
with test samples as well as achieving greater sensitivity for detect-
ing positive signals [138]. This platform could feature prominently
in dengue diagnostics in the coming years.
Disease prognostication
Progression of mild dengue infection to severe dengue
(DHF/dengue shock syndrome) is difficult to predict owing to an
incomplete understanding of disease pathogenesis. Symptoms and
signs of severe dengue have a sudden onset at the time of deferves-
cence [1,19]. Careful monitoring of hematocrit as well as signs of
circulatory failure or internal hemorrhage needs to be carried out
for at least 2 days after fever defervescence. Specifically, patients
should be observed for signs such as severe abdominal pain, passage
of black stools, bleeding into the skin, nose or gums, sweating or
cold skin, which could indicate the devel-
opment of DHF [7]. Depending on disease
progression, should DHF, occurs, oral rehy-
dration therapy is sufficient for milder DHF
while intravenous fluid therapy is suggested
for more severe manifestations, and blood
transfusion is suggested for critical cases [7].
However, hospitalization for close mon-
itoring of all patients in dengue-endemic
countries is often not feasible, particularly
during outbreaks, as it stresses the lim-
ited medical healthcare resources. Under
such circumstances, an ability to predict
the development of severe dengue at the
early stages of illness could thus be use-
ful for triaging patients. Various clinical
markers have been proposed as warning
signs of severe dengue progression, as
shown in Table 3. How well these clinical
symptoms/signs perform in predicting the
onset of severe dengue remains to be fully
determined.
Besides monitoring individual symptoms
or signs, several groups have also evaluated
the usefulness of combining these into an
algorithm for predicting severe dengue. Lee
et al. explored the use of a probability equa-
tion that combines four simple clinical lab-
oratory observations, including bleeding,
lymphocyte proportion, increased serum
urea and low total serum protein [139]. They
reported a sensitivity of 100% and speci-
ficity of 46%. They estimated that 43.9%
of the mild dengue cases could have been
prevented from hospitalization in 2004.
The authors followed up this study with a
Table 3. Warning signs and symptoms leading to potential severe
dengue (dengue hemorrhagic fever/dengue shock syndrome).
Warning signs for severe disease progression
Signs Den|OFIs p-value Ref.
Abdominal pain & tenderness 63.3|22.6% <0.05 [150,152]
78.0|22.0%†
0.03
Persistent vomiting NA NA [153]
Clinical fluid accumulation 46.4|7.1% 0.002 [154]
Mucosal bleed/ spontaneous bleeding 84.1|65.9% 0.008 [150,153]
26.6|10.4% 0.05
Lethargy, restlessness 12.7|2.2% 0.05 [150,152]
54.0|20.0%†
0.002
Liver enlargement >2 cm 91.6|72.4%‡
0.01 [146]
Severe dengue (DHF/DSS)
Symptoms Mild|severe p-value Ref.
Severe plasma leakage leading to
shock and fluid accumulation with
respiratory distress
92.9–100% in severe den NA [154]
Severe bleeding (evaluated by clinician) 10.0–35.7% in severe den <0.01 [139,154]
Gums: 5.7–6.0|65.0–67.8%
Nose: 0.9|12.0–16.9%
Severe organ involvement AST: 1293|196 IU/l 0.015 [37,145,153,155]
Liver: increased AST/ALT ALT: 309|132 IU/l 0.075
CNS: impaired consciousness AST: 76|12 U/l <0.01
Heart and other organs ALT: 30|20 U/l <0.01
Thrombocytopenia ≤100,000/mm3
16|82% NA [145]
†
Dengue and severe dengue comparison, performed in children younger than 15 years of age.
‡
Children (younger than 15 years of age) versus adults (older than 15 years of age).
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Den: Confirmed dengue cases;
DHF: Dengue hemorrhagic fever; DSS: Dengue shock syndrome; IU/l: International units per liter;
NA: Not applicable; OFI: Other febrile illness.
Tang & Ooi
7. 901www.expert-reviews.com
Review
prospective validation of their equation in the same hospital and
found similar levels of accuracy [140].
Another algorithm using platelet count, crossover threshold
of PCR-positive results (viremia in blood) and pre-existing anti
dengue IgG (secondary infection) measured during the first 72 h
of illness was shown to predict hospitalization with a sensitivity
and specificity of 78.2 and 80.2%, respectively [36]. Likewise,
as discussed earlier, the algorithm that distinguishes DHF from
dengue infection is able to achieve a sensitivity of 79.6% [37]. The
ability to calculate the probability of development of severe den-
gue based on routinely performed clinical tests could also be use-
ful to guide prognostication [37]. However, further prospective
clinical studies are needed to validate their usefulness.
Quality assurance
While the authors have reviewed the sensitivities and specificities
of the various tools for diagnosis of dengue, how these tests actu-
ally perform can be affected by a number of variables that differ
from laboratory to laboratory, or from region to region. Thus,
quality assurance programs should be instituted in all diagnos-
tic and reference laboratories that offer services in diagnosis of
dengue. This ensures that the tests perform at the expected levels
in different laboratories and in different hands. Details on such
quality assurance programs have been reviewed elsewhere [141].
Diagnosis of dengue in a vaccinated population
While an effective and safe vaccine against dengue is anticipated,
its introduction could also provide fresh challenges for diagnosis
of dengue. Even though the goal of vacci-
nation is to eliminate dengue cases entirely,
there are currently no data that indicate
that a complete elimination of DENV is
feasible with vaccination programs. On the
contrary, there remains a concern that the
antibodies generated by vaccination may
enhance dengue, particularly when anti-
body levels wane in the years following vac-
cination. Furthermore, vaccination may not
prevent infection against all strains [142] or
may drive the emergence of vaccine-escape
mutants [143], as encountered with other
infections, such as hepatitis B [144]. A com-
prehensive surveillance of dengue among
cases of febrile illness would thus be needed
to determine the true efficacy of vaccination
and to monitor for vaccine failure.
Epidemiologically, vaccination would
reduce DENV transmission and hence the
prevalence of dengue. Under such circum-
stances, diagnostic approaches or tests with
high sensitivity but poor specificity would
result in a high false-positive rate. However,
a low sensitivity could lead to false-negative
findings, which could result in an inability
to detect the emergence of vaccine failure
or escape mutants early enough to trigger the necessary public
health responses.
Given these requirements, clinical diagnosis using symptoms,
signs and standard routine hematological or biochemical tests is
unlikely to provide sufficient specificity (Figure 1). Furthermore,
vaccinated individuals may also present with a milder illness
than classical dengue infection, making approaches such as the
use of the WHO dengue classification schemes less sensitive.
Diagnosis of acute DENV infection must thus rely even more
on the laboratory.
Serologically, DENV infection in vaccinated individuals would
also resemble that of a secondary infection, where a rise in IgM
titers is not a consistent feature but a rapid rise in IgG titers or
the ratio of IgM and IgG could be suggestive of acute DENV
infection [117]. In this respect, collection of a convalescent serum
sample to demonstrate rising antibody titers would be very use-
ful in interpreting these serological tests. Caution will need to be
exercised in places where another flavivirus, such as West Nile
or Japanese encephalitis virus, circulates. Overall, however, sero-
logical approaches will probably lack the specificity required for
a definitive diagnosis of dengue in the low prevalence setting
expected in vaccinated populations (Figure 2).
Detection of DENV or components of DENV are likely to
provide the necessary sensitivity and specificity needed (Figure 2).
While NS1 antigen detection is easy to use and is suited to point-
of-care diagnosis, the presence of vaccine-induced antidengue IgG
antibodies, as with secondary DENV infection, could lower the
overall sensitivity of this test. Likewise, while virus isolation may be
0.8
1.00
0.95
0.90
0.85
0.6
0.4
PPV
NPV
0.2
0.0
0 10 20 30 0 10 20
WHO (<56 yrs)
WHO (≥56 yrs)
PCR
NS1
lgM (ELISA)
lgM (Rapid)
30
Prevalence Prevalence
Figure 2. Positive- and negative- predictive values of the various diagnostic
approaches for dengue at different rates of prevalence. Results were generated
from median values of sensitivity and specificity presented in Table 2 for PCR
(conventional and real time), IgM (ELISA), IgM (Rapid) and NS1 detection, respectively.
A specificity of 96% was assumed for conventional PCR and real-time PCR as most
studies have limited population sizes. Diagnosis using the WHO 2009 classification was
used to represent clinical diagnosis. Data for WHO criteria were obtained from Low et al.
[12] and separated into two age groups (<56 and ≥56 years).
NPV: Negative-predictive value; NS1: Non-structural protein 1; PPV: Positive-predictive value.
Diagnosis of dengue: an update
8. Expert Rev. Anti Infect. Ther. 10(8), (2012)902
Review
highly specific, it lacks sufficient sensitivity, especially since in most
places, a suitable insectary for mosquito inoculation is not likely to
be available and laboratories will have to rely on cell cultures.
However, virus isolation will not be redundant and would need
to be done in all RT-PCR-positive specimens, as isolation of
vaccine-escape mutants would be needed to characterize these
viruses. Such information could be useful in updating vaccine
composition through the development or selection of appropri-
ate vaccine strains or even updating the primers and probes used
in molecular diagnostic assays [143].
Nucleic acid detection offers the highest sensitivity and speci-
ficity, and would thus be the most appropriate approach for acute
diagnosis of dengue in vaccinated populations with low disease
prevalence (Figure 2). Emphasis should be on those assays that
have been carefully validated in different laboratories serving
different populations. The availability of panels of standard-
ized positive and negative controls, along with an internation-
ally coordinated quality assurance program, would be needed
to ensure consistency in the performance of the diagnostic
assays. Presently, such a molecular diagnostic assay is lacking.
RT-PCR method used in different laboratories differ in terms
of primers/probes, enzymes and buffers as well as cycling con-
ditions. The method of detection of the RT-PCR amplicon,
whether as an end point or real-time assay, is also likely to be
different, as with the method of viral RNA extraction from clini-
cal specimens. These limitations need to be addressed urgently
if we are to be prepared for diagnosis of dengue and surveillance
in a postvaccination world.
Expert commentary
DENV and its mosquito vectors have expanded geographically
throughout the tropical world and are now encroaching into
subtropical regions. These trends make dengue a global health
concern. In the absence of either a licensed vaccine or antiviral
drug, reduction of the disease burden relies on early clinical
recognition of dengue and the timely initiation of supportive
therapy. As differentiation between dengue and other causes of
febrile illnesses is difficult based on presenting symptoms and
signs, laboratory tests are needed for a confirmatory diagnosis.
This review summarizes the current knowledge on clinical as
well as laboratory diagnosis of dengue. It reveals that clinical
approaches generally have high sensitivities but poor specificities
and discusses the various decision algorithms that have been
designed to improve the specificity of clinical diagnosis. For
confirmatory diagnosis, a range of laboratory tools are avail-
able and the main consideration on which tool to use is the
time from illness onset. A central theme of this review is the
need for a systematic validation of the performance of both the
decision algorithms and laboratory assays in different popula-
tions and diagnostic laboratory settings, respectively. This need
for quality-assured standardized performance could, paradoxi-
cally, become more acute when a dengue vaccine or antiviral
drug becomes available. The consequent reduction in dengue
prevalence necessitates the use of the most sensitive and specific
method to derive useful positive and negative predictive val-
ues to support clinical decisions in treatment and public health
responses.
Five-year view
We speculate that a dengue vaccine will be near licensing in
5 years and that potential antiviral drugs against dengue will
also enter late stages of clinical trials. The implementation of
either countermeasure against dengue would shift the emphasis
of diagnosis of dengue from serological to virological. Tools that
detect either the viral genome or antigen, particularly at the bed-
side, would gain favor. These tools are better able to distinguish
dengue from other flaviviral infections and are also useful in
the early phases of illness, when initiation of antiviral therapy
would probably exert its maximal effect. Furthermore, definitive
diagnosis of dengue in vaccinated populations would become
even more important as it could herald waning immunity or
emergence of vaccine-escape mutants; either scenario would
trigger a public health emergency. Hence, the need for improve-
ments to existing approaches for the diagnosis of dengue would
not be diminished with the advent of either vaccination or anti-
viral drug therapy, but rather the demand for tests that achieve
near-perfect sensitivity and specificity will increase in the next
5 years.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Clinical diagnosis using the 1997–2009 WHO dengue classification schemes has high sensitivity but lacks specificity.
• Decision algorithms for diagnosis have been proposed but lack prospective validation.
• Choice of diagnostic assays should be guided by the time from illness onset.
• The presence of pre-existing antibodies from a previous heterologous dengue virus infection or a previous flavivirus infection can
affect the sensitivity or specificity of many diagnostic assays.
• Postvaccination surveillance would face the same challenges for diagnostics as currently encountered with secondary dengue infection.
• Despite the above, diagnosis of dengue in vaccinated individuals is critical for the surveillance of vaccine failure and escape mutants.
• Diagnostic assays with high sensitivity and specificity will be in particular demand in the low dengue prevalence setting following
vaccination.
Tang & Ooi
9. 903www.expert-reviews.com
Review
References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1 WHO. DENGUE: Guidelines for Diagnosis,
Treatment, Prevention and Control – New
Edition. WHO, Geneva,
Switzerland (2009).
•• This publication consolidates exceptional
efforts put in by the experts in the field.
It contains extensive information for
diagnosis, treatment, prevention and
control of dengue.
2 Westaway EG, Blok J. Taxonomy and
evolutionary relationships of flavivirus.
In: Dengue and Dengue Hemorrhagic
Fever. Gubler DJ, Kuno G (Eds). CAB
International, London, UK (1997).
3 Chambers TJ, Weir RC, Grakoui A et al.
Evidence that the N-terminal domain of
nonstructural protein NS3 from yellow
fever virus is a serine protease responsible
for site-specific cleavages in the viral
polyprotein. Proc. Natl Acad. Sci. USA
87(22), 8898–8902 (1990).
4 Rice CM, Lenches EM, Eddy SR, Shin SJ,
Sheets RL, Strauss JH. Nucleotide sequence
of yellow fever virus: implications for
flavivirus gene expression and evolution.
Science 229(4715), 726–733 (1985).
5 Harris E, Holden KL, Edgil D, Polacek C,
Clyde K. Molecular biology of flaviviruses.
Novartis Found. Symp. 277, 23–39; discussion
40, 71–73, 251–253 (2006).
6 Sabin AB. Research on dengue during
World War II. Am. J. Trop. Med. Hyg. 1(1),
30–50 (1952).
7 WHO-SEARO. Guidelines for Treatment of
Dengue Fever/Dengue Haemorrhagic Fever
in Small Hospitals. WHO-SEARO,
New Delhi, India (1999).
8 Halstead SB, O’Rourke EJ. Antibody-
enhanced dengue virus infection in primate
leukocytes. Nature 265(5596),
739–741 (1977).
9 Halstead SB, Venkateshan CN, Gentry
MK, Larsen LK. Heterogeneity of infection
enhancement of dengue 2 strains by
monoclonal antibodies. J. Immunol.
132(3), 1529–1532 (1984).
10 Halstead SB. Neutralization and antibody-
dependent enhancement of dengue viruses.
Adv. Virus Res. 60, 421–467 (2003).
11 Sessions OM, Barrows NJ, Souza-Neto JA
et al. Discovery of insect and human dengue
virus host factors. Nature 458(7241),
1047–1050 (2009).
12 Low JG, Ong A, Tan LK et al. The early
clinical features of dengue in adults:
challenges for early clinical diagnosis.
PLoS Negl. Trop. Dis. 5(5), e1191 (2011).
13 Khor CC, Chau TN, Pang J et al.
Genome-wide association study identifies
susceptibility loci for dengue shock
syndrome at MICB and PLCE1. Nat.
Genet. 43(11), 1139–1141 (2011).
14 Pastorino B, Nougairède A, Wurtz N,
Gould E, de Lamballerie X. Role of host
cell factors in flavivirus infection:
implications for pathogenesis and
development of antiviral drugs. Antiviral
Res. 87(3), 281–294 (2010).
15 Martina BE, Koraka P, Osterhaus AD.
Dengue virus pathogenesis: an integrated
view. Clin. Microbiol. Rev. 22(4),
564–581 (2009).
16 Rico-Hasse R. Dengue virus virulence
and transmission determinants. Curr.
Trop. Microbiol. Immunol. 338,
45–55 (2010).
17 Tuiskunen A, Wahlström M, Bergström J,
Buchy P, Leparc-Goffart I, Lundkvist A.
Phenotypic characterization of patient
dengue virus isolates in BALB/c mice
differentiates dengue fever and dengue
hemorrhagic fever from dengue shock
syndrome. Virol. J. 8, 398 (2011).
18 OhAinle M, Balmaseda A, Macalalad AR
et al. Dynamics of dengue disease severity
determined by the interplay between viral
genetics and serotype-specific immunity. Sci.
Transl. Med. 3(114), 114ra128 (2011).
19 Gubler DJ. Dengue and dengue
hemorrhagic fever. Clin. Microbiol. Rev.
11(3), 480–496 (1998).
20 Xu G, Dong H, Shi N et al. An outbreak of
dengue virus serotype 1 infection in Cixi,
Ningbo, People’s Republic of China, 2004,
associated with a traveler from Thailand
and high density of Aedes albopictus. Am. J.
Trop. Med. Hyg. 76(6), 1182–1188 (2007).
21 Lambrechts L, Scott TW, Gubler DJ.
Consequences of the expanding global
distribution of Aedes albopictus for dengue
virus transmission. PLoS Negl. Trop. Dis.
4(5), e646 (2010).
22 Ooi EE, Goh KT, Gubler DJ. Dengue
prevention and 35 years of vector control in
Singapore. Emerging Infect. Dis. 12(6),
887–893 (2006).
23 Sabin AB, Schlesinger RW. Production of
immunity to dengue with virus modified
by propagation in mice. Science 101(2634),
640–642 (1945).
24 WHO. Dengue Vaccine Development: the
Role of the WHO South-East Asia Regional
Office. WHO, Geneva, Switzerland (2010).
25 Halstead SB, Diwan AR, Marchette NJ,
Palumbo NE, Srisukonth L. Selection of
attenuated dengue 4 viruses by serial
passage in primary kidney cells. I.
Attributes of uncloned virus at different
passage levels. Am. J. Trop. Med. Hyg.
33(4), 654–665 (1984).
26 Halstead SB, Marchette NJ, Diwan AR,
Palumbo NE, Putvatana R. Selection of
attenuated dengue 4 viruses by serial
passage in primary kidney cells. II.
Attributes of virus cloned at different dog
kidney passage levels. Am. J. Trop. Med.
Hyg. 33(4), 666–671 (1984).
27 Halstead SB, Marchette NJ, Diwan AR,
Palumbo NE, Putvatana R, Larsen LK.
Selection of attenuated dengue 4 viruses by
serial passage in primary kidney cells. III.
Reversion to virulence by passage of cloned
virus in fetal rhesus lung cells. Am. J. Trop.
Med. Hyg. 33(4), 672–678 (1984).
28 Halstead SB, Eckels KH, Putvatana R,
Larsen LK, Marchette NJ. Selection of
attenuated dengue 4 viruses by serial
passage in primary kidney cells. IV.
Characterization of a vaccine candidate in
fetal rhesus lung cells. Am. J. Trop. Med.
Hyg. 33(4), 679–683 (1984).
29 Halstead SB, Marchette NJ. Biologic
properties of dengue viruses following
serial passage in primary dog kidney cells:
studies at the University of Hawaii. Am. J.
Trop. Med. Hyg. 69(6 Suppl.), 5–11 (2003).
30 Halstead SB. Studies on the attenuation of
dengue 4. Asian J. Infect. Dis. 2,
112–117 (1978).
31 Russell PK. Progress toward dengue
vaccines. Asian J. Infect. Dis. 2,
118–120 (1978).
32 Swaminathan S, Batra G, Khanna N.
Dengue vaccines: state-of-the-art. Expert
Opin. Ther. Pat. 20(6), 819–835 (2010).
33 Gubler DJ. Emerging vector-borne flavivirus
diseases: are vaccines the solution? Expert
Rev. Vaccines 10(5), 563–565 (2011).
34 Coller BA, Clements DE. Dengue vaccines:
progress and challenges. Curr. Opin.
Immunol. 23(3), 391–398 (2011).
35 WHO. Dengue Haemorrhagic Fever:
Diagnosis, Treatment, Prevention and
Control (2nd Edition). WHO, Geneva,
Switzerland (1997).
36 Tanner L, Schreiber M, Low JG et al.
Decision tree algorithms predict the
diagnosis and outcome of dengue fever in
Diagnosis of dengue: an update
10. Expert Rev. Anti Infect. Ther. 10(8), (2012)904
Review
the early phase of illness. PLoS Negl. Trop.
Dis. 2(3), e196 (2008).
37 Potts JA, Thomas SJ, Srikiatkhachorn A
et al. Classification of dengue illness based
on readily available laboratory data. Am. J.
Trop. Med. Hyg. 83(4), 781–788 (2010).
•• Points out the fundamental shortcomings
and limitations of clinical studies in
dengue and the need for a consolidated
clinical and laboratory data collection for
better disease management.
38 Potts JA, Rothman AL. Clinical and
laboratory features that distinguish dengue
from other febrile illnesses in endemic
populations. Trop. Med. Int. Health 13(11),
1328–1340 (2008).
39 Vaughn DW, Green S, Kalayanarooj S
et al. Dengue viremia titer, antibody
response pattern, and virus serotype
correlate with disease severity. J. Infect. Dis.
181(1), 2–9 (2000).
40 Jarman RG, Nisalak A, Anderson KB et al.
Factors influencing dengue virus isolation
by C6/36 cell culture and mosquito
inoculation of nested PCR-positive clinical
samples. Am. J. Trop. Med. Hyg. 84(2),
218–223 (2011).
41 Kuberski TT, Rosen L. A simple technique
for the detection of dengue antigen in
mosquitoes by immunofluorescence. Am. J.
Trop. Med. Hyg. 26(3), 533–537 (1977).
42 Kuberski TT, Rosen L. Identification of
dengue viruses using complement fixing
antigen produced in mosquitoes. Am. J.
Trop. Med. Hyg. 26(3), 538–543 (1977).
43 Gubler DJ, Nalim S, Tan R, Saipan H,
Sulianti Saroso J. Variation in susceptibility
to oral infection with dengue viruses
among geographic strains of Aedes aegypti.
Am. J. Trop. Med. Hyg. 28(6),
1045–1052 (1979).
44 Thet W. Detection of dengue virus by
immunofluorescence after intracerebral
inoculation of mosquitoes. Lancet 1(8262),
53–54 (1982).
45 Yeh WT, Chen RF, Wang L, Liu JW, Shaio
MF, Yang KD. Implications of previous
subclinical dengue infection but not virus
load in dengue hemorrhagic fever. FEMS
Immunol. Med. Microbiol. 48(1),
84–90 (2006).
46 Meiklejohn G, England B, Lennette EH.
Propagation of dengue virus strains in
unweaned mice. Am. J. Trop. Med. Hyg.
1(1), 51–58 (1952).
47 Sabin AB. The dengue group of viruses and
its family relationships. Bacteriol. Rev.
14(3), 225–232 (1950).
48 Yuill TM, Sukhavachana P, Nisalak A,
Russell PK. Dengue-virus recovery by
direct and delayed plaques in LLC-MK2
cells. Am. J. Trop. Med. Hyg. 17(3),
441–448 (1968).
49 Matsumura T, Stollar V, Schlesinger RW.
Studies on the nature of dengue viruses. V.
Structure and development of dengue virus
in Vero cells. Virology 46(2),
344–355 (1971).
50 Fujita N, Tamura M, Hotta S. Dengue
virus plaque formation on microplate
cultures and its application to virus
neutralization (38564). Proc. Soc. Exp. Biol.
Med. 148(2), 472–475 (1975).
51 Igarashi A. Isolation of a Singh’s Aedes
albopictus cell clone sensitive to dengue and
chikungunya viruses. J. Gen. Virol. 40(3),
531–544 (1978).
52 Tesh RB. A method for the isolation and
identification of dengue viruses, using
mosquito cell cultures. Am. J. Trop. Med.
Hyg. 28(6), 1053–1059 (1979).
53 Gubler DJ, Kuno G, Sather GE, Velez M,
Oliver A. Mosquito cell cultures and
specific monoclonal antibodies in
surveillance for dengue viruses. Am. J.
Trop. Med. Hyg. 33(1), 158–165 (1984).
54 Chua KB, Mustafa B, Abdul Wahab AH
et al. A comparative evaluation of dengue
diagnostic tests based on single-acute
serum samples for laboratory confirmation
of acute dengue. Malays. J. Pathol. 33(1),
13–20 (2011).
55 Lanciotti RS, Calisher CH, Gubler DJ,
Chang GJ, Vorndam AV. Rapid detection
and typing of dengue viruses from clinical
samples by using reverse transcriptase-
polymerase chain reaction. J. Clin.
Microbiol. 30(3), 545–551 (1992).
56 Harris E, Roberts TG, Smith L et al. Typing
of dengue viruses in clinical specimens and
mosquitoes by single-tube multiplex reverse
transcriptase PCR. J. Clin. Microbiol. 36(9),
2634–2639 (1998).
57 Raengsakulrach B, Nisalak A, Maneekarn N
et al. Comparison of four reverse
transcription-polymerase chain reaction
procedures for the detection of dengue virus
in clinical specimens. J. Virol. Methods
105(2), 219–232 (2002).
58 Gijavanekar C, Añez-Lingerfelt M, Feng C
et al. PCR detection of nearly any dengue
virus strain using a highly sensitive primer
‘cocktail’. FEBS J. 278(10), 1676–1687
(2011).
59 Yong YK, Thayan R, Chong HT, Tan CT,
Sekaran SD. Rapid detection and
serotyping of dengue virus by multiplex
RT-PCR and real-time SYBR green
RT-PCR. Singapore Med. J. 48(7),
662–668 (2007).
60 Upanan S, Cabrera-Hernandez A,
Ekkapongpisit M, Smith DR. A simplified
PCR methodology for semiquantitatively
analyzing dengue viruses. Jpn. J. Infect. Dis.
59(6), 383–387 (2006).
61 Dash PK, Parida M, Santhosh SR et al.
Development and evaluation of a 1-step
duplex reverse transcription polymerase
chain reaction for differential diagnosis of
chikungunya and dengue infection. Diagn.
Microbiol. Infect. Dis. 62(1), 52–57 (2008).
62 Barkham TM, Chung YK, Tang KF,
Ooi EE. The performance of RT-PCR
compared with a rapid serological assay for
acute dengue fever in a diagnostic
laboratory. Trans. R. Soc. Trop. Med. Hyg.
100(2), 142–148 (2006).
63 Chutinimitkul S, Payungporn S,
Theamboonlers A, Poovorawan Y. Dengue
typing assay based on real-time PCR using
SYBR Green I. J. Virol. Methods 129(1),
8–15 (2005).
64 Chien LJ, Liao TL, Shu PY, Huang JH,
Gubler DJ, Chang GJ. Development of
real-time reverse transcriptase PCR assays to
detect and serotype dengue viruses. J. Clin.
Microbiol. 44(4), 1295–1304 (2006).
65 Lai YL, Chung YK, Tan HC et al.
Cost-effective real-time reverse
transcriptase PCR (RT-PCR) to screen for
Dengue virus followed by rapid single-tube
multiplex RT-PCR for serotyping of the
virus. J. Clin. Microbiol. 45(3),
935–941 (2007).
66 Pok KY, Lai YL, Sng J, Ng LC. Evaluation
of nonstructural 1 antigen assays for the
diagnosis and surveillance of dengue in
Singapore. Vector Borne Zoonotic Dis.
10(10), 1009–1016 (2010).
67 Hue KD, Tuan TV, Thi HT et al.
Validation of an internally controlled
one-step real-time multiplex RT-PCR assay
for the detection and quantitation of
dengue virus RNA in plasma. J. Virol.
Methods 177(2), 168–173 (2011).
68 Hirayama T, Mizuno Y, Takeshita N et al.
Detection of dengue virus genome in urine
by real-time reverse transcriptase PCR: a
laboratory diagnostic method useful after
disappearance of the genome in serum.
J. Clin. Microbiol. 50(6),
2047–2052 (2012).
69 Tripathi NK, Shrivastava A, Dash PK,
Jana AM. Detection of dengue virus.
Methods Mol. Biol. 665, 51–64 (2011).
Tang & Ooi
11. 905www.expert-reviews.com
Review
70 Leparc-Goffart I, Baragatti M, Temmam S
et al. Development and validation of
real-time one-step reverse transcription-PCR
for the detection and typing of dengue
viruses. J. Clin. Virol. 45(1), 61–66 (2009).
71 Gurukumar KR, Priyadarshini D, Patil JA
et al. Development of real-time PCR for
detection and quantitation of dengue
viruses. Virol. J. 6, 10 (2009).
72 Poloni TR, Oliveira AS, Alfonso HL et al.
Detection of dengue virus in saliva and
urine by real-time RT-PCR. Virol. J. 7,
22 (2010).
73 Sadon N, Delers A, Jarman RG et al. A new
quantitative RT-PCR method for sensitive
detection of dengue virus in serum samples.
J. Virol. Methods 153(1), 1–6 (2008).
74 Singh K, Lale A, Eong Ooi E et al. A
prospective clinical study on the use of
reverse transcription-polymerase chain
reaction for the early diagnosis of dengue
fever. J. Mol. Diagn. 8(5), 613–616; quiz
617 (2006).
75 Kong YY, Thay CH, Tin TC, Devi S. Rapid
detection, serotyping and quantitation of
dengue viruses by TaqMan real-time
one-step RT-PCR. J. Virol. Methods
138(1–2), 123–130 (2006).
76 Saxena P, Dash PK, Santhosh SR,
Shrivastava A, Parida M, Rao PL.
Development and evaluation of one step
single tube multiplex RT-PCR for rapid
detection and typing of dengue viruses.
Virol. J. 5, 20 (2008).
77 Dos Santos HW, Poloni TR, Souza KP
et al. A simple one-step real-time RT-PCR
for diagnosis of dengue virus infection.
J. Med. Virol. 80(8), 1426–1433 (2008).
78 Klungthong C, Gibbons RV,
Thaisomboonsuk B et al. Dengue virus
detection using whole blood for reverse
transcriptase PCR and virus isolation.
J. Clin. Microbiol. 45(8), 2480–2485
(2007).
79 Watthanaworawit W, Turner P, Turner CL
et al. A prospective evaluation of diagnostic
methodologies for the acute diagnosis of
dengue virus infection on the Thailand–
Myanmar border. Trans. R. Soc. Trop. Med.
Hyg. 105(1), 32–37 (2011).
80 Compton J. Nucleic acid sequence-based
amplification. Nature 350(6313), 91–92
(1991).
81 Wu SJ, Lee EM, Putvatana R et al. Detection
of dengue viral RNA using a nucleic acid
sequence-based amplification assay. J. Clin.
Microbiol. 39(8), 2794–2798 (2001).
82 Bhatnagar J, Blau DM, Shieh WJ et al.
Molecular detection and typing of dengue
viruses from archived tissues of fatal cases
by rt-PCR and sequencing: diagnostic and
epidemiologic implications. Am. J. Trop.
Med. Hyg. 86(2), 335–340 (2012).
83 Peeling RW, Artsob H, Pelegrino JL et al.
Evaluation of diagnostic tests: dengue.
Nat. Rev. Microbiol. 8(12 Suppl.),
S30–S38 (2010).
84 Winkler G, Maxwell SE, Ruemmler C,
Stollar V. Newly synthesized dengue-2 virus
nonstructural protein NS1 is a soluble
protein but becomes partially hydrophobic
and membrane-associated after dimerization.
Virology 171(1), 302–305 (1989).
85 Flamand M, Megret F, Mathieu M,
Lepault J, Rey FA, Deubel V. Dengue virus
type 1 nonstructural glycoprotein NS1 is
secreted from mammalian cells as a soluble
hexamer in a glycosylation-dependent
fashion. J. Virol. 73(7), 6104–6110 (1999).
86 Libraty DH, Young PR, Pickering D et al.
High circulating levels of the dengue virus
nonstructural protein NS1 early in dengue
illness correlate with the development of
dengue hemorrhagic fever. J. Infect. Dis.
186(8), 1165–1168 (2002).
87 Avirutnan P, Punyadee N, Noisakran S
et al. Vascular leakage in severe dengue
virus infections: a potential role for the
nonstructural viral protein NS1 and
complement. J. Infect. Dis. 193(8),
1078–1088 (2006).
88 Hang VT, Nguyet NM, Trung DT et al.
Diagnostic accuracy of NS1 ELISA and
lateral flow rapid tests for dengue
sensitivity, specificity and relationship to
viraemia and antibody responses. PLoS
Negl. Trop. Dis. 3(1), e360 (2009).
89 Young PR, Hilditch PA, Bletchly C,
Halloran W. An antigen capture enzyme-
linked immunosorbent assay reveals high
levels of the dengue virus protein NS1 in
the sera of infected patients. J. Clin.
Microbiol. 38(3), 1053–1057 (2000).
90 Alcon S, Talarmin A, Debruyne M,
Falconar A, Deubel V, Flamand M.
Enzyme-linked immunosorbent assay
specific to dengue virus type 1
nonstructural protein NS1 reveals
circulation of the antigen in the blood
during the acute phase of disease in
patients experiencing primary or secondary
infections. J. Clin. Microbiol. 40(2),
376–381 (2002).
91 Dussart P, Labeau B, Lagathu G et al.
Evaluation of an enzyme immunoassay for
detection of dengue virus NS1 antigen in
human serum. Clin. Vaccine Immunol.
13(11), 1185–1189 (2006).
92 Xu H, Di B, Pan YX et al. Serotype
1-specific monoclonal antibody-based
antigen capture immunoassay for detection
of circulating nonstructural protein NS1:
implications for early diagnosis and
serotyping of dengue virus infections.
J. Clin. Microbiol. 44(8),
2872–2878 (2006).
93 Kumarasamy V, Wahab AH, Chua SK
et al. Evaluation of a commercial dengue
NS1 antigen-capture ELISA for laboratory
diagnosis of acute dengue virus infection.
J. Virol. Methods 140(1–2), 75–79 (2007).
94 Kumarasamy V, Chua SK, Hassan Z et al.
Evaluating the sensitivity of a commercial
dengue NS1 antigen-capture ELISA for
early diagnosis of acute dengue virus
infection. Singapore Med. J. 48(7),
669–673 (2007).
95 McBride WJ. Evaluation of dengue NS1
test kits for the diagnosis of dengue fever.
Diagn. Microbiol. Infect. Dis. 64(1),
31–36 (2009).
96 Bessoff K, Delorey M, Sun W, Hunsperger
E. Comparison of two commercially
available dengue virus (DENV) NS1
capture enzyme-linked immunosorbent
assays using a single clinical sample for
diagnosis of acute DENV infection. Clin.
Vaccine Immunol. 15(10),
1513–1518 (2008).
97 Blacksell SD, Mammen MP Jr,
Thongpaseuth S et al. Evaluation of the
Panbio dengue virus nonstructural
1 antigen detection and immunoglobulin
M antibody enzyme-linked immunosorbent
assays for the diagnosis of acute dengue
infections in Laos. Diagn. Microbiol. Infect.
Dis. 60(1), 43–49 (2008).
98 Bessoff K, Phoutrides E, Delorey M,
Acosta LN, Hunsperger E. Utility of a
commercial nonstructural protein
1 antigen capture kit as a dengue virus
diagnostic tool. Clin. Vaccine Immunol.
17(6), 949–953 (2010).
99 Lima Mda R, Nogueira RM, Schatzmayr
HG, dos Santos FB. Comparison of three
commercially available dengue NS1 antigen
capture assays for acute diagnosis of dengue
in Brazil. PLoS Negl. Trop. Dis. 4(7),
e738 (2010).
100 Wang SM, Sekaran SD. Evaluation of a
commercial SD dengue virus NS1 antigen
capture enzyme-linked immunosorbent
assay kit for early diagnosis of dengue virus
infection. J. Clin. Microbiol. 48(8),
2793–2797 (2010).
101 Tricou V, Vu HT, Quynh NV et al.
Comparison of two dengue NS1 rapid tests
for sensitivity, specificity and relationship
Diagnosis of dengue: an update
12. Expert Rev. Anti Infect. Ther. 10(8), (2012)906
Review
to viraemia and antibody responses. BMC
Infect. Dis. 10, 142 (2010).
102 Blacksell SD, Jarman RG, Bailey MS et al.
Evaluation of six commercial point-of-care
tests for diagnosis of acute dengue
infections: the need for combining NS1
antigen and IgM/IgG antibody detection
to achieve acceptable levels of accuracy.
Clin. Vaccine Immunol. 18(12), 2095–2101
(2011).
• Comprehensive evaluation of diagnostic
kits for dengue point-of-care tests.
103 Chaterji S, Allen JC Jr, Chow A, Leo YS,
Ooi EE. Evaluation of the NS1 rapid test
and the WHO dengue classification
schemes for use as bedside diagnosis of
acute dengue fever in adults. Am. J. Trop.
Med. Hyg. 84(2), 224–228 (2011).
104 Lima MDA R, Noguieira RM, Schatzmayr
HG, de Pilippis AM. A new approach to
dengue fatal cases diagnosis: NS1 antigen
capture in tissues. PLoS Negl. Trop. Dis.
5(5), e1147 (2011).
105 Ding X, Hu D, Chen Y et al. Full
serotype- and group-specific NS1 capture
enzyme-linked immunosorbent assay for
rapid differential diagnosis of dengue virus
infection. Clin. Vaccine Immunol. 18(3),
430–434 (2011).
106 Shu PY, Chen LK, Chang SF et al. Dengue
NS1-specific antibody responses: isotype
distribution and serotyping in patients with
dengue fever and dengue hemorrhagic
fever. J. Med. Virol. 62(2),
224–232 (2000).
107 Shu PY, Chen LK, Chang SF et al. Potential
application of nonstructural protein NS1
serotype-specific immunoglobulin G
enzyme-linked immunosorbent assay in the
seroepidemiologic study of dengue virus
infection: correlation of results with those
of the plaque reduction neutralization test.
J. Clin. Microbiol. 40(5),
1840–1844 (2002).
108 Shu PY, Chen LK, Chang SF et al. Dengue
virus serotyping based on envelope and
membrane and nonstructural protein NS1
serotype-specific capture immunoglobulin
M enzyme-linked immunosorbent assays.
J. Clin. Microbiol. 42(6),
2489–2494 (2004).
109 Puttikhunt C, Prommool T, U-thainual N
et al. The development of a novel
serotyping-NS1-ELISA to identify
serotypes of dengue virus. J. Clin. Virol.
50(4), 314–319 (2011).
110 Watanabe S, Tan KH, Rathore AP et al.
The magnitude of dengue virus NS1
protein secretion is strain dependent and
does not correlate with severe pathologies
in the mouse infection model. J. Virol.
86(10), 5508–5514 (2012).
111 De Paula SO, Fonseca BA. Dengue: a
review of the laboratory tests a clinician
must know to achieve a correct diagnosis.
Braz. J. Infect. Dis. 8(6), 390–398 (2004).
112 Innis BL, Nisalak A, Nimmannitya S et al.
An enzyme-linked immunosorbent assay to
characterize dengue infections where
dengue and Japanese encephalitis
co-circulate. Am. J. Trop. Med. Hyg. 40(4),
418–427 (1989).
113 Kuno G, Gómez I, Gubler DJ. An ELISA
procedure for the diagnosis of dengue
infections. J. Virol. Methods 33(1–2),
101–113 (1991).
114 Lam SK, Fong MY, Chungue E et al.
Multicentre evaluation of dengue IgM dot
enzyme immunoassay. Clin. Diagn. Virol.
7(2), 93–98 (1996).
115 Hunsperger EA, Yoksan S, Buchy P et al.
Evaluation of commercially available
anti-dengue virus immunoglobulin M
tests. Emerging Infect. Dis. 15(3),
436–440 (2009).
116 Groen J, Koraka P, Velzing J, Copra C,
Osterhaus AD. Evaluation of six
immunoassays for detection of dengue
virus-specific immunoglobulin M and G
antibodies. Clin. Diagn. Lab. Immunol.
7(6), 867–871 (2000).
117 Prince HE, Matud JL. Estimation of
dengue virus IgM persistence using
regression analysis. Clin. Vaccine Immunol.
18(12), 2183–2185 (2011).
118 Blacksell SD, Doust JA, Newton PN,
Peacock SJ, Day NP, Dondorp AM. A
systematic review and meta-analysis of the
diagnostic accuracy of rapid
immunochromatographic assays for the
detection of dengue virus IgM antibodies
during acute infection. Trans. R. Soc. Trop.
Med. Hyg. 100(8), 775–784 (2006).
• Comprehensive review on dengue
diagnostics.
119 Tomashek KM. Dengue fever & dengue
hemorrhagic fever. In: CDC Health
Information for International Travel 2010,
The Yellow Book, Centers for Disease Control
and Prevention. Gw B (Ed.). Oxford
University Press, NC, USA (2010).
120 Prince HE, Yeh C, Lapé-Nixon M.
Development of a more efficient algorithm
for identifying false-positive reactivity
results in a dengue virus immunoglobulin
M screening assay. Clin. Vaccine Immunol.
15(8), 1304–1306 (2008).
121 Russell PK, Nisalak A. Dengue virus
identification by the plaque reduction
neutralization test. J. Immunol. 99(2),
291–296 (1967).
122 Russell PK, Nisalak A, Sukhavachana P,
Vivona S. A plaque reduction test for
dengue virus neutralizing antibodies.
J. Immunol. 99(2), 285–290 (1967).
123 Dulbecco R, Vogt M, Strickland AG. A
study of the basic aspects of neutralization
of two animal viruses, western equine
encephalitis virus and poliomyelitis virus.
Virology 2(2), 162–205 (1956).
124 Putnak JR, de la Barrera R, Burgess T et al.
Comparative evaluation of three assays for
measurement of dengue virus neutralizing
antibodies. Am. J. Trop. Med. Hyg. 79(1),
115–122 (2008).
125 Roehrig JT, Hombach J, Barrett AD.
Guidelines for plaque-reduction
neutralization testing of human antibodies
to dengue viruses. Viral Immunol. 21(2),
123–132 (2008).
126 Vorndam V, Beltran M. Enzyme-linked
immunosorbent assay-format
microneutralization test for dengue viruses.
Am. J. Trop. Med. Hyg. 66(2), 208–212
(2002).
127 Martin NC, Pardo J, Simmons M et al. An
immunocytometric assay based on dengue
infection via DC-SIGN permits rapid
measurement of anti-dengue neutralizing
antibodies. J. Virol. Methods 134(1–2),
74–85 (2006).
128 Rodrigo WW, Alcena DC, Rose RC, Jin X,
Schlesinger JJ. An automated dengue virus
microneutralization plaque assay performed
in human Fc{γ} receptor-expressing CV-1
cells. Am. J. Trop. Med. Hyg. 80(1),
61–65 (2009).
129 Thomas SJ, Nisalak A, Anderson KB et al.
Dengue plaque reduction neutralization
test (PRNT) in primary and secondary
dengue virus infections: how alterations in
assay conditions impact performance. Am.
J. Trop. Med. Hyg. 81(5), 825–833 (2009).
130 Liu L, Wen K, Li J et al. Comparison of
plaque- and enzyme-linked immunospot-
based assays to measure the neutralizing
activities of monoclonal antibodies specific
to domain III of dengue virus envelope
protein. Clin. Vaccine Immunol. 19(1),
73–78 (2012).
131 Moi ML, Lim CK, Kotaki A, Takasaki T,
Kurane I. Discrepancy in dengue virus
neutralizing antibody titers between plaque
reduction neutralizing tests with Fcγ
receptor (FcγR)-negative and FcγR-
expressing BHK-21 cells. Clin. Vaccine
Immunol. 17(3), 402–407 (2010).
Tang & Ooi
13. 907www.expert-reviews.com
Review
132 Moi ML, Lim CK, Chua KB, Takasaki T,
Kurane I. Dengue virus infection-
enhancing activity in serum samples with
neutralizing activity as determined by using
Fc?R-expressing cells. PLoS Negl. Trop. Dis.
6(2), e1536 (2012).
133 Chan KR, Zhang SL, Tan HC et al.
Ligation of Fc γ receptor IIB inhibits
antibody-dependent enhancement of
dengue virus infection. Proc. Natl Acad.
Sci. USA 108(30), 12479–12484 (2011).
134 Ramos MM, Tomashek KM, Arguello DF
et al. Early clinical features of dengue
infection in Puerto Rico. Trans. R. Soc.
Trop. Med. Hyg. 103(9), 878–884 (2009).
135 Aytur T, Foley J, Anwar M, Boser B, Harris
E, Beatty PR. A novel magnetic bead
bioassay platform using a microchip-based
sensor for infectious disease diagnosis.
J. Immunol. Methods 314(1–2),
21–29 (2006).
136 Lee YF, Lien KY, Lei HY, Lee GB. An
integrated microfluidic system for rapid
diagnosis of dengue virus infection. Biosens.
Bioelectron. 25(4), 745–752 (2009).
137 Duval D, González-Guerrero AB, Dante S
et al. Nanophotonic lab-on-a-chip platforms
including novel bimodal interferometers,
microfluidics and grating couplers. Lab Chip
12(11), 1987–1994 (2012).
138 Fang X, Tan OK, Tse MS, Ooi EE. A
label-free immunosensor for diagnosis of
dengue infection with simple electrical
measurements. Biosens. Bioelectron. 25(5),
1137–1142 (2010).
139 Lee VJ, Lye DC, Sun Y, Leo YS. Decision
tree algorithm in deciding hospitalization
for adult patients with dengue
haemorrhagic fever in Singapore. Trop.
Med. Int. Health 14(9), 1154–1159 (2009).
140 Thein TL, Leo YS, Lee VJ, Sun Y, Lye DC.
Validation of probability equation and
decision tree in predicting subsequent
dengue hemorrhagic fever in adult dengue
inpatients in Singapore. Am. J. Trop. Med.
Hyg. 85(5), 942–945 (2011).
141 Peeling RW, Smith PG, Bossuyt PM. A
guide for diagnostic evaluations. Nat. Rev.
Microbiol. 8(12 Suppl.), S2–S6 (2010).
142 Shrestha B, Brien JD, Sukupolvi-Petty S
et al. The development of therapeutic
antibodies that neutralize homologous and
heterologous genotypes of dengue virus
type 1. PLoS Pathog. 6(4),
e1000823 (2010).
143 Gromowski GD, Roehrig JT, Diamond
MS, Lee JC, Pitcher TJ, Barrett AD.
Mutations of an antibody binding energy
hot spot on domain III of the dengue 2
envelope glycoprotein exploited for
neutralization escape. Virology 407(2),
237–246 (2010).
144 Ma Q, Wang Y. Comprehensive analysis of
the prevalence of hepatitis B virus escape
mutations in the major hydrophilic region
of surface antigen. J. Med. Virol. 84(2),
198–206 (2012).
145 Kalayanarooj S, Vaughn DW,
Nimmannitya S et al. Early clinical and
laboratory indicators of acute dengue
illness. J. Infect. Dis. 176(2),
313–321 (1997).
146 Kittigul L, Pitakarnjanakul P, Sujirarat D,
Siripanichgon K. The differences of clinical
manifestations and laboratory findings in
children and adults with dengue virus
infection. J. Clin. Virol. 39(2),
76–81 (2007).
147 Phuong CX, Nhan NT, Kneen R et al.;
Dong Nai Study Group. Clinical diagnosis
and assessment of severity of confirmed
dengue infections in Vietnamese children:
is the World Health Organization
classification system helpful? Am. J. Trop.
Med. Hyg. 70(2), 172–179 (2004).
148 Chau TN, Anders KL, Lien le B et al.
Clinical and virological features of dengue
in Vietnamese infants. PLoS Negl. Trop.
Dis. 4(4), e657 (2010).
149 Nunes-Araújo FR, Ferreira MS, Nishioka
SD. Dengue fever in Brazilian adults and
children: assessment of clinical findings
and their validity for diagnosis. Ann.
Trop. Med. Parasitol. 97(4),
415–419 (2003).
150 Alexander N, Balmaseda A, Coelho IC et al.;
on behalf of the European Union, World
Health Organization (WHO-TDR) supported
DENCO Study Group. Multicentre
prospective study on dengue classification in
four South-east Asian and three Latin
American countries. Trop. Med. Int. Health
16(8), 936–948 (2011).
151 Fry SR, Meyer M, Semple MG et al. The
diagnostic sensitivity of dengue rapid test
assays is significantly enhanced by using a
combined antigen and antibody testing
approach. PLoS Negl. Trop. Dis. 5(6),
e1199 (2011).
152 Giraldo D, Sant’Anna C, Périssé AR et al.
Characteristics of children hospitalized
with dengue fever in an outbreak in Rio de
Janeiro, Brazil. Trans. R. Soc. Trop. Med.
Hyg. 105(10), 601–603 (2011).
153 Binh PT, Matheus S, Huong VT, Deparis
X, Marechal V. Early clinical and biological
features of severe clinical manifestations of
dengue in Vietnamese adults. J. Clin. Virol.
45(4), 276–280 (2009).
154 Leo YS, Thein TL, Fisher DA et al.
Confirmed adult dengue deaths in
Singapore: 5-year multi-center
retrospective study. BMC Infect. Dis. 11,
123 (2011).
155 Ong A, Sandar M, Chen MI, Sin LY. Fatal
dengue hemorrhagic fever in adults during
a dengue epidemic in Singapore. Int. J.
Infect. Dis. 11(3), 263–267 (2007).
Diagnosis of dengue: an update