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Copyright 2004 Tara K. Harper.  All rights reserved.

TKH Virology Notes:

•  Description      •  Mechanism      •  Outbreaks
•  Location      •  Symptoms      •  Vaccine
•  Vector      •  Diagnosis      •  Odds 'n' Ends
     •  Mortality Rates      •  Links
     •  Treatment

Science and Literary  Links for Writers
Science and Technical  References for Writers

NOTE:  This file is for information only.  It is not intended for diagnosis.

     Hemorrhagic fever with renal syndrome  (HFRS)
     Hanta pulmonary syndrome  (HPS)

Description.  An acute, infectious, hemorrhagic virus.  Hantaviruses are biologically unique members of the largest animal virus family, Bunyaviridae.  They are enveloped, single-stranded, mostly negative-sense RNA viruses.  Like other Bunyaviridae, hantaviruses have three genomic segments:  large, medium, and small; and segment reassortment within a species appears common.  They include three structural proteins:  glycoproteins G1 and G2, and nucleoprotein N.

Hantaviruses have much larger nucleocapsids than do other Bunyaviridae.  They also display an unusual gridlike pattern on their surfaces, and often include elongated particles.  Also in contrast to other Bunyaviridae, hantaviruses do not appear to have an arthropod vector.  Instead, they cause persistent asymptomatic infections in their natural hosts (rodents), and each hantavirus is perpetuated in only its single or few specific genus or species of rodent.

There are several distinct, regional hantaviruses:
     •  Hantaan virus or Korean hemorrhagic fever  (also known as epidemic hemorrhagic fever), found in Asia
     •  Seoul virus, associated with domestic rats
     •  Sin Nombre virus  (previously, Muerto Canyon virus), found in the U.S.  Casues HPS.  Also known as:
               - Four Corners virus
               - Hantavirus-Associated Respiratory Distress Syndrome (HARDS)
     •  Puumala virus, found in Scandanavia, Europe, western Soviet Union
     •  Dobrava or Belgrade virus, found in Eastern Europe
     •  Baltimore rat virus or New York virus, a fairly unrecognized form, which is suspected of causing chronic renal disease and/or hypertension.
     •  Thai virus

In addition, other serologically distinct viruses have been recently identified:
     •  Porogia virus, found in the Balkans
     •  Convict Creek virus, similar to Sin Nombre; on the border of California and Nevada.
     •  Andes virus, identified in 1995 in South America
     •  Prospect Hill hantavirus subtype, which does not appear to cause infection in humans.
     •  Bayou virus, which also causes HPS.

Hantaan virus and Sin Nombre virus diseases are severe;  Seoul virus disease can be mild or severe; and Puumala virus disease is comparatively mild.  The Prospect Hill hantavirus does not appear to cause infection in humans.

Hantavirus is associated with seasonal changes which concur with the life cycle of the host rodents.  Although Korean hemorrhagic fever first came to the attention of western doctors during the Korean conflict, the vector (rodents) was not identified until 1976.  Hantavirus is named for the Hantaan River which flows through the endemic region in Korea.  It is now thought that hantaviruses have been infecting rodent populations for thousands, if not millions of years.

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Location.  Asia, western Russia, Europe, the U.S.; and in South and Central America.

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Vector.   Aerosols of rodent excreta, saliva, and urine.   The most common mode of transmission is inhalation of dust or dried particles that carry dried saliva or wate products of an infected rodent.   Hantaviruses are found world-wide, and appear to be host-specific to rodent genus and possibly rodent species.  

Once infected, a rodent experiences a brief viremia that lasts from 5 to 10 days.  Following this stage, the viral antigens remain present in many major organs for weeks to months.  In spite of the antibody presence in the rodent's serum, infectious virus is shed in the rodent's saliva, urine, and feces possibly throughout the rest of its life.  Mice appear to be at their most infectious 40 days after their infection  with the virus.

In general, there are two seasonal peaks for almost all outbreaks of hantavirus diseases:  a small one in spring, and a large one in fall.  It is suspected that this corresponds with seasonal increases in the infection rate of the rodents, and with farming cycles, by which farmers are exposed to rodents in the fields during planting and harvest periods.  Unusually high rainfall in dry parts of the country result in increased food sources for rodents, and subsequently increased rodent populations.  Fall/winter outbreaks, such as those in Greece, correspond to the movement of rodents from the fields into man-made structures.

Some known vectors for human infectious disease:
     •  Asia:  Apodemus agrarius, the striped field mouse
     •  Greece:   suspected to be Apodemus flavicollis, the common, yellow-necked field mouse
     •  U.S.:  Peromyscus maniculatus, the deer mouse
     •  Scandanavia, Europe, western Russia:  Clethrionomys glareolus, the bank vole  
     •  Asia and seaports worldwide:  Rattus species, wild, domestic, and laboratory rats

In Florida, cotton rats, Sigmondon hispidus, have demonstrated hantavirus sequences, and may have been the cause of a severe but nonfatal case of HPS.

No arthropod vector has been established for hantaviruses.

With the exception of the Andes virus, there is no evidence of human-to-human transmission of hantavirus.  Human-to-human transmission has not been confirmed with the Andes virus, but the pattern of infection implies a human vector.

Nosocomial transmission is rare.  

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Mechanism.  Almost all hantaviruses cause kidney impairment and/or failure; however, the precise mechanism which produces renal failure is unknown.

Sin Nombre and Convict Creek viruses cause respiratory distress and failure.  With HPS, as vascular permeability increases, the capillaries leak fluids into the surrounding tissues and organs.  This causes irritation in the lungs and interstitial pulmonary edema.  Hypoxia results within hours, followed by bradycardia (increasingly slowed heartbeat), and finally, death by cardiac or respiratory failure.

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Symptoms.   Symptoms of HFRS usually occur between 1 and 6 weeks after exposure to the virus.  Initial onset is marked by nonspecific flu-like symptoms:  fever, myalgia, headache, abdominal pain, nausea, and vomiting.  There is a characteristic facial flushing, and usually a petechial rash (usually limited to the axilla, or armpit).   Sudden and extreme albuminuria occurs about day 4;  this is characteristic of severe HFRS.  Ecchymosis also occurs, and commonly, scleral injection and bloodshot eyes.  Additional symptoms include: hypotension, shock, respiratory distress and/or failure, and renal impairment and/or failure.  The characteristic damage to the renal medulla is unique to hantaviruses.

There are five stages of HFRS.  However, any one or more of these stages may be inapparent.
   1.  febrile
   2.  hypotensive - shock, which can last for hours or days, during which nausea and vomiting are common.  One-third of deaths occur at this stage.
   3.  oliguric - renal impairment and relative hypervolemia.  Half of all deaths occur during this stage.
   4.  diuretic - improved renal function; but death can still occur from shock or pulmonary complications.
   5.  convalescent - fluid and electrolyte imbalance.  Can last weeks or months.

Hantavirus pulmonary syndrome, caused by Sin Nombre virus, is primarily a lung infection;  the kidneys are largely unaffected.  HPS is characterized by flu-like symptoms:  fever, myalgia, headache, and cough.  Other symptoms can include chills, abdominal pain, diarrhea, and malaise.   Subsequent symptoms include coughting and shortness of breath, tachypnea, tachycardia, dizziness, arthralgia, sweating, and back or chest pain.  Uncommon symptoms include:  inflammation of the eardrum, sinuses, and throat;  conjunctivitis;  and/or rhinorrhea   The disease progresses rapidly;  further symptoms can include thrombocytopenia, hypoxemia, and interstitial pulmonary edema.  Eventually, the patient experiences hypotension, shock, and respiratory distress.  In severe cases, respiratory distress is followed by respiratory failure.  Most patients infected with Sin Nombre virus die within a few days of onset of symptoms.

Baltimore rat virus is characterized by acute onset of nausea, vomiting, fever, upper abdominal pain, protein in the urine, and hypertension.  In some cases, renal and liver involvement occurs.  Patients suffer fever, then 1-2 days of hypotension, followed by renal failure with liver synzyme derangements.  Survivors can experience chronic renal impairment and disease.

Puumala virus is characterized by sudden onset of acute fever with renal impairment or failure.  Other symptoms include:  abdominal pain, lower back pain, and polyuria.  Hemorrhages, if demonstrated, are mild.

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Diagnosis.   Diagnosis is confirmed by IgM and or a rising IgG titer, and/or by PCR.  

Laboratory tests may indicate:
     •  Unsuccessful detection of Hantaan viral antigen in serum from acutely ill patients.
     •  Increased levels of serum creatinine (a muscle enzyme), which indicates kidney damage
     •  Atypical or elevated white blood-cell count
     •  Thrombocytopenia
     •  Hypoxemia

Initial possible diagnoses of HPS include severe, generalized pneumonia;  interstitial pneumonia, and eosinophilic pneumonia.  Chest X-rays may reveal a diffuse, interstitial infiltrate

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Mortality Rates.  
     •  Sin Nombre virus - 70% to 80%.  However, with recognition of milder forms of the disease, as well as better fluid management of severe cases, overall mortality rate is probably closer to 40%.
     •  Porogia hantavirus (Balkans) - 15%
     •  Asian hantavirus - 5% to 20%
     •  Nephropathia epidemica (Scandanavia) - 1%
     •  Baltimore rat virus - 3%

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Treatment.   No specific treatment.  However, intensive care is required, including the monitoring of respiratory status, fluid balances, electrolyte balances, and blood pressure.  Hypoxemia may be treated with oxygen.  Shock and hypotension may be treated with drugs to increase blood flow in order to improve the delivery of blood and oxygen to organs.  In severe infections, immune system response might actually speed death.

One study in Korea showed that ribavirin appeared effective if administered early in the course of the disease, but questions of safety and efficacy are still being raised.  Best results occured when ribavirin was administered on or before day 3.  Ribavirin also appeared to reduce mortality rates, and to reduce the amount of time the patient spends in each of the five stages of the disease.  However, in an uncontrolled trial, ribavirin showed no success in treating or preventing the disease.

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Outbreaks and History of Infection.   Hantavirus is responsible for over 100,000 cases in China, and it is suspected that the number of cases is significantly underreported.  Worldwide, approximately 150,000 to 200,000 cases are reported annually.  Because hantavirus has been isolated from rodents and other creatures across the world, it is suspected that the virus is not new, but has a long history.  For example, in Russia, between 1985 and 1992, almost 69,000 people were infected with hantaviruses caused by over 70 different strains.

Some outbreaks:
   - 1913, Russia
   - 1918, Four Corners (Arizona, New Mexico, Colorado, Utah) area in the U.S.
   - 1932, Manchuria, Japanese troops; and in Russia
   - 1934, Sweden
   - 1936, Four Corners area in the U.S.
   - 1951-1955, Korea:  nearly 2,500 U.S. soldiers contracted Korean hemorrhagic fever
   - 1955-1977, South Korea:  over 9000 documented cases; mortality rate was 6.5%
   - 1977-1986, Belgium and France:  76 cases documented; other cases suspected of being misdiagnosed as flu, back problems, and other conditions.
   - 1979, Korea:  urban and laboratory areas
   - 1986, Texas:  a migrant Mexican worker died of internal hemorrhaging and kidney failure.
   - 1993, Germany, France, Belgium, and the Netherlands:  outbreaks of Puumala infection.
   - 1993, Four Corners, U.S.:  55 cases, with 32 deaths.

As of November, 1998, more than 300 cases have been reported in South America.

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Vaccine.   Animal research has shown that immunization with recombinant GP (glycoproteins) can partially prevent infection.  Vaccines based on two glycoproteins (G1 and G2) were more effective.  An experimental vaccine for the Seoul virus has been developed.

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Odds 'n' Ends.  
     •  The successful isolation of Hantaan virus also resulted in the identification of the virus which causes nephropathia epidemica, a less severe form of HFRS.   Nephropathia epidemica, first described in the 1930's, is caused by Puumala virus.  The disease occurs in Scandanavia, Europe, and the western part of the former Soviet Union.

     •  Researchers in Baltimore have found that almost every tested rat over 2 years of age was infected with a hantavirus.  Research at Johns Hopkins has indicated that 6.5% of all patients undergoing dialysis had serum that reacted with Seoul hantavirus antibodies.  It is suspected that these patients suffered chronic kidney disease after infection with the virus.  It is also suspected that many cases of kidney disease and hypertension in the U.S. are actually caused by hantaviruses.

     •  Sin Nombre is not a new virus.  Native American stories indicate that even hundreds of years ago, medicine men and women knew of the deer-mouse vector and identified that the "spirit" of the disease was carried by aerosol particles.  They also understood that to eradicate the disease, they had to burn everything which had come in contact with mice (objects which might be contaminated with dried mouse feces, urine, or saliva).

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     •  Fact Sheet:  CDC Special Pathogens Branch:  public information area
     •  A Global Disease Problem - Report from the Journal of Emerging Infectious Diseases
     •  Sin Nombre - electron micrograph of Sin Nombre virus in tissue culture

Copyright 2004 Tara K. Harper

All rights reserved.  It is illegal to reproduce or transmit in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, any part of this copyrighted file without permission in writing from Tara K. Harper.  Permission to download this file for personal use only is hereby granted by Tara K. Harper.

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