Viral-Induced Inflammatory Coagulation Disorders: Preparing for Another Epidemic.

Several viral infectious diseases have emerged or re-emerged from wildlife vectors that have generated serious threats to global health. Increased international travel and commerce increase the risk of transmission of viral or other infectious diseases. In addition, recent climate changes accelerate the potential spread of domestic disease. The coronavirus disease 2019 (COVID-19) pandemic is an important example of the worldwide spread, and the current epidemic will unlikely be the last. Viral hemorrhagic fevers, such as dengue and Lassa fevers, may also have the potential to spread worldwide with a significant impact on public health with unpredictable timing. Based on the important lessons learned from COVID-19, it would be prudent to prepare for future pandemics of life-threatening viral diseases. The key concept that connect COVID-19 and viral hemorrhagic fever is the coagulation disorder. This review focuses on the coagulopathy of acute viral infections since hypercoagulability has been a major challenge in COVID-19, but represents a different presentation compared with viral hemorrhagic fever. However, both thrombosis and hemorrhage are understood as the result of thromboinflammation due to viral infections, and the role of anticoagulation is important to consider.

Hantavirus causing hemorrhagic fever with renal syndrome enters from the apical surface and requires decay-accelerating factor (DAF/CD55).

The Old World hantaviruses, members of the family Bunyaviridae, cause hemorrhagic fever with renal syndrome (HFRS). Transmission to humans occurs via inhalation of aerosols contaminated with the excreta of infected rodents. The viral antigen is detectable in dendritic cells, macrophages, lymphocytes, and, most importantly, microvascular endothelial cells. However, the site and detailed mechanism of entry of HFRS-causing hantaviruses in polarized epithelial cells have not yet been defined. Therefore, this study focused on the entry of the pathogenic hantaviruses Hantaan and Puumala into African green monkey kidney epithelial cells and primary human endothelial cells. The polarized epithelial and endothelial cells were found to be susceptible to hantavirus infection exclusively from the apical surface. Treatment with phosphatidylinositol-specific phospholipase C, which removes glycosylphosphatidylinositol (GPI)-anchored proteins from the cell surface, protects cells from infection, indicating that hantaviruses require a GPI-anchored protein as a cofactor for entry. Decay-accelerating factor (DAF)/CD55 is a GPI-anchored protein of the complement regulatory system and serves as a receptor for attachment to the apical cell surface for a number of viruses. Infection was reduced by the pretreatment of hantaviral particles with human recombinant DAF. Moreover, the treatment of permissive cells with DAF-specific antibody blocked infection. These results demonstrate that the Old World hantaviruses Hantaan and Puumala enter polarized target cells from the apical site and that DAF is a critical cofactor for infection.

Replication of Marburg virus in human endothelial cells. A possible mechanism for the development of viral hemorrhagic disease.

Marburg and Ebola virus, members of the family Filoviridae, cause a severe hemorrhagic disease in humans and primates. The disease is characterized as a pantropic virus infection often resulting in a fulminating shock associated with hemorrhage, and death. All known histological and pathophysiological parameters of the disease are not sufficient to explain the devastating symptoms. Previous studies suggested a nonspecific destruction of the endothelium as a possible mechanism. Concerning the important regulatory functions of the endothelium (blood pressure, anti-thrombogenicity, homeostasis), we examined Marburg virus replication in primary cultures of human endothelial cells and organ cultures of human umbilical cord veins. We show here that Marburg virus replicates in endothelial cells almost as well as in monkey kidney cells commonly used for virus propagation. Our data support the concept that the destruction of endothelial cells resulting from Marburg virus replication is a possible mechanism responsible for the hemorrhagic disease and the shock syndrome typical of this infection.

Multiple circulating infections can mimic the early stages of viral hemorrhagic fevers and possible human exposure to filoviruses in Sierra Leone prior to the 2014 outbreak.

Lassa fever (LF) is a severe viral hemorrhagic fever caused by Lassa virus (LASV). The LF program at the Kenema Government Hospital (KGH) in Eastern Sierra Leone currently provides diagnostic services and clinical care for more than 500 suspected LF cases per year. Nearly two-thirds of suspected LF patients presenting to the LF Ward test negative for either LASV antigen or anti-LASV immunoglobulin M (IgM), and therefore are considered to have a non-Lassa febrile illness (NLFI). The NLFI patients in this study were generally severely ill, which accounts for their high case fatality rate of 36%. The current studies were aimed at determining possible causes of severe febrile illnesses in non-LF cases presenting to the KGH, including possible involvement of filoviruses. A seroprevalence survey employing commercial enzyme-linked immunosorbent assay tests revealed significant IgM and IgG reactivity against dengue virus, chikungunya virus, West Nile virus (WNV), Leptospira, and typhus. A polymerase chain reaction-based survey using sera from subjects with acute LF, evidence of prior LASV exposure, or NLFI revealed widespread infection with Plasmodium falciparum malaria in febrile patients. WNV RNA was detected in a subset of patients, and a 419 nt amplicon specific to filoviral L segment RNA was detected at low levels in a single patient. However, 22% of the patients presenting at the KGH between 2011 and 2014 who were included in this survey registered anti-Ebola virus (EBOV) IgG or IgM, suggesting prior exposure to this agent. The 2014 Ebola virus disease (EVD) outbreak is already the deadliest and most widely dispersed outbreak of its kind on record. Serological evidence reported here for possible human exposure to filoviruses in Sierra Leone prior to the current EVD outbreak supports genetic analysis that EBOV may have been present in West Africa for some time prior to the 2014 outbreak.

Arenaviral haemorrhagic fevers.

Three arenaviruses--Lassa, Junin and Machupo--cause severe haemorrhagic disease in humans: Lassa fever, Argentine haemorrhagic fever and Bolivian haemorrhagic fever, respectively. These conditions are a source of considerable economic hardship in endemic areas and remain a worldwide concern for public-health officials. They are characterised by an insidious onset of influenza-like symptoms followed, in severe cases, by a generalised bleeding diathesis, encephalopathy and death. Central to studies of their pathogenesis is evidence for cellular dysfunction disproportionate to overt histopathology. Recent studies of patients with Lassa fever indicate that platelet and possibly endothelial-cell dysfunction play an important role in the bleeding tendency. The platelet defect appears to be mediated by an inhibitory factor in plasma; the nature of this is uncertain but it seems to be neither viral protein nor virus antibody. A similar inhibitor has since been demonstrated in patients with Argentine haemorrhagic fever. Plasma from patients with Lassa fever also profoundly modulates the amount of superoxide generated by normal neutrophils in response to the chemotactic peptide f-met-leu-phe, suggesting the inhibitor(s) has global effects on cellular function. These findings may have important implications for future therapeutic strategies.

Viral hemorrhagic fever--a vascular disease?

The syndrome of "viral hemorrhagic fever" in man caused by certain viruses, such as Ebola, Lassa, Dengue, and Crimean-Congo hemorrhagic fever viruses, is often associated with a shock syndrome of undetermined pathogenesis. However, the vascular system, particularly the vascular endothelium, seems to be directly and indirectly targeted by all these viruses. Here we briefly summarize the current knowledge on Marburg and Ebola virus infections, the prototype viral hemorrhagic fever agents, and formulate a working hypothesis for the pathogenesis of viral hemorrhagic fever. Infections with filoviruses show lethality up to 89% and in severe cases lead to a shock syndrome associated with hypotension, coagulation disorders and an imbalance of fluid distribution between the intravascular and extravascular tissue space. The primary target cells for filoviruses are mononuclear phagocytotic cells which are activated upon infection and release certain cytokines and chemokines. These mediators indirectly target the endothelium and are thought to play a key role in the pathogenesis of filoviral hemorrhagic fever. In addition, direct infection and subsequent destruction of endothelial cells might contribute to the pathogenesis. Filoviruses, particularly Ebola virus, encode nonstructural glycoproteins which are released from infected host cells. Their function as potential determinants in pathogenicity remains to be investigated.

Haemorrhagic fevers and ecological perturbations.

Hemorrhagic fever is a clinical and imprecise definition for several different diseases. Their main common point is to be zoonoses. These diseases are due to several viruses which belong to different families. The Flaviviridae have been known for the longest time. They include the Amaril virus that causes yellow fever and is transported by mosquitoes. Viruses that have come to light more recently belong to three other families: Arenaviridae, Bunyaviridae, and Filoviridae. They are transmitted by rodents (hantaviruses and arenaviruses) or from unknown reservoirs (Ebola Marburg). The primary cause of most outbreaks of hemorrhagic fever viruses is ecological disruption resulting from human activities. The expansion of the world population perturbs ecosystems that were stable a few decades ago and facilitates contacts with animals carrying viruses pathogenic to humans. Another dangerous human activity is the development of hospitals with poor medical hygiene. Lassa, Crimean-Congo or Ebola outbreaks are mainly nosocomial. There are also natural environmental changes: the emergence of Sin Nombre in the U.S. resulted from heavier than usual rain and snow during spring 1993 in the Four Corners. Biological industries also present risks. In 1967, collection of organs from monkeys allowed the discovery in Marburg of a new family of viruses, the Filoviridae. Hemorrhagic fever viruses are cause for worry, and the avenues to reduce their toll are still limited.

Simian hemorrhagic fever: Studies of coagulation and pathology.

Simian hemorrhagic fever (SHF) was induced in three species of monkeys (Macaca mulatta, M. radiata and M. fascicularis) using plasma from animals that died with SHF in the 1967 outbreak at the California Primate Research Center. The disease was uniformly fatal in all three species with death occurring by day 5 in M. radiata and M. fascicularis and by day 7 in M. mulatta. Serial studies of hemostasis were consistent with the occurrence of disseminated intravascular coagulation, particularly in the M. mulatta. Studies of pathology were typical of previously reported findings in SHF and support the possibility of intravascular coagulation. The role of intravascular coagulation in the pathogenesis and outcome of SHF remains uncertain but studies of the influence of heparin on the disease are in progress.

Human infections tick-transmitted.

In this monograph are analysed the principal infections transmitted by ticks and particularly those interesting Europe and North America. Besides the main species of these arthropods are described in consideration of their characteristics and geographic diffusion. In particular the infections caused by Borrelia genus and tick born encephalitis virus are treated more exhaustively in consideration of their potential severity and because the diagnosis of these infections is sometimes difficult. However also the main rickettsial infections transmitted by ticks are reported together the hemorragic fevers transmitted by such arthropods. In particular it is exhaustively analysed the Mediterranean tick fever in consideration of its presence in some regions of Italy and of the wrong opinion of considering this pathology not very severe. Lastly has been included a treatment about some emergent infections transmitted by ticks, like as the ehrlichiosis and babesiasis, but also the mention of tularaemia that can be considered a re-emergent infection, also in consideration of the epidemic focus now present in Kossovo. The above-mentioned pathologies are analysed also as regards the laboratory diagnosis (direct and serologic methods), the therapeutic treatment and the prophilaxis, both directed against the arthropods vectors and that of individual type, employing also some vaccines, when disposable.

Computational genomic analysis of hemorrhagic fever viruses. Viral selenoproteins as a potential factor in pathogenesis.

A number of distinct viruses are known as hemorrhagic fever viruses based on a shared ability to induce hemorrhage by poorly understood mechanisms, typically involving the formation of blood clots ("disseminated intravascular coagulation"). It is well documented that selenium plays a significant role in the regulation of blood clotting via its effects on the thromboxane/prostacyclin ratio, and effects on the complement system. Selenium has an anticlotting effect, whereas selenium deficiency has a proclotting or thrombotic effect. It is also well documented that extreme dietary selenium deficiency, which is almost never seen in humans, has been associated with hemorrhagic effects in animals. Thus, the possibility that viral selenoprotein synthesis might contribute to hemorrhagic symptoms merits further consideration. Computational genomic analysis of certain hemorrhagic fever viruses reveals the presence of potential protein coding regions (PPCRs) containing large numbers of in-frame UGA codons, particularly in the -1 reading frame. In some cases, these clusterings of UGA codons are very unlikely to have arisen by chance, suggesting that these UGAs may have some function other than being a stop codon, such as encoding selenocysteine. For this to be possible, a downstream selenocysteine insertion element (SECIS) is required. Ebola Zaire, the most notorious hemorrhagic fever virus, has a PCR with 17 UGA codons, and several potential SECIS elements can be identified in the viral genome. One potential viral selenoprotein may contain up to 16 selenium atoms per molecule. Biosynthesis of this protein could impose an unprecedented selenium demand on the host, potentially, leading to severe lipid peroxidation and cell membrane destruction, and contributing to hemorrhagic symptoms. Alternatively, even in the absence of programmed selenoprotein synthesis, it is possible that random slippage errors would lead to increased encounters with UGA codons in overlapping reading frames, and thus potentially to nonspecific depletion of SeC in the host.

[Viral hemorrhagic fevers: what is the risk for travelers?]. / Les fièvres hémorragiques virales: quel risque pour le voyageur?

The term hemorrhagic fever covers a number of diseases with different clinical and epidemiologic features. All these diseases are zoonoses but their occurrence is not confined to tropical areas. Some occur in polar zones. Travelers to endemic areas for these diseases are at risk of infection. There are two modes of transmission. Arthropods are vectors for some diseases such as yellow fever, dengue fever, and Rift Valley fever which are carried by mosquitos and Congo-Crimea virus which is carried by ticks. Airborne contamination by rodent excrement is responsible for transmission of hantaviruses and arenaviruses. Nosocomial infection is a risk for health care providers. Some types of hemorrhagic fever such as Bolivian hemorrhagic fever are highly localized, while other types such as dengue are observed worldwide. Judging from the small number of cases observed in European countries, the overall risk for travelers seems low except unless high-risk activities are planned. The main exceptions are yellow fever and dengue which can easily be transmitted to tourists by mosquitos. Yellow fever can be prevented by vaccination. Typical dengue is usually self-limited but hemorrhagic forms require treatment to prevent shock.

Co-circulation of multiple hemorrhagic fever diseases with distinct clinical characteristics in Dandong, China.

Hemorrhagic fevers (HF) caused by viruses and bacteria are a major public health problem in China and characterized by variable clinical manifestations, such that it is often difficult to achieve accurate diagnosis and treatment. The causes of HF in 85 patients admitted to Dandong hospital, China, between 2011-2012 were determined by serological and PCR tests. Of these, 34 patients were diagnosed with Huaiyangshan hemorrhagic fever (HYSHF), 34 with Hemorrhagic Fever with Renal Syndrome (HFRS), one with murine typhus, and one with scrub typhus. Etiologic agents could not be determined in the 15 remaining patients. Phylogenetic analyses of recovered bacterial and viral sequences revealed that the causative infectious agents were closely related to those described in other geographical regions. As these diseases have no distinctive clinical features in their early stage, only 13 patients were initially accurately diagnosed. The distinctive clinical features of HFRS and HYSHF developed during disease progression. Enlarged lymph nodes, cough, sputum, and diarrhea were more common in HYSHF patients, while more HFRS cases presented with headache, sore throat, oliguria, percussion pain kidney area, and petechiae. Additionally, HYSHF patients displayed significantly lower levels of white blood cells (WBC), higher levels of creations kinase (CK) and alanine aminotransferase (ALT), while HFRS patients presented with an elevation of blood urea nitrogen (BUN) and creatinine (CREA). These clinical features will assist in the accurate diagnosis of both HYSHF and HFRS. Overall, our data reveal the complexity of pathogens causing HFs in a single Chinese hospital, and highlight the need for accurate early diagnosis and a better understanding of their distinctive clinical features.

[Pathogenesis of classical swine fever--similarities to viral haemorrhagic fevers: a review]. / Pathogenese der Klassischen Schweinepest--Parallelen zu viralen hämorrhagischen Fiebern: eine Ubersicht.

In spite of differences in etiology, viral haemorrhagic diseases share similarities in their pathogenesis. Characteristic for these diseases are thrombocytopenia, petechia and increased vascular leakage. Most lesions can be attributed to cytokine-mediated interactions triggered by infected and activated monocytes and macrophages, rather than by virus-induced direct cell damage. Causative agents of viral hemorrhagic diseases are enveloped RNA viruses. In most cases, they are transmitted to humans from their animal hosts by rodents or arthropod vectors (Arboviruses). Due to the clinical picture, the acute lethal form of classical swine fever (CSF) is also considered as a viral haemorrhagic disease. CSF is caused by an RNA virus in the family Flaviviridae, and members of the Suidae family are the only ones clinically affected. It is a highly contagious, therefore notifiable disease. In contrast to other viral hamorrhagic diseases, it is mainly transmitted oro-nasally by contact with infected pigs, or by contaminated items (semen, swill feed, clothing). The present survey summarizes analogies between classical representatives of viral haemorrhagic fevers, and recapitulates current knowledge concerning the pathogenesis of classical swine fever.