Is dengue a threat to the blood supply?

summary .  Dengue is the most common arthropod-borne infection worldwide, affecting at least 50 million people every year and endemic in more than 100 countries. The dengue virus is a single-stranded RNA virus with four major serotypes. Infection with one serotype confers homotypic immunity but not heterologous immunity, and secondary infection with another serotype may lead to more severe disease. The major route of transmission occurs through the Aedes aegypti mosquito vector, but dengue has also been transmitted through blood transfusion and organ transplantation. Infection results in a spectrum of clinical illness ranging from asymptomatic infection, undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF) to dengue shock syndrome (DSS). Dengue is spreading rapidly to new areas and with increasing frequency of major outbreaks. A trend has also been observed towards increasing age among infected patients. This will impact blood supply availability as more blood donors are deferred because of dengue infection or exposure to infection. The risk of transmission through transfusion of blood from asymptomatic viraemic donors will also increase. Although screening tests for dengue and effective pathogen reduction processes are now available for the blood supply, the value of implementing these costly measures needs to be carefully considered. Demand for platelets and fresh frozen plasma will rise with increasing number of DHF/DSS. Evidence-based guidelines for the clinical use of these blood components in the management of patients with DHF/DSS have not been well established, and inappropriate use will contribute to the challenges faced by blood services.     

登革热147例临床特点分析

目的：探讨新时期登革热发病的临床特点，提高临床医师对登革热的全面认识。方法：将2002．8—2002．9收治住院的147例登革热进行临床特点分析。结果：登革热发病有家庭聚集性；临床表现为发热、头痛、畏寒、皮疹较常见；伴随有多脏器损害，其中以肝功能异常、白细胞及血小板减少、肾功能损害多见；所有病例登革热病毒IgM阳性。结论：登革热各年龄组均可发病；临床表现无特异性；多脏器损害以肝功能异常最多见；确诊依据登革热IgM抗体检查。     

Patterns of disease among adults hospitalized with dengue infections

BACKGROUND: 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. AIM: To study clinical and laboratory findings in adult dengue patients hospitalized in Sri Lanka during a recent major dengue epidemic. DESIGN: Prospective observational study. METHODS: 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. RESULTS: 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%. DISCUSSION: 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 fever leading to acute dengue hemorrhagic leukoencephalitis: A case report

Rationale: Dengue fever is a prevalent tropical infectious disease that has a broad panorama of presentations from mild febrile illness to life-threatening manifestations in the form of dengue hemorrhagic fever and dengue shock syndrome. Patient's concerns: A 20-year-old male presented with a 2-day history of fever, multiple episodes of vomiting, and altered sensorium. Diagnosis: Dengue fever leading to acute hemorrhagic leukoencephalitis. Interventions: Multiple transfusions of single donor platelets, intravenous methylprednisolone, intravenous immunoglobulin, anti-seizure prophylaxis, and broad-spectrum antibiotics. Outcomes: Repeat brain magnetic resonance imaging showed resolution of lesions. The patient was subsequently discharged from the hospital in a healthy state. Lessons: This report helps us to gain a better understanding of the patient's presentation, which will help to improve the timely recognition and prevention of this rare devastating presentation.     

Update: The diagnosis and management of dengue virus infection in North America

Dengue is a mosquito-transmitted infection that poses significant global health risks for travelers and individuals living in the tropics and subtropics. The reported global incidence has increased dramatically in the past century, with dengue now ranking as the most common cause of febrile illness in travelers. While sporadic cases have been reported within the southern United States since 1980, autochthonous outbreaks have now been described in Hawaii, St. Croix (US Virgin Islands), along the Texas-Mexico border, and, most recently, in Key West, Florida. Although many infections are mild or asymptomatic, 5-10% of patients may experience hemorrhagic disease, with shock and even death. Laboratory identification commonly involves serologic and nucleic acid amplification methods. Due to rising incidence worldwide, physicians should be familiar with the clinical manifestations, laboratory diagnosis, and management of this illness.     

Dengue fever in the Western Hemisphere.

Dengue virus, an arthropod-borne viral agent, causes two distinct diseases: classic dengue fever (DF) and dengue hemorrhagic fever (DHF). There are four dengue virus serotypes: DEN-1, DEN-2, DEN-3, and DEN-4. Although infection with dengue stimulates immunologic response to a serotype, there is no cross-immunity conferred. Hence, a person can potentially be infected with each serotype during his or her lifetime. An infected female Aedes mosquito transmits the virus from person to person while feeding. The disease, now endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, Southeast Asia, and Western Pacific, is spreading to new areas and causing explosive outbreaks. Because of the major impact on lives and local economies epidemics produce, rapid detection of dengue infection has become an important public health research issue. Recently developed serological procedures to detect dengue infections have shown great potential for field use.     

Transcranial Doppler Sonography is Useful for the Decision-Making at the Point of Care in Patients with Acute Hepatic Failure: A Single Centre’s Experience

Acute hepatic failure (ALF) is an uncommon disease characterized by a rapid deterioration of the hepatic function with severe derangements of the mental status in previously healthy subjects due to massive hepatocytes necrosis. Neurological impairment, due to intracranial hypertension and cerebral ischemia, is a key factor because it is a main criterion to decide when to proceed to liver transplantation, which is only treatment for these patients. Therefore, neurological monitoring holds an essential role in the clinical management of ALF patients but it needs to be performed at the point-of-care in the majority of the cases as such critically ill patients cannot be moved away from the ICU because they frequently need continuous hemodynamic, ventilatory and renal support. We herein report and discuss our experience relating to the use of transcranial sonography as a neuro-monitoring tool in ALF patients. In our series this technique allowed a repeatable and reliable non-invasive assessment of cerebral blood flow changes at the bedside thus avoiding the complications associated with the use of an intracranial probe to measure intra-cranial pressure and making it possible to correctly evaluate the timing and feasibility of liver transplantation. Bindi ML, Biancofiore G, Esposito M, Meacci L, Bisà M, Mozzo R, Urbani L, Catalano G, Montin U, Filipponi F. Transcranial Doppler sonography is useful for the decision-making at the point of care in patients with acute hepatic failure: a single centre’s experience.     

A comparative,prospective study of serological,virus isolation and PCR amplification techniques for the laboratory diagnosis of dengue infection

Serum specimens from 58 hospitalized patients with clinical suspicion of dengue fever were obtained in a prospective study. All 58 acute serum samples were tested by IgM capture enzyme-linked immunosorbent assay (ELISA) and commercial Dengue Blot serological assays, virus isolation in C6/36 mosquito cells, and polymerase chain reaction (PCR) by single-step and semi-nested approaches using NS3 gene primers. Of the 22 acute sera positive by any one of the five methods, 17 (77.3%) were positive by IgM capture ELISA, 12 (54.5%) by Dengue Blot, none (0%) by virus isolation, two (9.1%) by single-step PCR and three (13.6%) by the more sensitive semi-nested PCR approach. Dengue virus type 2 was detected by both PCR assays. Convalescent sera were also collected from 13 of the 58 patients and haemagglutination inhibition (HI) tests performed on paired serum samples. HI confirmed five positive sera, while the other eight sera were negative or inconclusive. In our study cohort, although PCR was more sensitive than virus isolation for detecting the presence of dengue virus in sera, serological techniques were able to identify more dengue infections than both PCR and virus isolation. These results may be attributed to the collection of serum samples after the period of viraemia which is appropriate for serological assays, in contrast to early or highly viraemic sera which are more suitable for PCR and virus isolation methods.     

A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection

BACKGROUND: Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown.
CASE REPORT: Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed.
RESULTS: The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up.
CONCLUSIONS: Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue.     

New dengue antibody assay with unique differential detection of IgG and IgM antibodies

Objectives

Most of the serological methods, traditional and recent, that have been developed to assess laboratory confirmation of dengue infection, suffer from the need to use separate tests for IgM and for IgG and the need for paired serum specimens in order to establish a clinical interpretation. Moreover, most of the IgG tests ignore early convalescence as well as past exposure. The objectives of this study is to demonstrate the advantages of the ImmunoComb Dengue BiSpot, a new dengue antibody assay, that detects simultaneously both dengue-specific IgM and IgG, in determining type and status of infection in a single test.

Designs and methods

Single and paired positive and negative specimens obtained from various dengue-high prevalent regions and from dengue-free areas were used. The specimens were comprised of admission samples of suspected patients and secondary dengue infection individuals, a group of hospital patients, asymptomatic to dengue who originated from dengue high prevalence areas and dengue-negative volunteers. All samples were tested by the ImmunoComb Dengue BiSpot kit along with the gold standard assays of Hemagglutination-inhibition (HAI) and MAC ELISA.

Results

Testing 365 gold standard positive specimens from different regions, the ImmunoComb Dengue BiSpot kit revealed sensitivity for IgM of 97.5% and 99.1% for IgG. The IgG was segregated into 2 groups: 86.6% for high titer and 12.5% for low titer of IgG. The overall sensitivity was 98.9%. The overall specificity of the kit, testing 657 samples, mostly from dengue-free area was 97.9%. The higher diagnostic resolution of the Dengue BiSpot test was demonstrated when the performance of the kit on the various groups was compared to the gold standard tests and the dengue status was determined in paired specimens by the new assay.

Conclusions

The results of the present studies demonstrate the advantages of ImmunoComb Dengue BiSpot assay as an alternate strategy for the determination of dengue infection status. The combined use of IgM and IgG to discriminate between primary and secondary infections, on one hand, and providing high resolution in distinction of convalescence stage and past infection, on the other hand, endow the kit with improved capacity in assessing the clinical status of a tested individual in a single test.     

Pulmonary hemorrhage syndrome associated with an autochthonous case of dengue hemorrhagic fever

Dengue fever is a major public health problem worldwide. Dengue hemorrhagic fever, a much rarer form of the disease, occurs when a person previously infected with dengue is re-infected with a different viral serotype. In recent years the infection rates of dengue and both clinical syndromes have increased along the United States-Mexico border. We present the case of a 61-year-old Laotian female who presented with a 1-week history of fever, altered mental status, oral ulceration, and rash. The patient developed diffuse pulmonary hemorrhage and anemia requiring multiple transfusions. She eventually sustained multi-organ system failure and expired. Both the titer data and serologies were consistent with the diagnosis of dengue hemorrhagic fever. We hypothesize that this syndrome was the result of re-infection occurring within the United States. This case is also unusual in that it is the second reported in the literature of pulmonary hemorrhages associated with dengue hemorrhagic fever.     

Febrile Illness in a Young Traveler: Dengue Fever and its Complications

Background

Dengue fever, a tropical disease once confined mostly to endemic areas in developing countries, is becoming more prevalent. Globalization has led to an increased incidence of the virus both in foreign travelers returning home and local outbreaks in traditionally nonendemic areas, such as the southern United States and southern Europe. Advances in diagnostic tests, therapies, and vaccines for dengue virus have been limited, but research is ongoing.

Objectives

To review the current literature regarding the diagnosis and management of dengue fever.

Case Report

This case report describes a young woman returning from Central America with many of the common signs and symptoms who was misdiagnosed both abroad and at home. We explore the epidemiology, disease course, complications, and treatment of dengue fever.

Conclusion

Emergency physicians should consider dengue fever in patients with acute febrile illnesses, especially among those with recent travel.     

Dengue hemorrhagic fever and cardiac involvement

Dengue viral infection (DVI) is one of the world’s most significant viral infections spreading. Most of the patients have been asymptomatic, with relatively benign clinical manifestations and outcomes. However, a small number of patients have progressed to severe dengue diseases, including hemorrhage, multi-organ impairment, and increased vascular leakage causing hypovolemic shock, which can cause cardiovascular collapse and death. Numerous lines of evidence have demonstrated that DVI could also cause cardiac dysfunction, arrhythmias, and severe myocarditis. The treatment for dengue hemorrhagic fever (DHF) patients remains symptomatic and supportive, with close monitoring of hemodynamic status. The contributory role of cardiac dysfunction in DHF patients has potentially critical implications on the management. This review will address the current knowledge of cardiac involvement in DHF patients and the management strategy to reduce the fatality outcome.     

Brain edema in acute liver failure

Acute liver failure (ALF) is a syndrome of rapidly deteriorating liver function that manifests as coagulopathy and encephalopathy in a previously healthy individual. This article analyzes the repercussions of ALF on the brain through a discussion of special features of this syndrome, important for the interpretation of neurologic findings. Of particular interest within the context of ALF are hepatic encephalopathy and the pathogenesis of brain edema in acute liver failure as well as its clinical and therapeutic aspects.     

儿童急性肝衰竭的诊疗进展

急性肝衰竭（acute liver failure,ALF）是一种严重的累及多个系统的临床综合征,在短时间内出现严重的肝功能损伤,并有脑水肿、肝性脑病、多器官衰竭等并发症的出现,病死率极高。ALF在儿童中的确切发生率还不清楚,在需要肝移植的儿童患者中,ALF的患者占10％～15％。对儿童ALF的诊断和治疗,缺乏大规模、多中心的临床研究。目前儿童ALF的诊疗方案,主要来源于成人ALF的经验。但是,儿童ALF的病因、临床特点、发病机制等都有别于成人ALF,因此有必要对儿童ALF进行专门的探讨。本文就儿童ALF的诊疗进展作一综述。     

Evaluation of dengue NS1 antigen detection tests with acute sera from patients infected with dengue virus in Venezuela

The performances of 2 commercial enzyme-linked immunosorbent assay (ELISA) kits (PLATELIA™ Dengue NS1 AG and Dengue Early ELISA) and a rapid immunochromatography test (Dengue NS1 AG Strip) for detection of dengue NS1 protein were compared using a panel of 87 sera from viremic dengue patients, as well as 36 sera from patients with other acute febrile illnesses. PLATELIA™ was more sensitive and slightly less specific than Dengue Early ELISA (sensitivity, 71.3% versus 60.9%; specificity, 86.1% versus 94.3%, respectively). The strip test showed an overall sensitivity of 67.8% with a specificity of 94.4%. A lower sensitivity was observed with Dengue Early ELISA for dengue virus (DENV) type 4 (30%) and by the 3 tests for DENV type 2 (56.5%). The use of these kits allows for rapid and specific early diagnosis of dengue infection; however, their sensitivity for each serotype must be further evaluated to guarantee an accurate diagnosis, particularly in those regions where the 4 dengue serotypes are cocirculating.     

Analysis of saturation binding and saturation infection for dengue serotypes 1 and 2 in liver cells

OBJECTIVE: The liver has been increasingly recognized as a significant target organ in the pathogenesis of dengue virus infection. However, only two contradictory studies have examined the binding of the dengue virus to liver cells. This study therefore sought to investigate the binding of the dengue virus to HepG2 cells. METHODS: Radiolabeled dengue virus serotypes 1 and 2 were prepared through viral propagation in Vero cells. Increasing amounts of virus were then incubated with HepG2 cells to determine the ability of the virus to achieve saturation of binding on HepG2 cells. RESULTS: Results indicated that it was not possible to reach saturation of binding under experimentally achievable conditions. We then sought to determine whether it was possible to reach a state of saturation of infection, by using increasingly high titers of virus on a constant number of cells. Dengue serotype 1 showed no evidence of saturation of infection, even at titers of 5,000 viruses per cell. In contrast, dengue serotype 2 became saturated at levels of approximately 3,000 viruses per cell. CONCLUSIONS: These results are consistent with proposals that dengue virus binding to cells is mediated initially through a low-affinity interaction with an abundant molecule on the surface of the cell and secondly through interaction with a less commonly expressed molecule, which is required for viral internalization.     

Analysis of cross-reactivity among flaviviruses using sera of patients with dengue showed the importance of neutralization tests with paired serum samples for the correct interpretations of serological test results for dengue

Dengue is a febrile illness caused by the dengue virus (DENV) that belongs to the genus Flavivirus in the family Flaviviridae. Cross-reactivity between flaviviruses poses a challenge while interpreting serological test results. In the present study, the cross-reactivity of sera of the patients with dengue, who traveled from Japan to DENV-endemic countries, was analyzed by using an enzyme-linked immunosorbent assay (ELISA) and neutralization test (NT). Sixteen serum samples were collected from patients with dengue and were tested for: i) IgM antibodies against Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) using IgM ELISA, ii) IgG antibody against TBEV using IgG ELISA, and iii) neutralizing antibody against ZIKV, WNV, TBEV, and JEV. Among the 16 samples tested using ELISA, seven samples were IgM-positive for at least one of the other flaviviruses, and nine samples were IgG-positive for TBEV. Neutralizing antibody titers (NATs) against ZIKV, WNV, and TBEV were one-fourth or lower than those against the causative DENV in all samples. The NATs against JEV were one-fourth or lower than those against the causative DENV in six convalescent-phase serum sample among the seven convalescent-phase serum samples. The NAT against DENV of the residual one convalescent-phase serum was similar to that against JEV and that against JEV of its relevant acute-phase serum sample. These results showed that NTs with paired serum samples are important to correctly interpret the serological test results for DENV.     

Dengue vaccine

Dengue fever is the most important mosquito-borne viral disease in the world, for which preventive vaccines are urgently required. Several strategies have been used for dengue tetravalent vaccine development. Strategies with traditional attenuation, chimerization, engineered attenuation are in the more advanced stages. In addition, inactivated, subunit, virus-vectored, pseudo-infectious virus, and DNA vaccines have been developed. Although these strategies produced high levels of neutralizing antibodies against dengue virus types 1-4 and/or viremia protection following challenge in preclinical evaluations and clinical trials, concerns have been raised. This brief article focused on three strategies in the more advanced stages and reviewed the recent status of their development and the concerns against them.