CBRNE - Viral Hemorrhagic Fevers 

Viral hemorrhagic fevers (VHFs) are a group of febrile illnesses caused by RNA viruses from several viral families. These highly infectious viruses lead to a potentially lethal disease syndrome characterized by fever, malaise, vomiting, mucosal and gastrointestinal (GI) bleeding, edema, and hypotension. The 4 viral families known to cause VHF disease in humans include the Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. General characteristics of these viral families can be found in the table below.

Table. Viral Families Causing Viral Hemorrhagic Fever (Open Table in a new window)

Arenaviridae

Arenaviridae are spread to humans by rodent contact and include Lassa virus in Africa and several rare South American hemorrhagic fevers such as Machupo, Junin, Guanarito, and Sabia. Lassa virus is the most clinically significant of the Arenaviridae, accounting for serious morbidity and mortality in West Africa.

Lassa fever first appeared in Lassa, Nigeria, in 1969. It has been found in all countries of West Africa and is a significant public health problem in endemic areas. In populations studied, Lassa fever accounts for 5-14% of hospitalized febrile illnesses. Its natural reservoir is a small rodent whose virus-containing excreta is the source of transmission.

Bunyaviridae

This group includes Rift Valley fever (RVF) virus, Crimean-Congo hemorrhagic fever (CCHF) virus, and several hantaviruses. The RVF and CCHF viruses are both arthropod-borne viruses. RVF virus, an important African pathogen, is transmitted to humans and livestock by mosquitos and by the slaughter of infected livestock. CCHF virus is carried by ticks and causes a fulminant, highly pathogenic form of VHF notable for aerosol transmission of infective particles. Outbreaks of CCHF have occurred in Africa, Asia, and Europe.

Many hantaviruses are spread worldwide, causing 2 major syndromes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). They are divided into Old World hantaviruses (such as the prototypical Hantaan virus of Korea), which generally cause HFRS, and New World hantaviruses, causing HPS. Rodents carry both types. A previously undiscovered Hantavirus, Sin Nombre virus, was the cause of an outbreak of highly lethal HPS in the southwestern US in 1993. More than 450 cases have been identified in the US since 1993 with a 35% mortality rate.^[1]

Filoviridae

The most notorious of the VHF viruses, including Ebola and Marburg viruses, belong to the Filoviridae family. Ebola virus first was described in 1976 after outbreaks of a febrile, rapidly fatal hemorrhagic illness were reported along the Ebola River in Zaire (now the Democratic Republic of the Congo) and Sudan. Sporadic outbreaks have continued since that time, usually in isolated areas of central Africa. An outbreak in Kikwit, Zaire, in 1995 led to 317 confirmed cases, with an 81% mortality rate. Two thirds of the patients were among health care workers caring for infected individuals. An outbreak in Uganda in late 2000 resulted in 425 cases and claimed 225 lives.

In September 2007, the cause of a VHF outbreak in the Congo was identified as Ebola. Ebola has 4 distinct subtypes: Ebola-Zaire, Ebola-Sudan, Ebola-Ivory Coast, and Ebola-Reston, a form that causes illness in nonhuman primates, and as has been recently discovered, in pigs.^[2] A 2007 Ebola outbreak in Uganda, however, has been attributed to a new form of Ebola. This new Ebola subtype, which appears to be closely related to Ebola-Ivory Coast, has been given the proposed name Bundibugyo Ebola virus (named after the Bundibugyo district in Western Uganda).^[3]

The natural reservoir of Ebola virus remains unknown, although some recent studies have suggested that bats may be a potential reservoir for Ebola.^[4]

Marburg virus, named after the German town where it first was reported in 1967, is another highly pathogenic member of the Filoviridae family that is traced to central Africa. As in Ebola, the natural host for the virus is unknown. Marburg virus was contracted by a traveler to central Africa in 1987 and has been endemic since 1998 in Durba, Democratic Republic of the Congo, and in persons exposed in gold mines. Marburg virus was determined to be the causative agent in a 2004-2005 outbreak of hemorrhagic fever in Angola that led to 252 confirmed cases and 227 deaths (90% case-fatality rate).

Flaviviridae

Yellow fever and dengue fever are the most well known diseases caused by flaviviruses. Both are mosquito-borne; yellow fever is found in tropical Africa and South America, and dengue fever is found in Asia, Africa, and the Americas. They are notable for their significant effect on prior military campaigns and their continued presence throughout endemic areas.

Due to a resurgence in the last 3 decades, dengue fever is now considered second only to malaria in terms of importance as a tropical disease. Multiple recent large outbreaks have occurred throughout the tropics, with the most severe outbreaks occurring in Southeast Asia and the western Pacific regions. Transmission is via the bite of the infected female Aedes mosquito, although dengue can also be transmitted via transfusion.^[5]

The primary defect in patients with viral hemorrhagic fever (VHF) is that of increased vascular permeability. Hemorrhagic fever viruses have an affinity for the vascular system, leading initially to signs such as flushing, conjunctival injection, and petechial hemorrhages, usually associated with fever and myalgias. Later, frank mucous membrane hemorrhage may occur, with accompanying hypotension, shock, and circulatory collapse. The relative severity of the clinical presentation may vary depending on the virus in question, amount, and route of exposure.

In acute disease, patients are extremely viremic, and messenger ribonucleic acid (mRNA) evidence of multiple cytokine activation exists. In vitro studies reveal these cytokines lead to shock and increased vascular permeability, the basic pathophysiologic processes most often seen in viral hemorrhagic fever infection. Another prominent pathologic feature is pronounced macrophage involvement. Inadequate or delayed immune response to these novel viral antigens may lead to rapid development of overwhelming viremia. Extensive infection and necrosis of affected organs also are described. Hemorrhagic complications are multifactorial and are related to hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes. Aerosol transmission of some viral hemorrhagic fever infections is reported among nonhuman primates and likely is a mode of transmission in patients with severe infection.

Multisystem organ failure affecting the hematopoietic, neurologic, and pulmonary systems often accompanies the vascular involvement. Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, CCHF, and yellow fever. Renal failure with oliguria is a prominent feature of HFRS seen in Hantavirus infection and may be seen in other VHFs as intravascular volume depletion becomes more pronounced. Bleeding complications are particularly prominent with Ebola, Marburg, CCHF, and the South American arenaviruses.

Although the pathophysiology of dengue infection is complex and incompletely understood, severe dengue infection can be differentiated from milder forms by the presence of increased vascular permeability. The greatest risk factor for severe dengue infection is secondary infection with a dengue serotype different from the initial dengue infection. This increased vascular permeability is thought to be secondary to widespread T-cell activation and apoptosis and is also thought to be related to a process known as antibody-dependent enhancement, best described as the balance between neutralizing versus enhancing antibodies after an initial dengue infection, which can contribute to the severity of secondary dengue infection.

Frequency

United States

Cases of viral hemorrhagic fever in the United States are extremely rare and usually are found in patients who recently have visited endemic areas or among those with potential occupational exposure to hemorrhagic fever viruses. Lassa fever has been reported in the United States in travelers from West Africa and was most recently reported in the United States in August 2004. In 1994, a virologist working with Sabia, a Brazilian HF virus, accidentally contracted the disease. Sporadic cases of HPS due to Sin Nombre virus continue to be reported throughout the southwestern United States.^[6]

No human cases of Ebola or Marburg virus disease have been reported in the United States. In 1989, an outbreak of hemorrhagic fever among imported macaque monkeys in Reston, Virginia, led to the discovery of Ebola-Reston, a variant of Ebola virus that originated in the Philippines and does not cause disease in humans.

An estimated 100-200 cases of imported dengue fever are reported in the United States each year. Occasional dengue outbreaks have occurred in the United States, and well-documented local transmission of dengue continues to occur in south Florida, specifically in Key West.^[7]

International

Lassa fever is responsible for an estimated 100,000-300,000 infections per year, with 5,000 deaths. Cases have been reported throughout West Africa, particularly in Nigeria, Sierra Leone, Guinea, and Liberia. Other arenaviruses are responsible for sporadic VHF outbreaks throughout South America.

Rift Valley fever (RVF) virus and Crimean-Congo hemorrhagic fever (CCHF) are responsible for intermittent epidemics in Africa (for RVF) and in areas of Africa, Asia, and Europe (for CCHF). HFRS due to Hantavirus infection continues to be an ongoing health concern, particularly in Asia, affecting up to 200,000 patients annually.

Ebola virus appears sporadically in endemic areas of the former Zaire and Sudan. Ebola virus also has been reported in Gabon, the Ivory Coast, and Uganda. Outbreaks appear to propagate in hospital settings, often involving health care providers.

Yellow fever continues to be a serious problem in tropical areas of South America and Africa, where vaccination is not widespread. The World Health Organization estimates that approximately 200,000 cases per year occur in Africa.

Dengue HF is endemic in Southeast Asia, Africa, Central America, and South America, and the WHO estimates that 50-100 million cases occur annually. In the first 3 months of 2011, Rio de Janeiro had already recorded more than 10,000 cases of dengue infection.^[8]

Mortality/Morbidity

Case-fatality rates of patients with VHF vary from less than 10% (eg, in dengue HF) to approximately 90%, as has been reported in patients with Ebola-Zaire and the recent Angola Marburg outbreak. The most recent outbreak of Ebola-Sudan in Uganda had a 50% case-fatality rate.

Complications from VHF infection include retinitis, orchitis, hepatitis, transverse myelitis, and uveitis. In patients who recover from Lassa fever infection, deafness is the most common complication. Spontaneous abortion also is common. Renal insufficiency is associated with HFRS infection.

Race

No racial predilection has been identified, although cases have originated in African areas.

Sex

No predilection for either sex has been identified.

Age

VHF affects all ages according to exposure and local demographics.