Immunopathogenesis of hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome

Hantaviruses (HTV) cause two serious human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), posing a considerable public health problem worldwide. Immunopathogenesis has been suggested to be involved in both HFRS and HPS. A common feature of hantavirus diseases is an increased microvascular bed permeability, suggesting that vascular endothelium is a prime target of virus infection. Although HTV infect numerous cell lines and primary cells, it was considered that they do cause no cytopathic effect. Recently, we found HTV to cause a cytopathic effect and apoptosis in 293 HEK cells. Monocytes/macrophages also represent the important target cells, which may also have an important role in the spread of HTV from the primary site of infection. Both endothelial cells and monocytes/macrophages may act as a rich source of cytokines/chemokines during the infection with HTV and additionally contribute to the HFRS/HPS immunopathogenesis. The main reservoirs of HTV are small rodents which are infected but do not have manifest disease. However, some studies show that T-lymphocytes may play an important role in rodent resistance to infection with HTV. Some clinical studies indicate the important role of pro-inflammatory cytokines in the immunopathogenesis of HFRS/HPS. The efficient anti-hantaviral cell-immune response in patients is mainly due to the generation of cytotoxic T-lymphocytes. Our study also pointed to a decrease in the percentage of total naive (CD45RA) cells and an increase in the percentage of memory cells (CD45RO). Specific IgM antibodies appear at the very beginning of the diseases followed by an increase in specific IgG. Additionally, IgE antibodies have been suggested to play a role in HFRS immunopathogenesis. Immune complexes have been detected in the sera, on the surface of red blood cells and platelets, in urine, glomerull and dermal capillaries of HFRS patients. They may be responsible for increased capillary permeability, vascular injury, platelet lysis and kidney damage. The immunopathologic disorders accompanying HFRS/HPS are complex. As there is no appropriate animal model to investigate HFRS/HPS immunopathogenesis, we mostly rely on in vitro and rare clinical studies. Additional efforts in the research of immunopathogenesis caused by HTV, may contribute to better understanding of HFRS/HPS characteristics and course of disease, and improve the treatment and prevention.     

Dengue NS1-specific antibody responses: isotype distribution and serotyping in patients with Dengue fever and Dengue hemorrhagic fever

To understand the antibody responses to dengue (DEN) nonstructural 1 (NS1) glycoprotein and their roles in protective immunity or pathogenesis of dengue fever (DF) and dengue hemorrhagic fever (DHF), we have analyzed the NS1-speccific IgM, IgA and IgG antibodies from patients with DF and DHF. An isotype-specific, indirect enzyme-linked immunosorbent assay (ELISA) was established by coating a NS1-specific monoclonal antibody (MAb), D2/8-1, to capture soluble NS1 antigens secreted in the culture supernatants of Vero cells infected with DEN virus. We observed strong anti-NS1 antibody responses in all of the convalescent sera of patients with DF and DHF. Similar NS1-specific isotypic and serotypic antibody responses were found in the sera from DF and DHF patients. The results showed that all DEN infections induced significant NS1-specific IgG, whereas 75% and 60% of primary DF patients vs. 40% and 90% of secondary DF patients produced IgM and IgA antibodies, respectively. Specificity analysis showed that DEN NS1-specific IgG and IgA antibodies cross-react strongly to Japanese encephalitis (JE) virus NS1 glycoprotein, whereas DEN NS1-specific IgM antibodies do not cross-react to JE virus NS1 glycoprotein at all. The serotype specificity of NS1-specific IgM, IgA and IgG were found to be 80%, 67% and 75% for primary infections, and 50%, 22% and 30% for secondary infections in positive samples of DF patients. Similar pattern was found in DHF patients. The results showed that all of the DF and DHF patients produced significant NS1-specific antibodies. We did not observe direct correlation between the anti-NS1 antibody responses and DHF because sera from patients with DF and DHF showed similar anti-NS1 antibody responses.     

Dengue hemorrhagic fever is associated with polymorphisms in JAK1

To identify genes associated with the clinical presentation of dengue, 50 cases of probable or possible dengue hemorrhagic fever (DHF), 236 dengue fever (DF), and 236 asymptomatic infections were genotyped for 593 single-nucleotide polymorphisms (SNPs) in 56 genes across the type 1 interferon (IFN) response pathway as well as other important candidate genes. By single locus analysis comparing DHF with DF, 11 of the 51 markers with P<0.05 were in the JAK1 gene. Five markers were significantly associated by false discovery rate criteria (q<0.20 when P<6 × 10⁻⁴). The JAK1 SNPs showed differential distribution by ethnicity and ancestry consistent with epidemiologic observations in the Americas. The association remained significant after controlling for ancestry and income. No association was observed with markers in the gene encoding CD209 (DC-SIGN). An association between DHF and JAK1 polymorphisms is in agreement with expression profiles showing generalized decreased type 1 IFN-stimulated gene expression in these patients.     

Immunopathogenesis of dengue hemorrhagic fever and shock syndrome: role of TAP and HPA gene polymorphism

Clinical outcomes of dengue infection such as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) could be attributed to host genetic factors. The transporters associated with antigen processing (TAP) genes are polymorphic genes located in the human leukocyte antigen (HLA) class II region and are essentially involved in class I antigen presentation. Therefore, these genes might grant susceptibility to severe dengue infection. Hence, the aim of the study was to type the TAP1 gene (using amplification refraction mutation system [ARMS] polymerase chain reaction [PCR]) and HPA1 and HPA2 gene polymorphism (by PCR–sequence specific primers) in different clinical spectrums of dengue infection. The study included 100 controls and 91 DF, 75 DHF, and 32 DSS patients. The results revealed that the frequencies of valine at TAP1 333 and HPA 1b at HPA1 were increased among DHF and DSS, respectively, in comparison to controls (p <0.05). The frequency of genotype TAP1 333 ILE/VAL (61.3%) was significantly higher in DHF compared with control (37%, p = 0.005) or DF (38.9%, p = 0.007) patients. A significantly greater proportion of DHF patients demonstrated HPA1a/1a and HPA 2a/2b genotypes than DF patients. DSS patients were more likely to be heterozygous at HPA1 than DHF (OR = 4.75, p = 0.003). A positive correlation existed between TAP1 333 and HPA1 in DHF (p = 0.017, r = 0.229). This first report on TAP and HPA gene polymorphism in dengue suggested that the heterozygous pattern at the TAP1 333 locus and HPA1a/1a and HPA2a/2b genotypes confer susceptibility to DHF and the HPA1a/1b genotype was determined to be a genetic risk factor for DSS.     

Dengue and dengue hemorrhagic fever in the Americas: lessons and challenges.

The incidence of dengue and dengue hemorrhagic fever (DF/DHF) has increased significantly over the last decades. Yearly, an estimated 50-100 million cases of DF and about 250000-500000 cases of DHF occur worldwide. The epidemiological situation in Latin America now resembles that in Southeast Asia. Here, the main clinical, epidemiological and virological observations in the American region are presented and compared with those previously reported from Southeast Asia. During 2002, more than 30 Latin American countries reported over 1000000 DF cases. DHF occurred in 20 countries with more than 17000 DHF cases, including 225 fatalities. The co-circulation of multiple serotypes has been reported from many countries. In the Americas, DHF is observed both in children and adults; secondary infection by a different dengue virus serotype has been confirmed as an important risk factor for this severe form of the disease. However, some new risk factors such as the interval of dengue virus infections and the ethnicity and underlying chronic conditions of the patient have also been identified. The sequence of dengue virus infections and association with certain genotypes are further factors of importance. We also discuss the control and prevention strategies. In conclusion, without urgent action for the prevention and control of dengue/DHF and its vector, the current situation will worsen and, more dramatical, there is a risk of the urbanization of yellow fever.     

Rhombencephalitis associated with Dengue fever

Dengue infection is gradually disseminating throughout the world in alarming proportions. It is a arbovirus infection,transmitted by aedes mosquitoes. It is a multi-systemic disorder associated with varied neurological complications. There is increased trend of development of neurological complications in dengue fever. The neurological complications arising due to dengue infection can be categorized into central and neuromuscular complications. The central nervous system disorders reported with dengue fever are encephalopathy,encephalitis and myelitis.Here we report a case of rhombencephalitis associated with dengue fever. The literature does not mention rhombencephalitis occurring with dengue illness.     

Dengue fever in the Corpus Hippocraticum

Dengue fever (DF) is a globally significant infection which causes a range of severe and non-severe clinical manifestations. It is transmitted by mosquitoes of the Aedes genus (primarily Aedes aegypti, but also Aedes albopictus). In this letter, a possible DF epidemic on Thasos Island in Greece, which is described in the Book of Epidemics I of the Corpus Hippocraticum, is presented and analyzed. To my knowledge, it is the first report of DF in the history of medicine.     

Dengue fever mimicking plasma cell leukemia

Extreme plasmacytosis in peripheral blood is a rare finding most often associated with plasma cell leukemia but rarely with other malignancies, infectious diseases, or drug reactions. We report the case of a 40-year-old man who was a US expatriate working and traveling in East Asia. He presented with complaints of fever, myalgia, headache, vomiting, and diarrhea of 3 days' duration. An initial evaluation revealed elevated liver function tests, thrombocytopenia (68 x 10(3)/microL), and a white blood cell count of 5.8 x 10(3)/microL with 19% plasma cells (1100/microL), 9% abnormal plasmacytoid lymphocytes (520/microL), 37% polymorphonuclear leukocytes, 3% band forms, 27% lymphocytes, 4% monocytes, and 1% eosinophils. An extensive evaluation was performed, including infectious disease serologies, a bone marrow biopsy, and flow cytometry. During the course of 3 days, his symptoms and hematologic findings improved dramatically. Serologic results were reactive for dengue (immunoglobulin M [IgM] positive, reciprocal IgG titer, 655 360), consistent with a secondary infection of unknown serotype. He remains well 4 years later. To our knowledge, plasmacytosis to this degree has not been described in dengue fever, but atypical lymphocytosis is common. In patients from dengue-endemic areas, even extreme plasmacytosis should be assessed to determine whether it is transient and related to an acute illness before proceeding to an extensive evaluation.     

Dengue fever and bone marrow myelofibrosis

Myelofibrosis is characterized by reticulin and/or collagen fibrosis in the bone marrow stroma resulting in secondary cytopenia. In addition to clonal hematologic neoplasms, myelofibrosis may also develop in association with other clinical conditions, including hematological disorders, solid malignancies, Down syndrome, autoimmune diseases and others. We report the first case to our knowledge of myelofibrosis associated with dengue fever. We briefly describe dengue infections and hypothesize the causes of myelofibrosis in this condition.     

Dengue fever with acute liver failure

A virus belonging to the Flaviviridae group causes dengue haemorrhagic fever. Dengue presenting as acute liver failure is rare. Dengue is endemic in India. The last epidemic of dengue occurred in Delhi in 2003. During this epidemic, 2185 confirmed cases of dengue were reported. Dengue virus serotypes 2 and 3 were responsible for this epidemic. A 19-yr-old male presented to our hospital with the complaints of fever for 12 days, during this epidemic. He was diagnosed as having dengue shock syndrome, stage IV with acute liver failure. He had primary dengue infection. He made complete recovery with supportive management.     

Pathogenesis of viral hemorrhagic fever

Single-stranded RNA viruses from four different families cause a syndrome of fever and malaise, 'capillary leak' with loss of plasma volume, and coagulation defects which can lead to bleeding. Although direct cytopathic effects can contribute to disease severity, most features of illness are caused by innate immune responses, as the systemic spread of virus to macrophages and dendritic cells leads to the release of mediators that modify vascular function and have procoagulant activity. The synthesis of tissue factor by infected cells can also trigger coagulation. Failure of adaptive immunity through impaired dendritic cell function and lymphocyte apoptosis can have a crucial role in fatal infection.