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Viral hemorrhagic fever (VHF)

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Related Terms
  • Arenavirus, Argentine hemorrhagic, Bolivian hemorrhagic fever, Brazilian hemorrhagic fever, bunyavirus, filovirus, flavivirus, GTOV, guanarito virus, junin virus, JUNV, lassa virus, LASV, LMCV, lymphocytic choriomeningitis virus, machupo virus, MACV, mosquitoes, rats, sabia virus, SABV, ticks, Venezuelan hemorrhagic fever, VHF.

Background
  • Viral hemorrhagic fever (VHF) is a severe, often fatal, illness caused by four distinct families of viruses: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. These viruses are all RNA viruses; are dependent upon a rodent, tick, or mosquito host for survival; have no drug treatment or cure, with few exceptions; and are restricted geographically to the areas where the host lives. The viruses that cause VHF are found all over the world but each virus is associated with one or more host species. Some VHF infections are rare while others affect millions of people each year.
  • VHF is spread to humans by contact with urine, saliva, or feces from infected rodents or a bite from an insect, such as a mosquito or tick. Each virus is usually associated with a specific insect or rodent host or closely related species. These animals maintain the virus and are not known to exhibit any symptoms of viral illness.
  • Some VHF organisms can enter the body by inhaled airborne particles or by direct contact with broken or chafed skin. Some arenaviruses, such as Machupo and Lassa viruses, can be spread by person-to-person contact. For example, hospital workers caring for infected individuals can acquire the infection.
  • Most VHF organisms are totally dependent on their host organism for replication and survival. The cotton rat, multimammate rat, house mouse, deer mouse, and other field rodents are examples of rodent hosts. The hosts of some VHF organisms, such as Marburg and Ebola, are currently unknown.

Signs and symptoms
  • All viral hemorrhagic fevers (VHF) begin gradually with flu-like symptoms that include fever, muscular aches, and cough. If the disease progresses, abdominal pain, vomiting, and diarrhea occur. The next stage involves sore throat, muscle pain, headache, chest pain, nausea and vomiting, facial swelling, conjunctivitis, or inflammation and swelling of the eyelids and portions of the eyeballs, and bleeding from the gums, intestinal tract, and other internal organs. If the disease progresses, individuals may develop temporary or permanent hearing loss, bleeding from the mouth and nose, blood in the urine, fluid in the lungs (pulmonary edema), and brain inflammation (encephalitis). In late stages, shock, seizures, coma, and death can occur.

Diagnosis
  • In many instances, humans infected with viral hemorrhagic fever (VHF) remain healthy and show no symptoms. In about 20% of cases, individuals develop severe disease that affects multiple systems of the body, including the liver, spleen, and kidneys. Hemorrhage and tissue damage may occur in these organs. This severe form of the disease has fatality rates ranging from 15% to 100%.
  • In the early stages of viral hemorrhagic fever (VHF), diagnosis is difficult because the symptoms, such as fever, muscular aches, and cough, resemble those of many other viral infections. A definite diagnosis can be made only in highly specialized laboratories. The arenavirus is composed of ribonucleic acid (RNA), which is a long chain of genetic material. The arenavirus RNA can be detected in patient specimens with a nested reverse transcriptase polymerase chain reaction (RT-PCR) assay, a laboratory procedure that is currently the most sensitive technique for detecting a specific type of RNA. In addition to identifying the RNA, this technique can determine the amount present in a sample.

Complications
  • One type of arenavirus, the lymphocytic choriomeningitis virus (LMCV), causes lymphocytic choriomeningitis (LCM). LCM infections have been reported in Europe, the Americas, Japan, and Australia. Bunyavirus, filovirus, and flavivirus infections all begin as arenavirus infections and can progress to internal bleeding.
  • Hantavirus pulmonary syndrome (PS) is a deadly disease that can cause dangerously low blood pressure (hypotension) and respiratory failure.
  • The Ebola virus is extremely deadly, having a mortality rate of 20% to 90%.
  • Flaviviruses are a family of viruses transmitted by mosquitoes and ticks. These viruses cause yellow fever, Kyasanur forest disease, Omsk hemorrhagic fever, and dengue fever. Dengue fever is one of the most common and widespread types of VHF. Fifty to 100 million cases occur worldwide each year.

Treatment
  • In the past several years, much progress has been made in understanding the molecular biology of viral hemorrhagic fever (VHF) viruses and how they cause disease. However, drugs or vaccines are currently unavailable for the treatment of most VHFs.
  • The antiviral drug ribavirin is effective for Lassa fever, which is caused by an arenavirus, if given early in the course of the disease. However, use of ribavirin is associated with birth defects. Therefore, women of childbearing age who are prescribed ribavirin should be advised to use birth control. Other antiviral drugs are under investigation for the treatment of VHF.
  • Treatment is generally aimed at the reduction of symptoms and prevention of management of complications. Treatment should ensure adequate fluids and electrolytes, maintenance of proper breathing, monitoring of kidney and bladder function, and treatment of any secondary infections.

Integrative therapies
  • Note: Currently, there is a lack of scientific evidence for the use of integrative therapies in the treatment or prevention of viral hemorrhagic fever. The therapies below have been studied for use in viral infections in general, should be used only under the supervision of a qualified healthcare provider, and should not be used in replacement of other proven therapies.
  • Unclear or conflicting scientific evidence:
  • Alizarin: Limited available evidence suggests that alizarin may improve various herpes infections. Additional study is needed before a firm recommendation can be made. Avoid if allergic or hypersensitive to alizarin or any plants in the Rubiaceae family. Alizarin may be toxic and should not be handled for long periods of time, rubbed in the eyes, or eaten. Avoid if pregnant or breastfeeding.
  • Astragalus: Astragalus products are derived from the roots of Astragalus membranaceus or related species, which are native to China. In traditional Chinese medicine, astragalus is commonly found in mixtures with other herbs, and is used in the treatment of numerous ailments, including heart, liver, and kidney diseases, as well as cancer, viral infections, and immune system disorders. Anti-viral activity has been reported with the use of astragalus in laboratory and animal studies. Limited human research has examined the use of astragalus for viral infections in the lung, heart (pericarditis, myocarditis, endocarditis), liver (hepatitis B and C), cervix (papilloma virus), and in HIV disease. Studies have included combinations of astragalus with the drug interferon, or as a part of herbal mixtures. However, most studies have been small and poorly designed. Due to a lack of well-designed research, firm conclusions cannot be drawn.
  • Avoid if allergic to astragalus, peas, or any related plants, or with a history of Quillaja bark-induced asthma. Avoid with aspirin or aspirin products or herbs or supplements with similar effects. Avoid with inflammation (swelling) or fever, stroke, transplant or autoimmune diseases (like HIV/AIDS). Stop use two weeks before surgery/dental/diagnostic procedures with a risk of bleeding and avoid use immediately after these procedures. Use cautiously with bleeding disorders, diabetes, high blood pressure, lipid disorders or kidney disorders. Use cautiously with blood-thinners, blood sugar drugs, or diuretics or herbs and supplements with similar effects. Avoid if pregnant or breastfeeding.
  • Blessed thistle: Blessed thistle leaves, stems, and flowers have traditionally been used in "bitter" tonic drinks and in other preparations taken by mouth to enhance appetite and digestion. Evidence of activity of blessed thistle against herpes viruses, influenza, or poliovirus is currently lacking in available preliminary research. Effects of blessed thistle (or chemicals in blessed thistle called lignans) against HIV are not clear. Human research of blessed thistle as a treatment for viral infections is lacking.
  • Avoid if allergic to blessed thistle, mugwort, bitter weed, blanket flower, chrysanthemum, coltsfoot, daisy, dandelion, dwarf sunflower, goldenrod, marigold, prairie sage, ragweed, Echinacea or any plants of the Asteraceae or Compositae families. Use cautiously with peptic ulcer disease. Avoid with a history of bleeding diseases or gastroesophageal reflux disease (GERD), or if taking drugs for blood thinning, stroke, stomach diseases, or to control stomach acid. Avoid if pregnant or breastfeeding. Stop use two weeks before surgery/dental/diagnostic procedures with bleeding risk and do not use immediately after these procedures.
  • Cranberry: Cranberry is popular as a food, and is often consumed as relish, sauce, jam, juice, or dried berries. Limited laboratory research has examined the antiviral activity of cranberry. Reliable human studies supporting the use of cranberry in this area are currently lacking. Avoid if allergic to cranberries, blueberries, or other plants of the Vaccinium genus. Sweetened cranberry juice can affect blood sugar levels. Use cautiously with history of kidney stones. Avoid more than the amount usually found in foods if pregnant or breastfeeding.
  • Focusing: Early research showed that increased experiential involvement (an indication of focusing taking place) did not have an effect on antibody titers to Epstein-Barr virus. More studies in the area of immune function and antibody production are required before a recommendation can be made in this area.
  • Green tea: Preliminary research suggests that green tea decreases viral load in carriers of the HTLV-1 virus. Additional well-designed controlled research is needed before a recommendation can be made for or against use of green tea in the treatment of HTLV-1 carriers. Avoid if allergic or hypersensitive to caffeine or tannin. Use cautiously with diabetes or liver disease.
  • Sorrel: Historically, sorrel has been used as a salad green, spring tonic, diarrhea remedy, weak diuretic, and soothing agent for irritated nasal passages. Sorrel has been used with other herbs to treat bronchitis and sinus conditions in Germany since the 1930s. There is currently a lack of well-conducted published studies that demonstrate antiviral or antibacterial activity of sorrel. In available laboratory study, sorrel did not demonstrate activity against herpes simplex virus-1, herpes simplex virus-2, HIV, B. subtilis, E. coli, Proteus morganii, Pseudomonas aeruginosa, P. vulgaris, Serratia marcescens, or Staphylococcus aureus.
  • Avoid with a known allergy to sorrel. Avoid large doses of sorrel because there have been reports of toxicity and death, possibly due to oxalates found in sorrel. Tinctures contain high levels of alcohol and should be avoided when driving or operating heavy machinery. High alcohol sorrel formulations may also cause nausea or vomiting when taken with the prescription drugs metronidazole (Flagyl®) or disulfiram (Antabuse®). Avoid if pregnant or breastfeeding.
  • Turmeric: The rhizome (root) of turmeric (Curcuma longa Linn.) has long been used in traditional Asian medicine to treat gastrointestinal upset, arthritic pain, and "low energy." Evidence suggests that turmeric may help treat viral infections. However, there is currently not enough human evidence in this area. Well-designed trials are needed to determine if these claims are true.
  • Avoid if allergic or hypersensitive to turmeric, curcumin, yellow food colorings, or plants belonging to the Zingiberaceae (ginger) family. Use cautiously with a history of bleeding disorders, immune system deficiencies, liver disease, diabetes, hypoglycemia, or gallstones. Use cautiously with blood-thinners, such as warfarin (like Coumadin®), and blood sugar-altering medications. Avoid in medicinal amounts if pregnant or breastfeeding. Turmeric should be stopped prior to scheduled surgery.
  • Vitamin A: The role of vitamin A in the prevention, transmission, or treatment of HIV is controversial and not well established. A clear conclusion cannot be formed based on the available scientific research. Vitamin A supplementation has also been suggested to help prevent NoV infection in children and reduce the symptoms associated with NoV infections. Additional research is needed in this area.

Prevention
  • Prevention of viral hemorrhagic fever (VHF) includes avoiding mosquito bites and promoting a clean community environment that discourages rodents from entering homes. Effective measures include insecticide-soaked mosquito nets, insect repellants, full-length clothing, staying indoors between dawn and dusk, storing food in rodent-proof containers, and disposing garbage away from the home.
  • Vaccines and treatment for the vast majority of VHF infections are at present extremely limited. Current treatment primarily consists of supportive measures, such as provision of fluids and electrolytes and maintenance of normal blood pressure.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
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  5. Dylla DE, Michele DE, Campbell KP, et al. Basolateral entry and release of new and old world arenaviruses from human airway epithelia. J Virol. 2008 Jun;82(12):6034-8.
  6. Ebihara H, Groseth A, Neumann G, et al. The role of reverse genetics systems in studying viral hemorrhagic fevers. Antiviral Res. 2008 Apr;78(1):79-90.
  7. Gowen BB, Holbrook MR. Animal models of highly pathogenic RNA viral infections: hemorrhagic fever viruses. Antiviral Res. 2008 Apr;78(1):79-90.
  8. Ha SJ, Mueller SN, Wherry EJ, et al. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J Exp Med. 2008 Mar 17;205(3):543-55.
  9. Lee AM, Rojek JM, Spiropoulou CF, et al. Unique small molecule entry inhibitors of hemorrhagic fever arena viruses. J Biol Chem. 2008 May 12.
  10. Monath TP. Treatment of yellow fever. Antiviral Res. 2008 Apr;78(1):116-24.
  11. Natural Standard: The Authority on Integrative Medicine. . Copyright © 2008. Accessed May 28, 2008.
  12. Swenson DL, Warfield KL, Larsen T, et al. Monovalent virus-like particle vaccine protects guinea pigs and nonhuman primates against infection with multiple Marburg viruses. Expert Rev Vaccines. 2008 May;7(4):417-29.
  13. Whitmire JK, Eam B, Whitton JL. Tentative T cells: memory cells are quick to respond, but slow to divide. PLoS Pathog. 2008 Apr 11;4(4):e1000041.
  14. Zhang QF, Li JD, Li WH, et al. Development and application of a two-step MacELISA for the early diagnosis of hemorrhagic fever with renal syndrome. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2008 Mar;22(1):6-8.

Causes
  • Viral hemorrhagic fever (VHF) is spread to humans by contact with urine, saliva, or feces from infected rodents or a bite from an insect, such as a mosquito or tick. Each virus is usually associated with a specific insect or rodent host or closely related species. These animals maintain the virus and are not known to exhibit any symptoms of viral illness.
  • Some VHF organisms can enter the body by inhaled airborne particles or by direct contact with broken or chafed skin. Some arenaviruses, such as Machupo and Lassa viruses, can be spread by person-to-person contact. For example, hospital workers caring for infected individuals can acquire the infection.

Risk factors
  • Viral hemorrhagic fever (VHF) is spread to humans by contact with urine, saliva, or feces from infected rodents or a bite from an insect, such as a mosquito or tick. Some VHF organisms can enter the body by inhaled airborne particles or by direct contact with broken or chafed skin. Each virus is usually associated with a specific insect or rodent host or closely related species. These animals maintain the virus and are not known to exhibit any symptoms of viral illness. Contact with these substances and hosts therefore places individuals at higher risk of contracting VHF.
  • Travel to regions in which VHF is endemic also places individuals at higher risk. Risk may increase depending on types of activities, length of stay, and rate of transmission of a specific disease.
  • Hospital workers treating patients with VHF and laboratory researchers working with the viruses that cause VHF are also at higher risk.

Types of the disease
  • Arenaviruses: In some parts of the world, arenavirus infections are fairly common in humans. Arenavirus infections range from inconsequential (i.e., a mild flu-like illness that resolves without treatment) to fatal. Arenaviruses are divided into two groups: the New World or Tacaribe complex and the Old World or Lassa complex. In Africa (Old World), the virus that causes VHF is the Lassa virus (LASV; Lassa fever). In South America (New World), arenavirus infections are caused by the Machupo virus (MACV), which causes Bolivian hemorrhagic fever; the Guanarito virus (GTOV), which causes Venezuelan hemorrhagic fever; the Junin virus (JUNV), which causes Argentine hemorrhagic fever; and the Sabia virus (SABV), which causes Brazilian hemorrhagic fever.
  • One type of arenavirus, the lymphocytic choriomeningitis virus (LMCV), causes lymphocytic choriomeningitis (LCM). LCM infections have been reported in Europe, the Americas, Japan, and Australia. Bunyavirus, filovirus, and flavivirus infections all begin as arenavirus infections and can progress to internal bleeding.
  • Bunyaviruses: With one notable exception, bunyaviruses are transmitted by mosquitoes, ticks, or sand flies. These insects are known as bunyavirus vectors. A vector is an organism that can transmit a virus or bacterium from one organism to another without developing the illness itself. Hantaviruses are transmitted by infected rodents through exposure to their urine, feces, or saliva. Rarely, humans are infected through a rodent bite. Hantavirus pulmonary syndrome (PS) is a deadly disease that can cause dangerously low blood pressure (hypotension) and respiratory failure.
  • Filoviruses: The first genus (type) of filovirus was discovered in 1967 when 31 people in Marburg, Germany, were infected with a virus that was subsequently named the Marburg virus. These individuals were working with tissue from monkeys imported from Uganda. Seven of the infected individuals died. Since that time, all outbreaks have occurred in sub-Saharan Africa. Ebola virus, the second filovirus genus, was discovered in 1976 when outbreaks occurred in southern Sudan and northern Zaire. The Ebola virus is extremely deadly, having a mortality rate of 20% to 90%. The mechanisms by which filoviruses are transmitted are unknown. Bats have been suspected as the vector.
  • Flaviviruses: Flaviviruses are a family of viruses transmitted by mosquitoes and ticks. These viruses cause yellow fever, Kyasanur forest disease, Omsk hemorrhagic fever, and dengue fever. Dengue fever is one of the most common and widespread types of VHF. Fifty to 100 million cases occur worldwide each year.

Research
  • Current research is focused on the control of the organisms that carry the disease and the development of antiviral medications and vaccines. Organisms that carry the disease are called vectors, and these include rodents and mosquitoes.
  • Researchers are currently seeking appropriate animal models in which to test vaccines. Nonhuman primate (i.e., monkeys) models usually mimic human disease. However, less costly and more readily available rodent models are also being studied.
  • A few antiviral medicines, including carboxamide, ribavirin, tiazofurin, and pyrazoline compounds, have been evaluated for the treatment of viral hemorrhagic fever (VHF). Ribavirin has successfully treated hamsters when a high dose of the drug is given within two days of infection. However, the drug has not produced similar results in nonhuman primate models. Potent inhibitors of both Old World and New World arenaviruses responsible for VHF are being identified in genetics laboratories.
  • Research is currently being done on virus-like particle (VLP)-based vaccines. These particles, which are produced from the live virus in a laboratory, have a similar form to the live virus from which they are produced. They also produce a similar immune response. To date, VLP-based vaccines have been tested on animal models such as the guinea pig. In these studies, the vaccines have been completely effective in preventing infection.
  • Researchers are currently studying the antiviral activity of the natural human hormones, dehydroepiandrosterone (DHEA) and epiandrosterone (EA), and 16 synthetic derivatives of these hormones. These hormones slow the replication of these viruses.
  • Early diagnosis is essential for the successful treatment of infected individuals, so researchers are developing and evaluating accurate and uncomplicated diagnostic tests. Antiviral medications, such as interferon, are highly effective when administered shortly after infection. However, they are ineffective when given after the infection is established.

Future research
  • Future research will focus on the development of new antiviral medications and vaccines as well as the control of rodents and mosquitoes that carry viral hemorrhagic fever (VHF). In addition, future work should focus on evaluating higher doses of ribavirin alone or in combination with other antiviral drugs, such as interferon, to increase the effectiveness of ribavirin. These combination drugs are known as synergistic drugs.
  • Because all the VHF viruses in a specific family (e.g., flaviviruses) have very similar structures, a drug that is effective against one type of VHF will likely be effective against other viruses in that family.
  • A better understanding of the ecology of VHF and the host organisms will help researchers to develop preventive public health measures that can reduce the chance of infection. Ecology refers to the relationships between an organism, in this case VHF, and its environment.
  • Other goals of future research include the development of molecular and immunologic tools for earlier diagnosis and better understanding of the transmission and progression of the viruses.
  • Recently, "reverse genetics systems" have been developed for several VHF organisms. These systems create infectious viruses from cloned complementary DNA (cDNA), or DNA synthetically produced from VHF RNA. This cDNA can generate mutated viruses, which can be used to develop antiviral medications and vaccines.
  • Several VHF viruses have gone through reverse genetics systems. This process has led to the generation of infectious viruses from cloned (copied) cDNA. The cloned cDNA is produced in a laboratory using VHF as a template. These reverse genetics systems will allow researchers to further understand how the virus replicates and how it produces an infection. The process will also lead to the development of antiviral medications and vaccines.
  • T cells are a specific type of infection-fighting white blood cell (lymphocyte) that can recognize invading viruses or bacteria that were present in a past infection. T cell memory is known to be the foundation of protective immunity. It is also the essential element of an effective VHF vaccine. Future research will be conducted in the area of T cell memory.
  • Further understanding of the molecular basis of VHF infections will increase the ability of physicians to treat these infections. The increased understanding of the molecular basis of VHF infections will include the identification of factors that determine the virulence of the virus, or how aggressive it is, and an understanding of how the host responds to the infection.

Copyright © 2011 Natural Standard (www.naturalstandard.com)


The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

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