SISTEMA bio~SIGNA

Hanta in the Park

 - The Yosemite National Park has become famous now, not because of the grandeur of the place, but because it is now in alarm mode owing to the Hanta Virus outbreak there. The RNA virus is acquired from contamination with rodent urine, saliva or contact with rodent waste products. Hantavirus are genetically stable in their natural rodent host. Hantavirus (genus Bunyavirus) co-evolution with its rodent host, suggests a 20 million year association. There are now many examples of species-specific RNA virus/host co-evolution, indicating very slow rates of virus evolution. The infamous rodent family in this current outbreak is the Deer Mouse. Phlebovirus (causing Rift Valley fever), and Nairovirus (causing Crimean-Congo HF) are two other known members of the Bunyavirus genus.

 - Hantaviruses cause millions of cases of haemorrhagic fever each year in many parts of the world. This rodent-borne Negative-sense single-strand RNA virus can cause serious and fatal disease in humans, the major problem of which would be hantavirus pulmonary syndrome (HPS). Another condition caused by this virus would be hemorrhagic fever with renal syndrome (HFRS). From the time of infection to clinical manifestations of this disease, the period could be even as long as  6 weeks, at which time of clinical discovery the condition could be potentially fatal. While rodent material to human transmission is the classic link, recent human-to-human transmission has been reported with the Andes virus in South America. The first identification of this virus was in the late 1970s in the South Korean River named Hantaan. In  the beginning, the name given to this febrile hemorrhagic condition was Korean hemorrhagic fever. This condition was actually responsible for the thousands of soldiers getting infected during the Korean War.

 - The Southwestern United States witnessed an outbreak in the early 90s.The viral cause of the disease was found only weeks later. Its rodent host, the Deer mouse (Peromyscus maniculatus) was first identified by a professor at the University of New Mexico. Initially, in the outbreak, the virus was called Sin Nombre (meaning, Without Name) Virus. It  is  now  known  that  at  least  three  different  hantaviruses  cause  HFRS  and four different viruses cause HPS. By 1995, HPS had been recognized in 102 patients in 21 states of the United States, in seven patients in Canada, and in three in Brazil,

with an  overall  mortality  rate  of  approximately  40%.

Genetic Characteristics

 - More than 16 different genotypes or serotypes have been identified (e.g., Puumala, Hantaan, Dobrava-Belgrade, Seoul, Sin Nombre). The family Bunyaviridae includes four medically significant genera. The genomes of negative-strand viruses are frequently segmented. Like other members of the Bunyavirus family, hantaviruses are lipid enveloped viruses with a genome that consists of three single-stranded, negative sense RNA segments where the  genome  is  comprised  of  three  molecules: L  (8.5 kb), M  (5.7 kb), and  S (0.9 kb). The S RNA encodes the nucleocapsid (N) protein. The M RNA encodes a polyprotein that is cotranslationally cleaved to yield the envelope glycoproteins Gn (formerly G1) and Gc (formerly G2). All three RNA species are linear, but in the virion they appear circular because the ends are held together by base-pairing. The three segments are not present in virus preparations in equimolar amounts.

Tools for Studying the Virus Genetic Make-up

 - Although viral genomes were the first to be sequenced, the initial focus was simply to identify similarity between viral genes, not to evaluate distant evolutionary relationships. The  most  popular  tool  for  finding  similarity is BLAST (Basic Local Alignment Search Tool) from the National Centers for Biotechnology Information (NCBI),which calculates similarity between query sequences and infers a probability based on a matrix database. The BLAST resource is located here   Basic BLAST and Specialized BLAST are available at the site. This site now features DELTA-BLAST “a more sensitive protein-protein” search. There are at least a dozen (plant, and animal) genome references that can be used to compare sequences. It is through comparison that one is able to get insight into the characteristics of the organism studied. BLAST finds regions of similarity between biological sequences. Another tool for genetic studies is the BioJava Project suite of biologic analysis modules which can be downloaded here (now at version 3.0.4

Transmission  electron  micrograph of the Sin Nombre Hantavirus.
Date:1993 Content Providers(s): CDC/Cynthia Goldsmith
Permission:PD-USGov-HHS-CDC

 

Clinical Manifestations of Hantavirus Infections

 - In all these situations, infection begins on an epithelial or mucosal surface and spreads along the mucosa and into deeper tissues. Disease manifestations usually arise as a consequence of viral replication, infected cell injury or death, and local inflammatory and innate immune responses. An immediate assessment of the patient's general appearance can yield valuable information.  Presenting symptoms are frequently nonspecific. A review of systems should focus on any neurologic signs or sensorium alterations, rashes or skin lesions, and focal pain or tenderness and should also include a general review of respiratory, gastrointestinal, or genitourinary symptoms. The most common symptoms of nephropathia epidemica are fever, nausea, vomiting, headache, stomach ache, back pain, tenderness in the kidney area, diarrhea or constipation.  Therefore it is most important to know the recent history of the patient, and his whereabouts in the days immediately preceding the report of the patient to a physician or nurse at the health facility. In the case of Hantavirus, there will probably be a form of cardiopulmonary distress, or a renal syndrome that’s not explained by intoxication, prior kidney disease, or metabolic disorder. After a quick clinical assessment, specimens must be collected from all accessible material (i.e. blood, urine, sputum, feces) rapidly, and antibiotic and supportive treatment begun. Empirical antibiotic therapy is critical and should be administered without undue delay.

 - The viruses in the Bunyaviridae genus that have to be distinguished now are the Hantavirus, California Encephalitis virus and the Sandfly Fever Virus. European hantaviruses, such as the Dobrova-Belgrade virus (from Slovenia), and the Puumala (identified in Scandinavian locations) which causes nephropathia epidemica. These are emerging viruses that can cause hemorrhagic fever with renal syndrome (HFRS) of differing severities. Both the Dobrova and Puumala varieties are likewise by rodents in those geographic locations. This important to note because of the possible introduction of “foreign” virus strains into a immune-naïve setting. The optimal use of antiviral compounds requires a specific and timely diagnosis.

Clinical Management

 - Firstly, acute management of the airways is crucial. If difficult airways are encountered, camera guided intubation is carried out. A CT scan is used for visualizing the pulmonary status after intubation. Occasionaly,  emphysema may be present especially in older individuals, and in heavy smokers. A previous history of lung infection (e.g. pulmonary tuberculosis, aspergilliosis) and pulmonary fibrosis may make pulmonary stabilization more challenging. But even before any anti-viral drugs are decided upon, proper antibiotic coverage must be provided. In the case of a cardiopulmonary picture, the stage at which the patient is seen will impact the treatment chosen. Nevertheless, one has to treat not just the viral infection, but also the opportunistic organisms that may be present at that point. If the patient has been previously admitted to a health facility one has to consider a community-acquired pneumonia as well as a nosocomial infection. Focal abscesses necessitate immediate CT or MRI as part of an evaluation for surgical intervention. If there is a necrosing organ or tissue, or if there is fulminating sepsis, more aggressive antibiotic treatment is required.

 - Two anti-viral drugs that are of help in Influenza A are Zanamivir and Oseltamivir, which are inhibitors of the influenza viral neuraminidase enzyme, which is essential for release of the virus from infected cells and for its subsequent spread throughout the respiratory tract of the infected host. This information is important because a patient presenting with pulmonary manifestations may either be super-infected, or, not given the proper anti-infectious therapy coverage. Orally inhaled zanamivir is generally well tolerated is administered orally via a hand-held inhaler, and where about 15% of the dose is deposited in the lower respiratory tract, and low plasma levels of the drug are detected. The drug is excreted unmetabolized by the kidneys.

 - IV Ribavirin in the picture of hanta virus cardiopulmonary syndrome has not shown clearcut benefits in the U.S.. Nevertheless, it is the opinion of this author that this treatment must be tried, particularly when no “ideal” pharmacotherapeutic agent available. In the acute setting, empirical antibiotic therapy is critical and should be administered without undue delay

Prevention

 - Hantavirus ranks among the dozen or so viruses that have no vaccine available. In this light, avoidance of contact with the Deer Mouse (and other rodent vectors) and its waste products, and in its extended habitat (meaning “out-of-the-woods and into-the-homes”) such as summer camps, tents and homes close to the exterior of normal human habitat. Since there is no available vaccine, and quite uncertain benefit of immunoglobulin therapy, prevention of exposure is the best approach. Travelers or vacationers would do well to avoid staying in less than optimal lodgings. And even then, it would be beast to stay away from any locations which would be in the periphery of the vector’s habitat. For those whose residences are in the nearby areas, judicious use of pest control measures should be exercised.

The Deer Mouse (Peromyscus maniculatus), Cotton Rat (Sigmodon hispidus), Rice Rat (Oryzomys palustris), and White-footed mouse (Peromyscus leucopus) have been identified as vectors of HantaVirus. For the geographic distributions of these rodents, kindly consult the CDC page here :

Current Situation of Hantavirus Outbreak

According to the CDC, “As of September 6, 2012, The National Park Service (NPS) announced that there were 8 confirmed cases of Hantavirus Pulmonary Syndrome (HPS) in visitors who stayed at Curry Village in Yosemite National Park since June of this year. Public health officials believe that these visitors may have been exposed to Hantavirus while staying at the Signature Tent Cabins in Curry Village.”

For more Clinical and Technical Information, kindly visit this page:

-Til next time, keep posted.

_ Fernando Yaakov Lalana, M.D.