| Virus | Disease | Geographic distribution of disease | Principal reservoir/vector | Annual cases | Case: infection ratio | Human-to-human transmissibility |
|---|---|---|---|---|---|---|
| Filoviridae | ||||||
| Ebolavirusa | Ebola HF | Sub-Saharan Africa | Fruit bat? | –b | 1:1 | High |
| Marburgvirus | Marburg HF | Sub-Saharan Africa | Fruit bat: Egyptian fruit bat (Rousettus aegyptiacus) | –b | 1:1 | High |
| Arenaviridaec, d | ||||||
| Old World Group | ||||||
| Lassa | Lassa fever | West Africa | Rodent: natal mastomys or multimammate rat (Mastomys natalensis) | 50 000–100 000 | 1:5–10 | Moderate |
| Lujoe | Lujo HF | Zambia | Unknown, presumed rodent | Unknown | Unknown | Moderate-to-high |
| New World Group | ||||||
| Junín | Argentine HF | Argentine pampas | Rodent: corn mouse (Calomys musculinus) | ~100 | 1:1.5 | Low |
| Machupo | Bolivian HF | Beni department, Bolivia | Rodent: large vesper mouse (Calomys callosus) | ≤50 | 1:1.5 | Low |
| Guanarito | Venezuelan HF | Portuguesa state, Venezuela | Rodent: cane mouse (Zygodontomys brevicauda) | ≤50 | 1:1.5 | Low |
| Sabiáf | Proposed name: Brazilian HF | Rural area near Sao Paulo, Brazil? | Unknown, presumed rodent | Unknown | 1:1.5 | Low? |
| Chapareg | Chapare HF | Cochabamba, Bolivia | Unknown, presumed rodent | Unknown | Unknown | Unknown |
| Bunyaviridaec | ||||||
| Old World Group | ||||||
| Hantaan, Seoul, Puumala, Dobrava-Belgrade, others | HF with renal syndrome | Hantaan: northeast Asia; Seoul: urban areas worldwide; Puumala and Dobrava-Belgrade: Europe | Rodent: Hantaan – striped field mouse (Apodemus agrarius); Seoul – Brown or Norway rat (Rattus norvegicus); Puumala – bank vole (Clethrionomys glareolus); Dobrava-Belgrade – yellow-necked field mouse (Apodemus flavicollis) | 50 000–150 000 | Hantaan: 1:1.5 Others: 1:20 | None |
| New World Group | ||||||
| Sin Nombre, Andes, Laguna Negra, others (see also Chapter 186, Hantavirus cardiopulmonary syndrome in the Americas) | Hantavirus cardiopulmonary syndrome | Americas | Rodent: Sin Nombre – deer mouse (Peromyscus maniculatus); Andes – long-tailed colilargo (Oligoryzomys longicaudatus); Laguna Negra – little laucha or small vesper mouse (Calomys laucha) | 50 000–150 000 | Sin Nombre: 1:1; others up to 1:20 | None, except for Andes virus |
| Rift Valley fever | Rift Valley fever | Sub-Saharan Africa, Madagascar, Saudi Arabia, Yemen | Domestic livestock/mosquitoes (sylvatic Aedes and others) | 100–100 000b,h | 1:100 | None |
| Crimean-Congo HF | Crimean-Congo HF | Africa, Balkans, southern Russia, Middle East, India, Pakistan, Afghanistan, western China | Wild and domestic vertebrates/tick (primarily Hyalomma species) | ~500 | 1:1–2 | High |
| Flaviviridae | ||||||
| Yellow fever | Yellow fever | Sub-Saharan Africa, South America up to Panama | Monkey/mosquito (Aedes aegypti, other Aedes and Hemagogus species) | 5000–200 000i | 1:2–20 | None |
| Dengue | Dengue HF | Tropics and subtropics worldwide | Human/mosquito (Ae. aegypti and Ae. albopictus) | 100 000–200 000i | 1:10–100 depending on age, previous infection, genetic background, and infecting serotype | None |
| Omsk HF | Omsk HF | Western Siberia | Rodent/tick (primarily Dermacentor and Ixodes species) | 100–200 | Unknown | Not reported |
| Kyasanur Forest disease | Kyasanur Forest disease | Karnataka state, India; Yunnan Province, China; Saudi Arabia | Vertebrate (rodents, bats, birds, monkeys, others)/tick (Haemophysalis species and others) | ~500 | Unknown | Not reported, but laboratory infections have occurred |
| Alkhumra HFj | Proposed name: Alkhumra HF | Saudi Arabia, Egypt | Ticks? | ≤50 | Unknown | Not reported |
Abbreviation: HF = hemorrhagic fever.
a Six species or subtypes of Ebolavirus are recognized with varying associated case-fatality ratios (see Table 194.2). All are endemic to sub-Saharan Africa, with the exceptions of Reston ebolavirus that is found in the Philippines and Lloviu ebolavirus which was detected in bats in Spain.
b Although some endemic transmission of the filoviruses (Ebolavirus>Marburgvirus) and Rift Valley fever virus occurs, these viruses have most often been associated with outbreaks. Filovirus outbreaks are typically less than 100 cases and have never been greater than 500.
c The virus families Arenaviridae and Bunyaviridae are serologically, phylogenetically, and geographically divided into Old World (i.e., Africa) and New World (i.e., the Americas) complexes.
d In addition to the arenaviruses listed in the table, Flexal and Tacaribe viruses have caused human disease as a result of laboratory accidents. Another arenavirus, Whitewater Arroyo, has been noted in sick persons in California but its role as a pathogen has not been clearly established.
e Discovered in 2008. Only 5 cases (4 of them fatal) from one outbreak have been noted. The index case came to South Africa from Zambia.
f Discovered in 1990. Only 3 cases (1 fatal) have been noted, 2 of them from laboratory accidents.
g Discovered in 2003 from a small outbreak from which blood was obtained from one fatal case and Chapare virus isolated. Few other details have been reported.
h Although Rift Valley fever virus can be found throughout sub-Saharan Africa, large outbreaks usually occur in East Africa’s Rift Valley region.
i Based on estimates from the World Health Organization. Significant underreporting occurs. Incidence may fluctuate widely in place and time.
j Alkhumra is considered by some to be a variant of Kyasanur Forest disease virus. Disagreement exists over the proper spelling of the virus, written as “Alkhurma” in some publications.
Epidemiology
Natural maintenance and transmission to humans
With the exception of dengue virus (see Chapter 183, Dengue), for which humans can now be considered to be the reservoir, hemorrhagic fever viruses are zoonotic and maintained in nature in mammals (Table 194.1). The endemic area of any given VHF is thus restricted by the distribution of its natural reservoir and/or arthropod vector, although the distribution of the virus and disease are often less vast than that of the reservoir. Infection is presumed to most often result from inadvertent inoculation of virus-contaminated reservoir excreta into mucous membranes or broken skin or, in the case of the arbovirus VHFs, mosquito or tick bite. Aerosol transmission has been suggested but there are few data to confirm or refute this route of exposure and empiric field observations suggest that aerosol transmission is not a predominant mode of spread, if it occurs at all. Nevertheless, artificially produced aerosols can infect laboratory animals, with obvious implications for potential use as bioweapons.
Human-to-human transmission
Secondary human-to-human transmission occurs in many VHFs, usually through direct contact with contaminated blood or body fluids (Table 194.1), although secondary attack rates are generally low (15%–20%). Infection probably occurs most often through oral or mucous membrane exposure. Again, there are few data on aerosol spread. Large outbreaks are almost always the result of amplification in healthcare settings in which basic infection control measures have broken down, usually in areas of extreme poverty or civil strife. The risk of transmission during the incubation period or from asymptomatic persons is negligible, although a case of Argentine hemorrhagic fever was reported due to blood transfusion from a donor who was asymptomatic. Although rare, sexual transmission during early convalescence has been suspected, best documented for Ebola, Marburg, Lassa, and Junín viruses. Despite the ease of modern-day travel, imported VHF cases remain extremely rare.
Pathology and pathogenesis
Microvascular instability, increased vascular permeability, and impaired hemostasis are the pathophysiologic hallmarks of VHF, although the mechanisms vary with each virus. Mortality usually results not from exsanguination but from a process akin to septic shock, with insufficient effective circulating intravascular volume leading to cellular dysfunction and multiorgan system failure. In fact, external bleeding is seen in a minority of cases of some VHFs (Table 194.2).
| Disease | Incubation period (days) | Onset | Bleeding | Rash | Jaundice | Heart | Lung | Kidney | Central nervous system | Eye | Case fatality ratio | Clinical management |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Filoviridae | ||||||||||||
| Ebola HF | 3–21 | Variable | ++ | +++ | + | ++? | + | + | + | + | 40%–85%a | Supportive |
| Marburg HF | 3–21 | Abrupt | ++ | +++ | + | ++? | + | + | + | + | 22%–85%b | Supportive |
| Arenaviridae | ||||||||||||
| Lassa fever | 5–16 | Gradual | + | +c | 0 | ++ | + | 0 | + | 0 | 20% | Ribavirin |
| Lujo HF | 9–13 | Abrupt | ++ | + | 0 | ? | + | + | + | 0 | 80% | Ribavirin |
| South American HFsd | 4–14 | Gradual | +++ | + | 0 | ++ | + | 0 | +++ | 0 | 15%–40% | Ribavirin, convalescent plasma |
| Bunyaviridae | ||||||||||||
| Hemorrhagic fever with renal syndrome | 9–35 | Abrupt | +++ | 0 | 0 | ++ | + | +++ | + | 0 | <1–50% depending on specific virus | Ribavirin |
| Hantavirus pulmonary syndrome | 7–35 | Gradual | 0 (except for Andes virus infection) | 0 | 0 | +++ | +++ | + | + | 0 | <1–50% depending on specific virus | Supportive, ECMO? |
| Rift Valley fevere | 2–5 | Abrupt | ++ | + | ++ | +? | 0 | + | ++ | ++ | Up to 50% in severe forms | Ribavirin? |
| Crimean-Congo HF | 1–12f | Abrupt | +++ | 0 | ++ | +? | + | 0 | + | 0 | 15%–30% | Ribavirin |
| Flaviviridae | ||||||||||||
| Yellow fever | 3–6 | Abrupt | +++ | 0 | +++ | ++ | + | ++ | ++ | 0 | 20%–50% | Supportive |
| Dengue HF | 3–15 | Abrupt | ++ | +++ | + | ++ | + | 0 | + | 0 | Untreated: 10–15% Treated: ≤1% | Supportive |
| Omsk HF | 3–8 | Abrupt | ++ | 0 | 0 | + | ++ | 0 | +++ | + | 1%–3% | Supportive |
| Kyasanur Forest disease | 3–8 | Abrupt | ++ | 0 | 0 | + | ++ | 0 | +++ | + | 3%–5% | Supportive |
| Alkhumra HFg | 3–8 | Abrupt | ++ | + | + | + | + | 0 | ++ | + | 20%–25% | Supportive |
Abbreviations: ECMO = extracorporeal membrane oxygenation; HF = hemorrhagic fever.
a Six species or subtypes of Ebolavirus are recognized with varying associated case-fatality ratios: Zaire – 85%, Sudan – 55%, Bundibugyo – 40%, Tai Forest (also called Cote d’Ivoire) – 0 (only one recognized case, who survived), Reston – 0 (not pathogenic to humans), Lloviu – no human infections recognized.
b The case fatality ratio was 22% in the first recognized outbreak of Marburg HF in Germany and Yugoslavia in 1967 but has been consistently over 80% in outbreaks in central Africa where the virus is endemic. Possible reasons for this discrepancy include differences in quality of care, strain pathogenicity, route and dose of infection, underlying prevalence of immunodeficiency and comorbid illnesses, and genetic susceptibility.
c A morbilliform or maculopapular skin rash almost always occurs in persons with lighter skin, who are usually expatriates, but, for unclear reasons, is rarely present in darker-skinned Africans from the endemic area.
d Data are insufficient to distinguish between the syndromes produced by the various arenaviruses found in the Americas. They are thus frequently grouped as the “South American hemorrhagic fevers.”
e HF, encephalitis, and retinitis may be seen in Rift Valley fever independently of each other.
f The incubation period of Crimean-Congo HF varies with the mode of transmission: typically 1–3 days after tick bite and 5–6 days after contact with infected animal blood or tissues.
g Based on preliminary observations. Fewer than 100 cases have been reported.
Key: 0 = sign not typically noted/organ not typically affected, + = sign occasionally noted/organ occasionally affected, ++ = sign commonly noted/organ commonly affected, +++ = sign characteristic/organ involvement severe.
After inoculation, virus typically replicates in dendritic cells before disseminating to regional lymph nodes and then through the lymph and blood monocytes to a broad array of organs, including liver, spleen, lymph node, adrenal gland, lung, and endothelium. The particular organs most affected vary with the VHF (Table 194.2). Virus interaction with immune cells, especially macrophages and endothelial cells, results in cell activation and the unleashing of an inflammatory vasoactive process consistent with the systemic inflammatory response syndrome. Impaired hemostasis may entail endothelial cell, platelet, and/or coagulation factor dysfunction. Disseminated intravascular coagulation (DIC) is frequent in some VHFs (Table 194.2). The degree of tissue damage varies with the VHF and may be mediated either through necrosis or apoptosis. Cardiac inotropy may be inhibited in some VHFs, further impairing organ perfusion. Adrenal or pituitary gland necrosis with consequent vascular collapse has been postulated but not specifically demonstrated. Virus is cleared rapidly from the blood in survivors but may remain for weeks or months in a few immunologically protected sites, such as the chambers of the eye, central nervous system, and gonads, the latter resulting in the aforementioned sexual transmission during convalescence.
The pathogenesis of most VHFs appears to be related to unchecked viremia, with most fatal cases failing to mount a significant antibody response, in some cases due to virus-induced suppression of the host adaptive immune response. Virus can be found in a wide variety of body fluids during the acute illness, including blood, saliva, stool, and breast milk. Inflammatory cell infiltration is usually mild, consisting of a mix of mononuclear cells and neutrophils. However, in dengue, yellow fever, and hantavirus infections (see Chapter 186, Hantavirus cardiopulmonary syndrome in the Americas), in which viremia is usually cleared prior to the most severe phase of the disease, the host immune response may play a detrimental role. The unique process of antibody-mediated enhancement may facilitate the development of dengue hemorrhagic fever (see Chapter 183, Dengue).
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