Viral hemorrhagic fevers are zoonoses, and humans are usually infected by the bite of an infected arthropod or by exposure to excreta from chronically infected mammalian reservoir hosts (Table 15.1). The geographic distribution of VHF correlates with the distribution of vector and reservoir hosts, and epidemiologic features of VHF closely reflect these transmission cycles. For example, Junin virus infection, transmitted by Calomys species which live in and around agricultural fields, is more prevalent in adult male rural workers (Maiztegui 1975). By contrast, the arenavirus Lassa, which is transmitted by the peridomestic multimammate rat (Mastomys natalensis), has slightly higher attack rates in females than males (Monath 1975). Rift Valley fever epidemics in Africa and the Arabian peninsula occur after periods of heavy rainfall, upon hatching of vertically infected eggs of the Aedes species mosquito vector (LaBeaud et al. 2010). Humans may be infected by VHF agents through contact with blood or tissue of infected livestock (e.g., Rift Valley fever, Crimean-Congo hemorrhagic fever) (LaBeaud et al. 2010; Whitehouse 2004) or other food animals (e.g., Lassa fever) (ter Meulen et al. 1996). Although VHF are endemic in regions where the appropriate reservoir and vector species exist, imported cases are seen increasingly with global air travel and commerce (Bannister 2010). Nosocomial, human-to-human transmission of VHF occurs in hospital settings in resource-poor areas (Monath et al. 1973). The demonstration that some viruses may be transmitted via aerosol provides part of the rationale for classifying these agents of potential bioterrorism concern (Borio et al. 2002).

All VHF-causing viruses are lipid-enveloped with single-stranded RNA genomes. Arenavirus particles are notable for their pleomorphism (ranging from 50 to 300 nm in diameter), surface peplomers comprising the two surface glycoproteins, and electron-dense granules which represent host cell-derived ribosomes (Compans 1993). Filoviruses have characteristic filamentous morphology with branching, circular, or U-shaped forms visible by electron microscopy. These filamentous virions can vary greatly in length but average around 860–1,200 nm in length and 80 nm in diameter. Their helical nucleocapsids are 50 nm in diameter. Flaviviruses particles are relatively small (30–50 nm) and spherical, with surface projections and an electron-dense nucleocapsid. Bunyaviruses are also spherical and somewhat larger than flaviviruses at 80–120 nm. Distinctive patterns of surface glycoprotein units are noted in bunyaviruses of the different genera (Sanchez et al. 2001; Schmaljohn and Hooper 2001; Lindenbach and Rice 2001).

The features of protective immune responses vary among different VHF and are incompletely understood. For some VHF, such as those caused by Junin and Rift Valley fever (RVF) virus, resolution and viral clearance coincide with the appearance of neutralizing antibodies (Peters 1997; Peters et al. 1989). In nonlethal filovirus infection, IgM responses are detectable beginning in the first week of illness, and IgG responses follow shortly thereafter. However, fatal filovirus HF is associated with undetectable serum antibody response (Kortepeter et al. 2011). Correlating with evidence of immune suppression in fatal filovirus HF, massive peripheral blood lymphocyte apoptosis has been noted in severe human cases (Baize et al. 1999; Wauquier et al. 2010). By contrast, for certain VHF, notably Lassa fever, antibody titers do not correlate with prognosis, and neutralizing antibody responses are delayed, appearing well into convalescence (Johnson et al. 1987). Despite the variability in the role of the humoral response in clearance of infection by VHF agents, in most cases neutralizing antibody is capable of protecting experimental animals against viral challenge, providing the rationale for passive immunotherapy and use of antibody titer as a surrogate for immune protection in preclinical vaccine studies. It is widely believed that cell-mediated immunity plays a role in protection in many VHF, although detailed mechanisms have not been well defined (Grant-Klein et al. 2011; Bradfute and Bavari 2011; Baize et al. 2009).

There are several VHF in which pathogenic immune responses are documented or suspected. Epidemiologic and experimental data for dengue virus infections support the concept that subneutralizing levels of anti-dengue antibody favor macrophage uptake of virus, subsequent viral replication, and severe hemorrhagic disease. The majority of cases of dengue hemorrhagic fever/shock syndrome occur in dengue-immune individuals experiencing a secondary infection with a dengue virus of heterologous serotype; in vitro so-called antibody-dependent enhancement of infection has been demonstrated for dengue virus (Thomas and Endy 2011). The pathogenesis of hantavirus pulmonary syndrome is believed to involve T cell dependent, cytokine-mediated injury of pulmonary capillary endothelium (Zaki et al. 1995; Mori et al. 1999). T cell immune-mediated contributions to disease have also been posited for Lassa fever (Grant-Klein et al. 2011).

Most VHF agents encode proteins that antagonize host cell type I interferon induction or responses (Moraz and Kunz 2011; Thomas and Endy 2011; Vinh and Embil 2009; LaBeaud et al. 2010; Bradfute and Bavari 2011). Researchers have demonstrated early suppression of a variety of other inflammatory or immune responses in vitro, in experimental models, and in humans (Bowick et al. 2006; Mahanty et al. 2003, 2001; Sanchez et al. 2004; Scott and Aronson 2008). Of note, many VHF agents target macrophages and/or dendritic cells, impacting the ability of these cells to function in innate and adaptive immune responses (Schnittler and Feldmann 1998; Baize et al. 2004; Chaturvedi et al. 2006). Pathogenic details of each viral hemorrhagic fever will certainly differ, but an emerging general theme is that early dysregulation of interferon and other innate immune and signaling responses delays the generation of a protective adaptive response and allows for explosive viral replication and dissemination.

By definition, VHF are acute febrile diseases with evidence of increased vascular permeability or vascular damage. It is important to note that each of the VHF agents can cause acute febrile disease which ranges in severity; hemorrhage or other evidence of vascular damage is seen only in the most severe cases. In the case of dengue virus infections, the clinical spectrum of diseases is emphasized by terminology—dengue hemorrhagic fever and shock syndrome are clinically defined to include manifestations of increased vascular permeability or hemorrhage, whereas classic dengue fever lacks these features (Gubler 1998).

Incubation periods vary for the different VHF, from less than 3 days (Rift Valley fever, Kyasanur forest disease, yellow fever) to up to 21 days (hantavirus pulmonary syndrome, hemorrhagic fever with renal syndrome), although incubation periods of 1–2 weeks are typical for most VHF (Peters 1997). Following the insidious onset of fever, symptoms and signs are protean and may include severe abdominal pain, nausea, vomiting, diarrhea, arthralgia, rash, malaise, and prostration. Hemorrhagic manifestations range from petechiae of skin and mucous membranes to frank hemorrhage with hematochezia, epistaxis, and hemoptysis. Shock may be seen in the most severe cases, but this usually results from vascular leak and myocardial suppression rather than from blood loss.

There is substantial variation of clinical manifestations among various VHF (Ippolito et al. 2012). Pharyngitis and periorbital edema are typical of Lassa fever, whereas hemorrhage, seizures, and other acute neurologic manifestations are characteristic of Argentine hemorrhagic fever. There is significant renal involvement in hemorrhagic fever with renal syndrome, and liver injury dominates the clinical picture of yellow fever. Hantavirus (cardio)pulmonary syndrome is characterized by acute pulmonary edema following a febrile prodrome. Kyasanur forest disease, Omsk hemorrhagic fever, and Rift Valley fever demonstrate encephalitic features. Disseminated intravascular coagulation is characteristic of Rift Valley fever and may be seen in Ebola hemorrhagic fever but does not consistently accompany hemorrhage in arenavirus hemorrhagic fevers. Lethality also differs among VHF. Ebola hemorrhagic fever is the most severe, with case fatality rates of up to 90 %. Case fatality rates of less than 1 % are seen in Kyasanur forest disease and Omsk hemorrhagic fever; arenavirus hemorrhagic fever, yellow fever, Crimean-Congo hemorrhagic fever, and Rift Valley fever have intermediate case fatality rates (Table 15.1). In some VHF, characteristic sequelae may develop during convalescence; examples are retinal vasculitis in Rift Valley fever and sensorineural deafness in Lassa fever (Kahlon et al. 2010; Solbrig and McCormick 1991).

VHF are systemic diseases, without primary pulmonary involvement, and there is no role for lung biopsy in their diagnosis. In patients who come to autopsy, pulmonary congestion, edema, microscopic hemorrhage, and tracheobronchitis may be seen. Pleural effusions are commonly noted, especially for dengue hemorrhagic fever and hantavirus pulmonary syndrome (Bhamarapravati et al. 1967; Zaki et al. 1995). These findings are compatible with the overall systemic microvascular insufficiency and/or coagulopathy.

Pulmonary histopathologic studies of VHF reveal four general categories of lung lesions: hemorrhage, edema, diffuse alveolar damage, and interstitial pneumonitis. Bronchopneumonia noted in some reports likely reflects superimposed bacterial infection. In general, these overlapping pathologic patterns do not coincide with etiology, nor are the pathologic findings in the lungs pathognomonic for any of the VHF. There is no specific viral cytopathic effect associated with pulmonary lesions in VHF. Notably absent in all descriptions are vasculitis, endothelial necrosis, or significant microvascular thrombosis. Many of the pulmonary changes are secondary to systemic alterations in cardiovascular function, coagulation, or immune function. However, different VHF do tend to demonstrate different levels of pulmonary inflammation or alveolar injury (summarized in Table 15.2), correlating with general pathogenic mechanisms. For example, hantavirus pulmonary syndrome cases are characterized by interstitial pneumonitis with expansion of alveolar septa by mononuclear cells, including immunoblast-like lymphocytes. It is believed that elaboration of inflammatory cytokines by these infiltrating, activated lymphocytes in the alveolar interstitium plays a key role in the alveolar damage in lethal hantavirus pulmonary syndrome (Mori et al. 1999). This pathologic picture contrasts with hemorrhagic fever with renal syndrome, caused by another hantavirus, in which interstitial pneumonitis is not seen. Whereas arenaviruses and hantaviruses are generally non-cytopathic, filoviruses are known to be highly cytopathic in vivo and in vitro. Accordingly, lung lesions in Ebola hemorrhagic fever include well-developed hyaline membranes evidencing diffuse alveolar damage and abundant viral antigen associated with necrotic debris in the alveolar interstitium (Zaki and Goldsmith 1999).