Secondary Dengue Infection Research Articles

Neutralizing antibodies after infection with dengue 1 virus.

Severity of disease is markedly increased when infection with dengue virus type 2 (DENV-2) follows infection with DENV-1 at an interval of 20 years. Studies have shown that heterologous neutralizing antibody titers are inversely correlated with severity of a second infection. If this mechanism controlled disease severity in Cuba, heterotypic antibody titers should have declined over time. To determine whether phenotypic changes in dengue antibodies occur over time, we analyzed serum samples collected 4-8 and 20-22 years after DENV-1 infection. We found a significant increase in mean titer of homologous DENV-1 neutralizing antibodies and a significant decrease in heterologous antibodies to 1 of 2 genotypes of DENV-2 virus (the American genotype). Asian DENV-2 viruses were not neutralized during either interval; however, the American genotype underwent phenotypic changes in heterotypic viral neutralizing antibodies in the predicted direction. This finding may be related to the time-dependent changes in severity of disease found with secondary dengue infection.

Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever‐dengue shock syndrome (DHF/DSS)

The past four decades has witnessed a consolidation of the original observations made in the 1970s that dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) have an immunological basis. Following reinfection with a dengue virus of different serotype, severe disease is linked to high levels of antibody-enhanced viral replication early in illness which is followed by a cascade of memory T-cell activation and a 'storm' of inflammatory cytokines and other chemical mediators. These compounds are released mainly from T cells, monocytes/macrophages and endothelial cells, and ultimately cause an increase in vascular permeability. The consolidation of the evidence has been largely due to several important prospective sero-epidemiological studies in areas endemic for DHF/DSS, which have shown that risk of severe disease is significantly higher in secondary dengue infections. These advances have underscored the fact that DHF/DSS pathogenesis is a complex, multifactorial process involving cocirculation of various dengue virus serotypes and the interplay of host and viral factors that influence disease severity. The continued search to define risk factors in susceptible populations must be combined with the new techniques of molecular virology and innovative approaches in vaccine design to achieve the ultimate objective of developing a safe and effective vaccine.

CD40 Ligand Enhances Dengue Viral Infection of Dendritic Cells: A Possible Mechanism for T Cell-Mediated Immunopathology

We have previously shown that dengue virus (DV) productively infects immature human dendritic cells (DCs) through binding to cell surface DC-specific ICAM-3-grabbing nonintegrin molecules. Infected DCs are apoptotic, refractory to TNF-alpha stimulation, inhibited from undergoing maturation, and unable to stimulate T cells. In this study, we show that maturation of infected DCs could be restored by a strong stimulus, CD40L. Addition of CD40L significantly reduced apoptosis of DCs, promoted IL-12 production, and greatly elevated the IFN-gamma response of T cells, but yet did not restore T cell proliferation in MLR. Increased viral infection of DCs was also observed; however, increased infection did not appear to be mediated by DC-specific ICAM-3-grabbing nonintegrin, but rather was regulated by decreased production of IFN-alpha and decreased apoptotic death of infected DCs. Because CD40L is highly expressed on activated memory (but not naive) T cells, the observation that CD40L signaling results in enhanced DV infection of DC suggests a possible T cell-dependent mechanism for the immune-mediated enhancement of disease severity associated with some secondary dengue infections.

Kinetics of antibodies in sera, saliva, and urine samples from adult patients with primary or secondary dengue 3 virus infections

The kinetics of three serological markers (IgM, IgA, and IgG) in serum, saliva, and urine samples from adult patients with primary or secondary dengue infection were studied. Serum, saliva, and urine samples were collected from 22 patients with clinical and confirmed dengue 3 virus infection during the outbreak in Havana City in 2001. They were tested by capture IgM (MAC-ELISA), IgA (AAC-ELISA), and IgE (EAC-ELISA) and IgG ELISA inhibition method (EIM) to detect specific dengue antibodies. Similar kinetics were observed in IgM, IgA, and IgG antibodies in saliva and IgA and IgG in urine samples from secondary cases compared with kinetics in serum samples, although the values were lower. No IgG antibody was detected in saliva and urine samples in primary cases and IgM antibody was not detected in urine samples from either primary or secondary infection. All secondary cases were positive for IgG in saliva and urine samples at day 7. The kinetics of specific IgE antibodies in primary and secondary cases were different. The kinetics of three serological markers (IgM, IgA, and IgG) in serum, saliva, and urine samples from adult patients with primary or secondary dengue 3 virus infection were studied for the first time, showing its behavior and usefulness in dengue virus diagnosis. The specific IgE could play a role as a serological marker in secondary infections.

Dengue infections during pregnancy: A case series from Sri Lanka and review of the literature

Background Dengue is a major public health problem in several countries. Few reports document presentations and outcomes of dengue during pregnancy. In many endemic countries as the average age of getting dengue infections is shifting upwards, dengue in pregnancy is likely to be encountered more frequently. Patterns of dengue in patients from different regions are needed if we are to draft evidence based management guidelines. Objectives To document clinical and laboratory findings in a cohort of hospitalised patients with dengue during pregnancy in Sri Lanka and compare their presentation and outcomes with previously published cases. Study design Clinical, laboratory, maternal and fetal outcomes and demographic information were collected from patients with confirmed dengue infections during pregnancy treated in a Maternity Hospital in Sri Lanka from 1 January 2000 to 30 June 2004. The Medline database was searched to identify reports relating to dengue infection during pregnancy since 1965. Results Twenty-six patients [mean (S.D.) age: 29 (4.2) years] were studied. One (3.8%), 2 (7.7%) and 20 (77%) presented in the first, second and third trimesters of pregnancy, and 3 (11.5%) in the immediate post-partum period. Seventeen (65.3%) had primary and nine (34.7%) secondary dengue infections. Ten (38.5%) had DF, 6 (23.1%): DHF grade I and 10 (38.5%): DHF grade II. Five (19.2%) and three (11.5%) patients who first presented with cough/breathlessness or vaginal bleeding, were initially managed as having a pulmonary embolism or a primary obstetric cause for their vaginal bleeding. Bradycardia was noted in three of the four patients who had a cardiac arrhythmia. Seven (26.9%) needed admission to an ICU. Raised AST and ALT levels were seen in 81.2% and 43.7% of 16 patients in whom liver function tests results were available. No fetal malformations were seen in any of the babies born. The single patient who developed DHF in the first trimester had an abortion while having acute symptoms of dengue. Conclusions Awareness of clinical and laboratory manifestations of dengue in pregnancy should allow its early recognition and institution of appropriate treatment. Reports on dengue in pregnancy from different regions should allow more evidence-based guidelines to be formulated for optimum evaluation and care of such patients. Our data contributes towards this goal.

Headache Features in Patients with Dengue Virus Infection

The aim of this study was to describe the frequency and features of headache among patients with confirmed dengue virus infection and to compare the headache features in patients with dengue fever and dengue haemorrhagic fever, primary and secondary dengue infection, and patients with and without neurological involvement. Patients with classic dengue fever had a more intense headache than those with the more severe form of the disease, dengue haemorrhagic fever.

The Comparative Accuracy of 8 Commercial Rapid Immunochromatographic Assays for the Diagnosis of Acute Dengue Virus Infection

The serological diagnosis of acute dengue virus infection relies on the detection of dengue-specific immunoglobulin M (IgM) antibodies. Immunochromatographic tests are rapid diagnostic tests (RDTs) that can be performed at the bedside, but they have not been fully validated for diagnosis of dengue infection. More than 20 RDTs for diagnosis of acute dengue infection are commercially available. Of these, 8 were selected for evaluation of performance by use of characterized dengue and nondengue serum specimens, and results were compared with those of a previously published dengue IgM/IgG enzyme-linked immunosorbent assay in conjunction with dengue virus serotyping by reverse-transcriptase polymerase chain reaction. Assay sensitivities were low, ranging from 6.4% (95% confidence interval [CI], 4.0%-9.7%) to 65.3% (95% CI, 59.9%-70.5%), and specificities ranged from 69.1% (95% CI, 61.4%-76.0%) to 100% (95% CI, 97.8%-100%). Of the 8 tests, only 2 had sensitivities of >50%, the level considered to be clinically useful, and, of these, 1 had relatively low specificity (69.1%). Samples collected early in the infection were less likely to test positive than those collected later. A thermal stability study demonstrated a loss in performance of some RDTs when they were stored at a high ambient temperature for 3 months. Users of RDTs for dengue should be aware that many of these tests have a diagnostic accuracy that falls well below the manufacturers' claims. If an acute specimen yields a negative result, a convalescent serum sample should be tested to confirm the result. No RDT adequately differentiated primary and secondary dengue infections, and the tests should not be used for this purpose.

Four dengue virus serotypes found circulating during an outbreak of dengue fever and dengue haemorrhagic fever in Jakarta, Indonesia, during 2004

Periodic outbreaks of dengue have emerged in Indonesia since 1968, with the severity of resulting disease increasing in subsequent years. In early 2004, a purported dengue outbreak erupted across the archipelago, with over 50,000 cases and 603 deaths reported. To confirm the disease aetiology and to provide an epidemiological framework of this epidemic, an investigation was conducted in ten hospitals within the capital city of Jakarta. Clinical and laboratory findings were determined from a cohort of 272 hospitalised patients. Exposure to dengue virus was determined in 180 (66.2%) patients. When clinically assessed, 100 (55.6%) of the 180 patients were classified as having dengue fever (DF), 31 (17.2%) as DF with haemorrhagic manifestations and 49 (27.2%) as dengue haemorrhagic fever (DHF). Evidence from haemagglutination inhibition assays suggested that 33/40 (82.5%) of those with DHF from which laboratory evidence was available suffered from a secondary dengue infection. All four dengue viruses were identified upon viral isolation, with DEN-3 being the most predominant serotype recovered, followed by DEN-4, DEN-2 and DEN-1. In summary, the 2004 outbreak of dengue in Jakarta, Indonesia, was characterised by the circulation of multiple virus serotypes and resulted in a relatively high percentage of a representative population of hospitalised patients developing DHF.

Patterns of disease among adults hospitalized with dengue infections

Recent years have seen an increase in dengue infections among adults in Sri Lanka, with similar trends seen in many other countries. Data on the natural history and outcome of dengue in adults are quite limited. To study clinical and laboratory findings in adult dengue patients hospitalized in Sri Lanka during a recent major dengue epidemic. Prospective observational study. Clinical, laboratory and demographic information were collected from adult patients with confirmed dengue infections (n = 108) treated in a general medical ward in Sri Lanka from 24 April to 31 July 2004. There were 68 male and 40 female patients, mean age 26.6 years. Dengue fever (DF) was seen in 33 (30.6%) and dengue haemorrhagic fever (DHF) in 75 (69.4%). Of the 37 (34.3%) with primary dengue infections, 19 (51.4%) developed DF and 18 (48.6%) developed DHF. Overall, 42 patients (38.9%) had bleeding manifestations. These adults showed differences in clinical and laboratory findings, disease severity and mortality, compared to children seen during the same epidemic. Secondary dengue infections were significantly associated with development of severe disease (OR 5.0, 95%CI 1.9-13.5, p < 0.001). Mortality was 3.7%. Pooling data on adult dengue patients from different regions should help us to understand the natural history of disease in this group. It would also help in developing evidence-based treatment guidelines and allocating limited and scarce health resources. Our data contribute towards this goal.

Dengue Virus-Reactive CD8+ T Cells Display Quantitative and Qualitative Differences in Their Response to Variant Epitopes of Heterologous Viral Serotypes

Reactivation of serotype cross-reactive CD8+ memory T lymphocytes is thought to contribute to the immunopathogenesis of dengue disease during secondary infection by a heterologous serotype. Using cytokine flow cytometry, we have defined four novel HLA-A*02-restricted dengue viral epitopes recognized by up to 1.5% of circulating CD8+ T cells in four donors after primary vaccination. All four donors had the highest cytokine response to the epitope NS4b 2353. We also studied the effect of sequence differences in heterologous dengue serotypes on dengue-reactive CD8+ memory T cell cytokine and proliferative responses. The D3 variant of a different NS4b epitope 2423 and the D2 variant of the NS4a epitope 2148 induced the largest cytokine response, compared with their respective heterologous sequences in all donors regardless of the primary vaccination serotype. Stimulation with variant peptides also altered the relative frequencies of the various subsets of cells that expressed IFN-gamma, TNF-alpha, MIP-1beta, and combinations of these cytokines. These results indicate that the prior infection history of the individual as well as the serotypes of the primary and heterologous secondary viruses influence the nature of the secondary response. These differences in the effector functions of serotype cross-reactive memory T cells induced by heterologous variant epitopes, which are both quantitative and qualitative, may contribute to the clinical outcome of secondary dengue infection.

Cocirculation of Dengue Serotypes, Delhi, India, 2003

To the Editor: Delhi, in the northern part of India, has had outbreaks of dengue caused by various dengue virus types in 1967, 1970, 1982, 1988, and 1996 (1–5). In 1988, for the first time, a few cases of dengue hemorrhagic fever (DHF) were seen (4). Subsequently, we reported the largest outbreak of DHF/dengue shock syndrome (DSS) in Delhi in 1996 and confirmed dengue virus type 2 as the etiologic agent (5). We report the results of virologic testing of samples received at the All India Institute of Medical Sciences from patients with suspected dengue fever or denguelike illness from Delhi and its adjoining areas during a 2003 outbreak of dengue. According to the World Health Organization (6), 2,185 laboratory-confirmed cases were reported during this outbreak. Of the blood samples received by the virology laboratory, 42 were received on ice from patients with acute denguelike illness. Serum was separated aseptically and stored at –70°C. The standard method of virus cultivation, which used the C6/36 clone of the Aedes albopictus cell line, was followed with some modifications (7). On days 5 and 10, harvested cells were tested by an indirect immunofluorescence assay (IFA) using monoclonal antibodies to dengue virus types 1–4 (provided by the Centers for Disease Control and Prevention, Atlanta, Georgia, USA, during the 1996 outbreak). If IFA results were negative for dengue viruses on first passage, a second passage was made, and cells were again harvested on days 5 and 10 for IFA. The 4 dengue virus types (obtained from the National Institute of Virology, Pune, India) were included as positive controls, and uninfected C6/36 cells were kept as negative controls. Dengue virus could be isolated in C6/36 cells from 8 (19%) of 42 samples processed for virus isolation (Table). Of the 8 isolates, two each were identified as dengue virus types 1 and 2, three as type 3, and one as type 4. All but one isolate were from patients with uncomplicated dengue fever. One dengue type 2 isolate was obtained from a 7-year-old boy with secondary dengue infection and DHF/DSS. The ages of culture-positive patients ranged from 5 to 62 years, with a median of 22 years. These patients were equally distributed between children (<12 years) and adults. The male-to-female ratio for these 8 patients was 5:3. The duration of fever at the time of viral isolation was 1–5 days, with a median of 3 days. Table Culture-positive dengue patients* All previous outbreaks in Delhi have occurred during the monsoon (rainy) season between August and November and subsided with the onset of winter. We recently reported the results of serologic testing during the 2003 outbreak, which also occurred from September to November, with a peak in mid-October 2003 (8). This outbreak was milder than the 1996 outbreak, with less illness and death; most patients had uncomplicated dengue fever, and only a few had DHF/DSS. Of the 874 serum samples that we tested, 456 (52.3%) were positive for dengue-specific immunoglobulin M antibodies by enzyme-linked immunosorbent assay (Panbio, Sinnamon Park, Queensland, Australia), and more than one third of these were from patients in the 21- to 30-year age group (8). Dengue virus types 1, 2, and 3 have all been isolated during previous dengue outbreaks in Delhi, but a particular type has always predominated. During the 1996 outbreak of DHF/DSS, we had 26 isolates of dengue virus type 2, but only 1 isolate was identified as dengue type 1 (5). However, we subsequently showed that dengue virus type 1 continued to circulate during the postepidemic period and became the predominant strain (9). Dengue virus type 3 has recently reemerged in South Asia, including north India (10). We now report this culture-confirmed outbreak of dengue from Delhi, during which the simultaneous transmission of all 4 dengue virus types has been demonstrated for the first time in India, with no particular type predominating. This finding suggests that dengue is now truly endemic in this region.

Patterns of disease in Sri Lankan dengue patients

Background: Dengue is the most important mosquito borne viral infection in the world. Nearly 90% of infections occur in children. At present, prospective information on clinical and laboratory findings in...

Specific IgM and IgG responses in primary and secondary dengue virus infections determined by enzyme-linked immunosorbent assay

IgM- and IgG-capture ELISAs are widely used as diagnostic tests for confirmation of dengue virus infection. The positive rate of anti-dengue IgM and IgG detection was examined in primary and secondary dengue virus infections in the setting of a provincial hospital using IgM- and IgG-capture ELISAs. Disease day 1 was defined as the day of onset of symptoms. In total, 232 plasma samples were collected from 106 confirmed dengue cases consisting of 12 primary and 94 secondary infections. In primary infection, anti-dengue IgM was detected in 4 out of 5 samples collected on disease day 5 and in all the 21 samples collected on disease day 6 or later. Specific IgG was detected in 2 out of 5 samples collected on day 12, and in 5 out of 6 samples collected on disease days 13-15, but was not detected in samples collected on disease day 10 or earlier. In secondary infection, IgM was not detected in the samples on disease days 2 and 3, but detected in 20 out of 79 samples collected on days 4-6, in 44 out of 65 on disease days 7-11 and in 40 out of 51 samples on disease days 12-14. In contrast, specific IgG was detected in 21 out of 60 samples on disease days 4 and 5, in 13 out of 19 on disease day 6, in 62 out of 65 on disease days 7-11 and in all the samples collected on disease day 12 or later. The result indicate that seroconversion rates of IgM and IgG are different between primary and secondary infections, and suggest that detection of specific IgM and IgG is necessary for determining dengue virus infection and for differentiating primary and secondary dengue infections.

Concurrent Dengue and Malaria

To the Editor: A 37-year-old woman, a logistics director for a nongovernment organization, returned to France in March 2004 from an 18-day trip to Guinea, Senegal, and Sierra Leone. Fever, chills, and myalgia developed in the woman 3 days before she returned to France, and she treated herself with aspirin and paracetamol (acetaminophen). Malaria prophylaxis was taken neither during nor after the trip. The day after returning to France, the woman's condition progressively worsened; diarrhea and extreme weakness that led to the inability to walk developed. Ten days after her return, she was admitted to the local hospital and treated with intravenous quinine and oral doxycycline (2 g per day) after thick and thin blood films showed 3% parasitemia with Plasmodium falciparum. Three days later, she was still febrile and had conjunctival jaundice, vomiting, insomnia, and moderate hemorrhagic manifestations (epistaxis, blood in urine and feces). Three days after initial hospitalization, the patient was transferred to the Infectious Diseases Unit in Marseille; fever (39.5°C) continued, and hepatosplenomegaly developed. Biologic analyses showed disseminated intravascular coagulation with platelet count of 22,000/mL, an elevated prothrombin time (54% higher than the control value), a longer activated clotting time (51 seconds versus a control value of 34 seconds), a fibrinogen level of 0.9 g/dL, exaggerated plasma fibrin formation and degradation, and hepatic cytolysis with both aspartate aminotransferase and alanine aminotransferase levels of 80 U/L. Although acute malaria had been diagnosed, viral serologic tests were performed because the patient had returned from a tropical country with a fever. Persons in these circumstances are systematically administered a series of tests to determine the cause of their fever. Serologic tests for dengue performed on the acute-phase serum (collected 13 days after onset of symptoms) and convalescent-phase serum (collected 23 days after onset of symptoms) showed the presence of immunoglobulin (Ig) M (titers 1:800 and 1:3,200, respectively) and IgG (titers 1:400 and 1:3,200, respectively), which suggested that the patient had dengue fever and malaria concurrently. These results were obtained by using the Dengue Duo IgM-capture and IgG-indirect enzyme-linked immunosorbent assay (Biotrin, PanBio Pty. Ltd., Brisbane, Australia). The same acute-phase serum was tested for flavivirus RNA by seminested reverse transcription–polymerase chain reaction (RT-PCR) by using flavivirus consensus primers PF1S and PF2R as previously described (1) in conjunction with the sense primer PF3S (GCIATHTGGTAYATGTGGYT). Attempts to isolate viruses by using C6/36 and Vero cells were unsuccessful, which might be expected given the delay between the onset of symptoms and specimen collection. Sequence analysis of the 163-bp (primers excluded) PCR product (GenBank accession no. {type:entrez-nucleotide,attrs:{text:AY862501,term_id:61744126,term_text:AY862501}}AY862501) showed 89%–99.4% range of homology with 34 dengue 3 virus strains by using the BLAST nucleotide program. Similarities obtained with sequences of dengue virus 1, 2, and 4 were ≤87%. Phylogenetic analysis performed with the patient sequence together with homologous sequences from dengue viruses and other flaviviruses showed that it corresponded to dengue 3 virus species. RT-PCR amplification on the convalescent-phase serum was negative. Based on World Health Organization criteria, the patient was diagnosed with dengue fever (2). The patient's interview showed a previous dengue fever episode in Haiti in 1995 and a previous malaria episode in Burundi in 2002, but biologic confirmation was not available, and serum was not collected before this episode. Therefore, we could not determine definitively whether this patient experienced primary or secondary dengue. In light of virologic tests results, the diagnosis of secondary dengue infection was more likely (3). A PubMed search using the keywords dengue, mixed infections, dual infections, simultaneous infections, and concurrent infections retrieved 14 references published since 1958. In most cases, concurrent infection was with 2 dengue virus strains from 2 different serotypes in a single patient (4,5). Only 6 published studies reported concurrent infection with dengue virus and a bacterium (Salmonella typhi, Shigella sonnei, Leptospira spp.) (6–8) or with a virus such as Chikungunya virus (9). To our knowledge, this is the first report of mixed dengue–parasite infection, dengue virus with P. falciparum. The authors previously questioned the accuracy of a serologic test to diagnosis dengue fever in patients experiencing malaria because reactivity was nonspecific on certain rapid serologic assays (10); however, serologic tests used in this study have demonstrated good specificity (10), and molecular tests are not prone to such specificity problems. Classifying this case as dengue hemorrhagic fever is questionable since some of the hemorrhagic signs may have been caused by acute malaria. In cases of concurrent infections involving a dengue virus, questions related to the influence of mixed infection on severity and prognosis are, therefore, impossible to address because of lack of information. Further investigations are required because this situation likely occurs frequently in nature, despite scant available data.

A custom-designed recombinant multiepitope protein as a dengue diagnostic reagent

Currently, dengue fever is the most important re-emerging mosquito-borne viral disease, with the major proportion of the target population residing in the developing countries of the world. In endemic areas, potentially fatal secondary dengue infections, characterized by high anti-dengue IgG antibody titers, are most common. Most currently available commercial dengue diagnostic kits rely on the use of whole virus antigens and are consequently associated with false positives due to serologic cross-reactivity, high cost of antigen production, and biohazard risk. This has prompted the need to develop an alternate antigen to replace the whole virus antigen in diagnostic tests. We have designed and expressed a novel recombinant protein antigen by assembling key immunodominant linear IgG-specific dengue virus epitopes, chosen on the basis of pepscan analysis, phage display, and computer predictions. The recombinant dengue multiepitope protein was expressed to high levels in Escherichia coli, purified in a single step, yielding >25 mg pure protein per liter culture. We developed an in-house enzyme-linked immunosorbent assay (ELISA) to detect anti-dengue antibodies in a panel of 20 patient sera using the purified recombinant dengue multiepitope protein as the capture antigen. The ELISA results were in excellent agreement with those obtained using a commercially available diagnostic test, Dengue Duo rapid strip test from PanBio, Australia. The high epitope density, careful choice of epitopes, and the use of E. coli system for expression, coupled to simple purification, jointly have the potential to lead to the development of an inexpensive diagnostic test with a high degree of sensitivity and specificity.

Risk factors and clinical features associated with severe dengue infection in adults and children during the 2001 epidemic in Chonburi, Thailand.

Dengue haemorrhagic fever (DHF) is an important cause of morbidity in South-east Asia and used to occur almost exclusively in young children. In recent years, there has been a progressive shift in age-distribution towards older children and adults. We investigated an outbreak in 2001 in both children and adults, in an endemic area of Thailand. Retrospective study of 347 patients with serologically confirmed dengue infection admitted to Chonburi Hospital during an epidemic in 2001. A total of 128 (37%) patients had dengue fever (DF) and 219 (63%) had DHF. Patients with DHF were significantly older than patients with DF (11 years vs. 8 years). Clinical bleeding was noted in 124 individuals, both with DF (n = 24) and DHF (n = 100), and significantly more frequently in adults. Twenty-nine (13.2%) of all DHF cases were caused by primary infection. Secondary dengue infection was associated significantly with the development of DHF in children, OR (95% CI) = 3.63 (1.94-6.82), P < 0.0001, but not in adults, OR (95% CI) = 0.6 (0.02-6.04), P = 1. Unusual clinical manifestations were observed in 23 patients: three presented with encephalopathy and 20 with highly elevated liver-enzymes. In the latter group, four patients were icteric and nine had gastrointestinal bleeding. These results indicate that DHF in South-east Asia is common in both children and adults. In dengue-endemic countries, dengue should be considered as a differential diagnosis in patients with clinical gastrointestinal bleeding in association with increased liver enzymes.

Correlation between increased platelet-associated IgG and thrombocytopenia in secondary dengue virus infections.

Although the public health impact of dengue is increasing rapidly, the mechanism of thrombocytopenia in this disease remains unknown. To elucidate this mechanism, the relationship between platelet-associated IgG (PAIgG) and platelet count in 53 patients in the acute phase of secondary dengue virus infection was investigated in a prospective-hospital-based study. A significant inverse correlation between the two parameters was found in these patients, while no correlation was observed in healthy volunteers. The low baseline platelet counts during the acute phase in 12 patients with secondary dengue virus infection significantly increased during the convalescent phase, while the increased PAIgG levels during the acute phase in these patients significantly decreased during the convalescent phase. Anti-platelet IgG autoantibody was detected rarely in the plasma of 53 patients with secondary dengue infection. The involvement of anti-dengue virus IgG was also shown in platelets from all of 8 patients in the acute phase of secondary dengue virus infection. These findings suggest that PAIgG formation involving anti-dengue virus IgG plays a pivotal role in the induction of transient thrombocytopenia during the acute phase of secondary dengue virus infection.

Dengue hemorrhagic fever in infants: research opportunities ignored.

The age distribution of cases of dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) in infants under the age of 1 year are reported from Bangkok, Thailand, and for the first time for Ho Chi Minh City, Vietnam; Yangon, Myanmar; and Surabaya, Indonesia. The four dengue viruses were isolated from Thai infants, all of whom were having a primary dengue infection. Progress studying the immunologically distinct infant DHF/DSS has been limited; most contemporary research has centered on DHF/DSS accompanying secondary dengue infections. In designing research results obtained in studies on a congruent animal model, feline infectious peritonitis virus (FIPV) infections of kittens born to FIPV-immune queens should be considered. Research challenges presented by infant DHF/DSS are discussed.

Clinical and laboratory differences between childrenwith primary and secondary dengue infection

Clinical and laboratory differences between childrenwith primary and secondary dengue infection

Effect of age on outcome of secondary dengue 2 infections

Objective: Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is a growing global health problem. It is not known how age affects the outcome of secondary dengue infections. In an island setting, a large DHF/DSS outbreak in Cuba occurred in 1981. Involved were individuals, 3–40 year old, whose only lifetime dengue exposure was to DEN-1 in 1977 and DEN-2 in 1981. In this report we calculate age-specific DHF/DSS hospitalization and death rates based on secondary DEN 2 infections. Methods: Published and unpublished hospital and seroepidemiologic data from the 1981 DHF/DSS outbreak were used for the analysis. Results: Children, aged 3 and 4 years, with secondary DEN-2 infections were found to have a high death rate (25.4/10 000 secondary DEN-2 infections). The death rate fell with increasing age, being 15.9-fold lower in the 10–14-year age group. The death rate for children aged 3–14 years was 14.5-fold higher than in young adults aged 15–39 years. The death rate rose somewhat in adults aged 50 years and older. DHF/DSS hospitalization rates showed the same trend as death rates. Conclusions: Age is an important variable in the outcome of secondary DEN-2 infections. DHF/DSS case fatality and hospitalization rates are highest in young infants and the elderly. The risk that a child will die during a secondary DEN-2 infection is nearly 15-fold higher than the risk in adults.