Ebola and Marburg haemorrhagic fever

Ebolaviruses and Marburgviruses (family Filoviridae) are among the most virulent pathogens for humans and great apes causing severe haemorrhagic fever and death within a matter of days. This group of viruses is characterized by a linear, non-segmented, single-stranded RNA genome of negative polarity. The overall burden of filovirus infections is minimal and negligible compared to the devastation caused by malnutrition and other infectious diseases prevalent in Africa such as malaria, dengue or tuberculosis. In this paper, we review the knowledge gained on the eco/epidemiology, the pathogenesis and the disease control measures for Marburg and Ebola viruses developed over the last 15 years. The overall progress is promising given the little attention that these pathogen have achieved in the past; however, more is to come over the next decade given the more recent interest in these pathogens as potential public and animal health concerns. Licensing of therapeutic and prophylactic options may be achievable over the next 5–10 years.     

Ultrastructural pathology of experimental Ebola haemorrhagic fever virus infection

The organs of monkeys infected with Ebola haemorrhagic fever were examined by light and electron microscopy during the acute stage of the disease. The virus caused focal coagulative necrosis in the liver, spleen, kidney, lung and testis and widespread mild vascular damage. In the brain there was intense congestion, with erythrocyte 'sludging', but no inflammatory reaction. There was significant injury to the microvasculature in all organs. Virus replicated in endothelial cytoplasm causing focal necrosis, separation of tight junctions and detachment from basement membranes. These changes were associated with oedema and haemorrhage, but though contributing to the hypovolaemic shock were not sufficiently extensive to account for the severity of vascular collapse. Renal involvement was also clinically important. Some renal cellular injury was caused by direct virus invasion of glomerular endothelium and tubular epithelium, but much tubular damage was probably due to ischaemia resulting from thrombosis in the peritubular capillaries. The virus also replicated in lymphocytes and monocytes and in interstitial cells of the testis. Since particles were not found in seminiferous epithelium, the degeneration of spermatogonia and spermatocytes was probably secondary to ischaemia.     

Multiple Ebola virus haemorrhagic fever outbreaks in Gabon, from October 2001 to April 2002

Outbreaks of Ebola virus haemorrhagic fever have been reported from 1994 to 1996 in the province of Ogooué Ivindo, a forest zone situated in the Northeast of Gabon. Each time, the great primates had been identified as the initial source of human infection. End of November 2001 a new alert came from this province, rapidly confirmed as a EVHV outbreak. The response was given by the Ministry of Health with the help of an international team under the aegis of WHO. An active monitoring system was implemented in the three districts hit by the epidemic (Zadié, Ivindo and Mpassa) to organize the detection of cases and their follow-up. A case definition has been set up, the suspected cases were isolated at hospital, at home or in lazarets and serological tests were performed. These tests consisted of the detection of antigen or specific IgG and the RT-PCR. A classification of cases was made according to the results of biological tests, clinical and epidemiological data. The contact subjects were kept watch over for 21 days. 65 cases were recorded among which 53 deaths. The first human case, a hunter died on the 28th of October 2001. The epidemic spreads over through family transmission and nosocomial contamination. Four distinct primary foci have been identified together with an isolated case situated in the South East of Gabon, 580 km away from the epicenter. Deaths happened within a delay of 6 days. The last death has been recorded on the 22nd of March 2002 and the end of the outbreak was declared on the 6th of May 2002. The epidemic spreads over the Gabon just next. Unexplained deaths of animals had been mentionned in the nearby forests as soon as August 2001: great primates and cephalophus. Samples taken from their carcasses confirmed a concomitant animal epidemic.     

First dengue haemorrhagic fever epidemic in the Americas, 1981: insights into the causative agent

Historical records describe a disease in North America that clinically resembled dengue haemorrhagic fever during the latter part of the slave-trading period. However, the dengue epidemic that occurred in Cuba in 1981 was the first laboratory-confirmed and clinically diagnosed outbreak of dengue haemorrhagic fever in the Americas. At that time, the presumed source of the dengue type 2 strain isolated during this epidemic was considered controversial, partly because of the limited sequence data and partly because the origin of the virus appeared to be southern Asia. Here, we present a molecular characterisation at the whole-genome level of the original strains isolated at different time points during the epidemic. Phylogenetic trees constructed using Bayesian methods indicated that 1981 Cuban strains group within the Asian 2 genotype. In addition, the study revealed that viral evolution occurred during the epidemic – a fact that could be related to the increasing severity from month to month. Moreover, the Cuban strains exhibited particular amino acid substitutions that differentiate them from the New Guinea C prototype strain as well as from dengue type 2 strains isolated globally.     

Dengue fever and dengue haemorrhagic fever: challenges of controlling an enemy still at large

Dengue virus infections are a serious cause of morbidity and mortality in most tropical and subtropical areas of the world: mainly Southeast and South Asia, Central and South America, and the Caribbean. Understanding the pathogenesis of dengue haemorrhagic fever (DHF), the severe form of dengue illness, is a very important and challenging research subject. Viral virulence and immune responses have been considered as two major factors responsible for the pathogenesis. Virological studies are attempting to define the molecular basis of viral virulence. The immunopathological mechanisms appear to include a complex series of immune responses. A rapid increase in the levels of cytokines and chemical mediators apparently plays a key role in inducing plasma leakage, shock and haemorrhagic manifestations. It is likely that the entire process is initiated by infection with a so-called virulent dengue virus, often with the help of enhancing antibodies in secondary infection, and then triggered by rapidly elevated cytokines and chemical mediators produced by intense immune activation. However, understanding of the DHF pathogenesis is not complete. We still have a long way to go.     

The immunopathogenesis of dengue haemorrhagic fever

Over the past 20 years, dengue haemorrhagic fever (DHF) has been the subject of intensive epidemiological, clinical, virological and immunological investigations. Considerable debate and controversy have surrounded its causation and the probable role of immunological mechanisms in its pathogenesis. The exact cause of DHF is still uncertain and this article reviews current thinking about the problem.     

Fulminant hepatitis in dengue haemorrhagic fever.

Dengue virus is estimated to cause over 100 million infections throughout the world annually. While dengue infections can have a wide range of infections, atypical manifestations have been described. These involve the central nervous system, cardiac alterations and hepatitis. Here, we highlight a case of dengue haemorrhagic fever (DHF) with fulminant hepatitis. A 55-year-old male was admitted for 16 days, developing severe thrombocytopenia as low as 6x10(9)/L, haematocrit of 48% with transaminitis: ALT: 3,515 U/L, AST: 12,541 U/L, GGT: 1,094 U/L. Subsequent investigations excluded any occult liver lesions, hepatitis A, B and C, Wilson's disease, Epstein-Barr virus and Cytomegalo virus as possible causes. His dengue PCR was positive. His condition subsequently improved with supportive treatment. Liver injury from dengue virus is mediated by its direct infection of hepatocytes and kupffer cells. While mild to moderate elevations of serum aminotransferases (ALT and AST<5X normal) are common in dengue virus infection, liver failure rarely dominate the clinical picture. Liver dysfunction was commoner in DHF, with case reports indicating that severe hepatic dysfunction (ALT and AST>10X normal) was seen with DHF associated with spontaneous bleeding tendencies. Overall prognosis depends on age and other concomitant co-morbidities. We seek to review the literature on dengue infections with hepatitis and discuss issues pertaining to pathophysiology of liver impairment in dengue, the frequency of transaminitis associated with DHF and the overall prognosis.     

Ebola and Marburg haemorrhagic fever viruses: major scientific advances,but a relatively minor public health threat for Africa

Ebola and Marburg viruses are the only members of the Filoviridae family (order Mononegavirales), a group of viruses characterized by a linear, non-segmented, single-strand negative RNA genome. They are among the most virulent pathogens for humans and great apes, causing acute haemorrhagic fever and death within a matter of days. Since their discovery 50 years ago, filoviruses have caused only a few outbreaks, with 2317 clinical cases and 1671 confirmed deaths, which is negligible compared with the devastation caused by malnutrition and other infectious diseases prevalent in Africa (malaria, cholera, AIDS, dengue, tuberculosis…). Yet considerable human and financial resourses have been devoted to research on these viruses during the past two decades, partly because of their potential use as bioweapons. As a result, our understanding of the ecology, host interactions, and control of these viruses has improved considerably.     

Seroepidemiology and active surveillance of dengue fever/dengue haemorrhagic fever in Delhi

The aims of the present study were to carry out surveillance for dengue virus infection in adults with short-duration fever, and serological study of dengue virus infection in persons without fever. Patients were divided into two groups. Group 1 included patients above 12 years of age with fever of 2-12 days duration without any apparent cause. Of these, patients who presented with fever for 2-5 days were included for virus isolation (group 1a) while those who presented within 6-12 days of the onset of fever were included for the dengue-specific IgM serology (group 1b). Group 2 included a sample of population belonging to all age groups but without pyrexia and blood was collected for dengue-specific IgG serology. Twenty-six patients were enrolled in group 1a over a period of 4 months (September to December, 1997). Of these, DEN1 was isolated in 5 cases. Group 1b included 182 patients, out of which 34 (18.68%) were positive for dengue-specific IgM antibodies. Significantly, all the positive cases were detected during the months of September to November. Retro-orbital pain was present in a significantly more number of IgM-positive cases as compared to IgM-negative cases. Group 2 included 125 cases without fever. The overall positivity for dengue-specific IgG antibodies was 77.6%, with the highest positivity of 100% in the age group of 31-40 years. It was concluded that dengue virus infection is endemic in and around Delhi with peak incidence between September and Novemver. The prevalent serotype during September and December 1997 was DEN1. Since previous epidemic of DHF was due to DEN2 type, isolation of DEN1 serotype indicates changes of another epidemic of DHF due to DEN1 serotype. The stresses the urgent need for implementation of measures to control the transmission of dengue infection.     

Functional activity of peritoneal macrophages in experimental Ebola fever

The phagocytic activity of peritoneal macrophages (a representative of mononuclear phagocytes) as well as the TNF-alpha were studied in animals with different susceptibility to Ebola virus (EV). The results denote the following: 1. Phagocytosis activation by peritoneal macrophages after EV is introduced into the body correlates directly with a susceptibility degree of an animal to EV. 2. The EV content in peritoneal lavage is inversely dependent on a phagocytic activity of peritoneal macrophages. The TNF-alpha activity increases, in blood serum of body susceptible to EV, 500-fold versus the unsusceptible body. Therefore, production of endogenous TNF-alpha can be interpreted as the development of body's immune protection but not as a reason for the development of vascular shock. Presumably, the nonspecific immunity factors condition the EV susceptibility.     

Outbreak of haemorrhagic fever with renal syndrome in Greece

An outbreak of eight cases of haemorrhagic fever with renal syndrome in North-West Greece is presented. The major clinical manifestation was fever and all patients subsequently developed decreased renal function and proteinuria. The disease was diagnosed by rising antibody titers to the Hantaan virus.     

Seroepidemiology of haemorrhagic fever with renal syndrome in Bulgaria

During the period of 1954-1986, 399 cases of haemorrhagic fever with renal syndrome (HFRS) were registered in Bulgaria with 63 (15.7%) deaths. Three hundred serum samples from 214 patients who had contracted the disease from 1957 to 1986 were investigated by indirect fluorescent antibody test (IF-AT). As antigen Vero-E6 cells infected with the Asian Hantaan virus were used, as well as lung sections from bank voles (Clethrionomys glareolus) infected with strains Udmurt and Kazan 6-Cg from the European part of the U.S.S.R. Specific antibodies were detected in 194 sera, i.e. in 90.6% of persons investigated: in 131 single serum samples and in 63 paired sera. The results of the serological studies which covered 53.6% of all known local cases showed the territorial distribution of the natural foci in this country and the aetiologic relationship with the HFRS virus from the European part of the U.S.S.R.     

Laboratory diagnosis of Ebola and Marburg hemorrhagic fever

The control of Filovirus outbreaks can be greatly enhanced by timely laboratory confirmation of infection or the identification of alternative disease processes. The status of current laboratory diagnostics for Ebola and Marburg virus infections is discussed in terms of the assays available and their interpretation. In addition, the role of field-based laboratory support and its limitations and capabilities in an outbreak response setting, especially in regards to real-time PCR and immunofiltration assays, is presented.