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The Lancet 1997; 350:1719-1720
DOI:10.1016/S0140-6736(05)63567-2
Early indicators in acute dengue infection
Thomas P Monath a
Dengue is the commonest arthropod-borne viral infection in man, and an estimated 50?100 million cases occur annually in the tropics, with over 10 000 deaths from dengue haemorrhagic fever (DHF). In the Americas DHF is emerging as an increasingly important consequence of dengue infection.1 There DHF first appeared in epidemic form in Cuba in 1981, and the increasing frequency of outbreaks since 1989 reflects an increase in dengue immunity, circulation of multiple serotypes, and (possibly) the introduction of virulent dengue strains from Asia.2
New information from a study by S Kalayanarooj and colleagues3 may help in the clinical differentiation of dengue from other febrile illnesses. The study was based on the hypothesis that the degree of T-cell activation in secondary dengue infection, with its attendant release of cytokines, vasoactive mediators, and procoagulants, will differentiate classic dengue fever from DHF at an early stage of infection
In the study at two hospitals in Thailand children aged 6 months to 14 years were admitted when they presented with fever of less than 72 hours' duration and facial flushing (a sensitive and specific sign associated with dengue4) but without a specific identifiable cause of the illness. Investigations included tests for abnormal haemostasis, capillary leakage, and decreased plasma volume, decubitus chest X-ray (to determine the presence of pleural effusion), and routine liver-function tests. Of the 60 patients with serological or virological evidence of dengue, 28 (47%) were diagnosed as having DHF5 (ie, they had fever, one or more haemorrhagic manifestations, thrombocytopenia, and haemoconcentration). These findings are similar to those reported by Halstead et al,6 who showed that 29% of all febrile illness in Bangkok was due to dengue, and by Burke et al,7 who found that 53% of Thai schoolchildren with dengue met WHO criteria for DHF. The 105 patients in the Kalayanarooj study without a specific bacteriological cause for their illness were categorised as having ?other febrile illness, OFI?.
93% of the patients with acute dengue infection had serological responses indicative of prior exposure to at least one other dengue serotype. Dengue is caused by four distinct viral species (all hyperendemic in Thailand), and immunity to a heterologous serotype is generally accepted as predisposing to DHF. Preexistng cross-reactive, nonneutralising IgG antibodies to a heterologous dengue serotype form immune complexes with virions of the current infection and bind the Fcγ receptor of monocytemacrophages, enhancing dengue viral replication in these cells and promoting the pathogenesis of DHF.6 Over 90% of DHF cases occur in children with preexisting immunity to dengue;7 in the Kalayanarooj study, the figure was 100%.
A comparison of clinical and laboratory features revealed several statistically significant differences between children with dengue fever or DHF and those with OFI. Children with dengue or DHF were older (mean 8?1 years) than those with OFI (6?2 years), had a longer febrile course, were more likely to have gastrointestinal symptoms (anorexia, nausea, vomiting), and to have a positive tourniquet test (>10 petechiae/2?5 cm2 skin area). Platelet, total white cell, absolute neutrophil, and absolute monocyte counts at study entry were lower than in the OFI group, and the plasma alanine and aspartate aminotransferases were significantly higher. However, a high proportion (39%) of children with OFI had a positive tourniquet test, so this test had a high negative (but a low positive) predictive value for differentiating dengue from OFI at the time of initial presentation. A serum aspartate aminotransferase of more than 60 U/mL, a leucocyte count of under 5000/μL, and an absolute neutrophil count of under 3000/μL had high positive and negative predictive values for differentiating dengue or DHF from OFI at initial presentation and may help in making decisions on whether to admit a patient and on frequency of follow-up.
Progression to DHF is the most feared complication of dengue infection, but no early prognostic markers of this disorder have been defined. In the Kalayanarooj study the only significant differences at study entry between those with dengue fever and those with DHF were a lower mean platelet count and higher aspartate aminotransferase concentrations among the latter. The variability of these factors greatly reduces their value in considering an individual patient, but a normal plasma aspartate aminotransferase concentration had a very high negative predictive value for DHF.
Given the lack of clear clinical prognostic indicators for DHF, attention must now turn elsewhere. The US collaborators in the Thai study are part of a team led by Francis A Ennis at the University of Massachusetts who have been trying to unravel the pathogenesis of DHF. They have found higher levels of viraemia and of soluble cellular proteins in DHF than in dengue fever patients8 and plan to measure chemical mediators and cytokines throughout the course of dengue infections. Such studies may lead to the identification of specific therapy, but the process will not be simple, as illustrated by the failure to interrupt the pathophysiological cascade in endotoxic shock. However, an antigen-specific immunopathological process underlies DHF, so appropriate immunosuppressive therapy might be effective. Since progress on the development of vaccines against dengue has been slow, and since vaccination of the huge at-risk population would be difficult, the case for improving strategies for diagnosis and the management of patients with dengue is urgent.
<!--start simple-tail=-->References
1. Monath TP. Dengue: the risk to developed and developing countries. Proc Natl Acad Sci (USA) 1994; 91: 2395-2400. MEDLINE | CrossRef
2. Rico-Hesse R, Harrison LM, Salas RA, et al. Origins of dengue type 2 viruses associated with increased pathogenicity in the Americans. Virology 1997; 230: 244-251. CrossRef
3. Kalayanarooj S, Vaughn DW, Nimmannitya S, et al. Early clinical and laboratory indicators of acute dengue illness. J Infect Dis 1997; 176: 313-321.
4. Teeraratkul A, Limpakarnjanaral K, Nisalak A, Nimmannitya S. Predictive value of clinical and laboratory findings for early diagnosis of dengue and dengue haemorrhagic fever. SE Asian J Trop Pub Hlth 1990; 21: 696-697.
5. World Health Organization. In: Dengue hemorrhagic fever: diagnosis, treatment and control. Geneva: WHO, 1986: 1-58.
6. Halstead SB. Pathogenesis of dengue hemorrhagic fever: challenges to molecular biology. Science 1988; 239: 476-481. MEDLINE
7. Burke DS, Nisalak A, Johnson PE, Scott R McN. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg 1988; 38: 172-180. MEDLINE
8. Kurane I, Innis BL, Nimmannitya S, et al. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-γ in sera of children with dengue. J Clin Invest 1991; 88: 1473-1480. MEDLINE
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DOI:10.1016/S0140-6736(05)63567-2
Early indicators in acute dengue infection
Thomas P Monath a
Dengue is the commonest arthropod-borne viral infection in man, and an estimated 50?100 million cases occur annually in the tropics, with over 10 000 deaths from dengue haemorrhagic fever (DHF). In the Americas DHF is emerging as an increasingly important consequence of dengue infection.1 There DHF first appeared in epidemic form in Cuba in 1981, and the increasing frequency of outbreaks since 1989 reflects an increase in dengue immunity, circulation of multiple serotypes, and (possibly) the introduction of virulent dengue strains from Asia.2
New information from a study by S Kalayanarooj and colleagues3 may help in the clinical differentiation of dengue from other febrile illnesses. The study was based on the hypothesis that the degree of T-cell activation in secondary dengue infection, with its attendant release of cytokines, vasoactive mediators, and procoagulants, will differentiate classic dengue fever from DHF at an early stage of infection
In the study at two hospitals in Thailand children aged 6 months to 14 years were admitted when they presented with fever of less than 72 hours' duration and facial flushing (a sensitive and specific sign associated with dengue4) but without a specific identifiable cause of the illness. Investigations included tests for abnormal haemostasis, capillary leakage, and decreased plasma volume, decubitus chest X-ray (to determine the presence of pleural effusion), and routine liver-function tests. Of the 60 patients with serological or virological evidence of dengue, 28 (47%) were diagnosed as having DHF5 (ie, they had fever, one or more haemorrhagic manifestations, thrombocytopenia, and haemoconcentration). These findings are similar to those reported by Halstead et al,6 who showed that 29% of all febrile illness in Bangkok was due to dengue, and by Burke et al,7 who found that 53% of Thai schoolchildren with dengue met WHO criteria for DHF. The 105 patients in the Kalayanarooj study without a specific bacteriological cause for their illness were categorised as having ?other febrile illness, OFI?.
93% of the patients with acute dengue infection had serological responses indicative of prior exposure to at least one other dengue serotype. Dengue is caused by four distinct viral species (all hyperendemic in Thailand), and immunity to a heterologous serotype is generally accepted as predisposing to DHF. Preexistng cross-reactive, nonneutralising IgG antibodies to a heterologous dengue serotype form immune complexes with virions of the current infection and bind the Fcγ receptor of monocytemacrophages, enhancing dengue viral replication in these cells and promoting the pathogenesis of DHF.6 Over 90% of DHF cases occur in children with preexisting immunity to dengue;7 in the Kalayanarooj study, the figure was 100%.
A comparison of clinical and laboratory features revealed several statistically significant differences between children with dengue fever or DHF and those with OFI. Children with dengue or DHF were older (mean 8?1 years) than those with OFI (6?2 years), had a longer febrile course, were more likely to have gastrointestinal symptoms (anorexia, nausea, vomiting), and to have a positive tourniquet test (>10 petechiae/2?5 cm2 skin area). Platelet, total white cell, absolute neutrophil, and absolute monocyte counts at study entry were lower than in the OFI group, and the plasma alanine and aspartate aminotransferases were significantly higher. However, a high proportion (39%) of children with OFI had a positive tourniquet test, so this test had a high negative (but a low positive) predictive value for differentiating dengue from OFI at the time of initial presentation. A serum aspartate aminotransferase of more than 60 U/mL, a leucocyte count of under 5000/μL, and an absolute neutrophil count of under 3000/μL had high positive and negative predictive values for differentiating dengue or DHF from OFI at initial presentation and may help in making decisions on whether to admit a patient and on frequency of follow-up.
Progression to DHF is the most feared complication of dengue infection, but no early prognostic markers of this disorder have been defined. In the Kalayanarooj study the only significant differences at study entry between those with dengue fever and those with DHF were a lower mean platelet count and higher aspartate aminotransferase concentrations among the latter. The variability of these factors greatly reduces their value in considering an individual patient, but a normal plasma aspartate aminotransferase concentration had a very high negative predictive value for DHF.
Given the lack of clear clinical prognostic indicators for DHF, attention must now turn elsewhere. The US collaborators in the Thai study are part of a team led by Francis A Ennis at the University of Massachusetts who have been trying to unravel the pathogenesis of DHF. They have found higher levels of viraemia and of soluble cellular proteins in DHF than in dengue fever patients8 and plan to measure chemical mediators and cytokines throughout the course of dengue infections. Such studies may lead to the identification of specific therapy, but the process will not be simple, as illustrated by the failure to interrupt the pathophysiological cascade in endotoxic shock. However, an antigen-specific immunopathological process underlies DHF, so appropriate immunosuppressive therapy might be effective. Since progress on the development of vaccines against dengue has been slow, and since vaccination of the huge at-risk population would be difficult, the case for improving strategies for diagnosis and the management of patients with dengue is urgent.
<!--start simple-tail=-->References
1. Monath TP. Dengue: the risk to developed and developing countries. Proc Natl Acad Sci (USA) 1994; 91: 2395-2400. MEDLINE | CrossRef
2. Rico-Hesse R, Harrison LM, Salas RA, et al. Origins of dengue type 2 viruses associated with increased pathogenicity in the Americans. Virology 1997; 230: 244-251. CrossRef
3. Kalayanarooj S, Vaughn DW, Nimmannitya S, et al. Early clinical and laboratory indicators of acute dengue illness. J Infect Dis 1997; 176: 313-321.
4. Teeraratkul A, Limpakarnjanaral K, Nisalak A, Nimmannitya S. Predictive value of clinical and laboratory findings for early diagnosis of dengue and dengue haemorrhagic fever. SE Asian J Trop Pub Hlth 1990; 21: 696-697.
5. World Health Organization. In: Dengue hemorrhagic fever: diagnosis, treatment and control. Geneva: WHO, 1986: 1-58.
6. Halstead SB. Pathogenesis of dengue hemorrhagic fever: challenges to molecular biology. Science 1988; 239: 476-481. MEDLINE
7. Burke DS, Nisalak A, Johnson PE, Scott R McN. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg 1988; 38: 172-180. MEDLINE
8. Kurane I, Innis BL, Nimmannitya S, et al. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-γ in sera of children with dengue. J Clin Invest 1991; 88: 1473-1480. MEDLINE
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