Hantavirus
Authors:Marcela Ferrés MD, MPH, Cecilia Perret MD
GENERAL DESCRIPTION
Virology
Hantaviruses form a separate genus within the Bunyaviridae family. They are the only genus not transmitted via an arthropod vector. Like all members of the Bunyaviridae family they are morphologically spherical, enveloped viruses 90 to 110 nm in diameter, and contain three negative sense RNA segments. Each one of the segments has a consensus 3`terminal nucleotide sequence which is complementary to the 5`terminal sequence and is different from those of the other four genera. Such complementary sequences are capable of forming pan-handle structures, a characteristic feature of the Bunyaviridae family. These loops play a role in viral transcription and replication similar to other viruses like influenza virus. The three segments are named by their size: L or large segment with 6530-6550 nucleotides (nt) coding for an RNA-dependent RNA polymerase, M or middle segment with 3613-3707 nt coding for two glycoprotein, G1 and G2 present in the viral envelope, and small or S segment with 1696-2083 nt which codes for the viral nucleocapsid protein N. The nucleocapsid and glycoprotein both evoke antibody responses and induces protective immunity. N protein is relatively conserved between hantavirus species but G1 protein is species-specific (36). Like other enveloped viruses, hantaviruses are inactivated by heat, detergents, organic solvents and hypochlorite solutions. The virion consists of more than 50% protein, 20 to 30% lipids and 2-7% of carbohydrate. Some of these properties are important to know for setting up biosafety procedures in the laboratory and for infection control in hospital practice.
Hantaviruses have been recognized in different rodent populations throughout the world and there are more than 20 sero/genotypes, but each hantavirus is specific to a different rodent species, the virus phylogeny resembling the rodent phylogeny. The general criterion for type classification are based on neutralization properties or the genomic differences between sequences in a short region of the M segment, 328 nt located between 1987-2315 nt (51).
Epidemiology
Hantavirus infections are a viral zoonosis transmitted from rodents to humans. There are two clinical forms of disease, the hemorrhagic fever with renal syndrome, which occurs primarily in Europe and Asia, and the hemorrhagic pulmonary syndrome or hemorrhagic cardiopulmonary syndrome first recognized as a human disease in the Americas in 1993. Both clinical entities differentiate not only in the target organs involved, but also in the rodent reservoir, geographical distribution and some of the modes of virus transmission to humans (Table 1).
Rodents are chronically infected and excrete infectious virus for prolonged periods even in presence of neutralizing antibodies. The virus is excreted in feces, urine and saliva, the most important fluids involved in transmission to humans. The viral infection among rodents increases towards adult age, observing the highest seroprevalence in adults and mature animals. Bites and fighting have been implicated in transmission between adult rats (35). Recent experiments on the Chilean wild sigmodontine rodents, Oligoryzomys longicaudatus the rodent reservoir of Andes virus, have suggested that contact with saliva or saliva aerosols is an important mechanism of virus transmission between rodents rather than via feces and urine (27).
Rodents associated with hemorrhagic fever with renal syndrome are mainly members of the murid subfamilies Arvicolinae (Old World voles) and Murinae (Old World rats and mice) while the viruses associated to hemorrhagic cardiopulmonary syndrome are spread by Sigmodontinae family (New World rats and mice). The pathogenic viral serotypes are Hantaan, Seoul, Puumala, and Dobrava which are for the most significant causes of hemorrhagic fever with renal syndrome, and Sin Nombre Virus, Black Creek Canal, Andes, Choclo, Laguna Negra, and Juquitiba which have been responsible for hemorrhagic cardiopulmonary syndrome along the Pan-American region (31,32,35).
Airborne transmission from hantavirus-infected aerosols is thought to be the most important route of transmission from the rodent reservoir to humans. This mechanism of transmission is associated with some risk activities such as agricultural and forestry, cleaning storage sheds or closed compartments where rodents have their nests. Some occupations represent a clear risk such as animal trappers, forestry workers, farmers and military personnel. For viruses of the Old World like Hantaan there have been reports of infected laboratory personnel exposed to infected laboratory rats (50). Rodent bites have been also reported as mechanism of infection but they are exceptional (23). Person-to-person transmission has been documented only for and virus infection in Argentina and Chile. In this last country up to a third of the hemorrhagic cardiopulmonary syndrome cases occur in household clusters (22, 29, 49). Recent studies of follow up of household contacts of a hemorrhagic cardiopulmonary syndrome case have estimated an increased risk of becoming a case among sex partners of hemorrhagic cardiopulmonary syndrome cases compared with other household contacts. (Ferres M, data unpublished).
Pediatric cases represent a variable proportion of the total reported hemorrhagic cardiopulmonary syndrome cases across the American continent. In USA the proportion of cases in children is less than 8% and in Chile 16% (11, 33). In all the clinical forms of hantavirus infection, males are always more affected than women, this is probably related to the inherent risk of occupational activities done more frequently by men than women.
More than 150.000 or 200.000 cases of hemorrhagic fever with renal syndrome involving hospitalization are seen throughout the world, more than a half of them in China and Russia, Korea also reports hundreds to thousands of hemorrhagic fever with renal syndrome cases each year. In Europe, nephropathia epidemica, with Puumala virus and Dobrava virus as etiology are more frequent in European Russia, Finland, Sweden, Germany and France. hemorrhagic cardiopulmonary syndrome occurs throughout much of the Panamerican region, United States, Canada, Brazil, Argentina, Chile and Panama are the countries who report the greatest numbers of cases. In the USA, the Center for Disease Control and Prevention (CDC) had by May 2006 reported 438 cases with an overall case fatality rate of 35%. In Chile, the Ministry of Health had reported 480 cases up to the same date with an overall case fatality rate of 37% (4,45).
Clinical Manifestations
Infections caused by Hantaan and Dobrava (DOO) viruses are the two clinical forms with the most severe presentation of hemorrhagic fever with renal compromise. Fever, hemorrhage and renal failure are the classical triad in the acute phase of the disease. The hemorrhagic fever with renal syndrome develops in five phases: febrile, hypotensive, oliguric, diuretic and convalescent. The febrile period lasts around 3-7 days, patients complain of headache, myalgia and conjunctival injection. After several days symptoms may worsen and be accompanied by nausea, vomiting, abdominal pain and lower back pain. Petechiae appears late in this part of the disease. Then, the hypotensive phase comes with a low platelets count, petechial hemorrhages and hemoconcentration. This is the most important phase of the disease when a severe hemorrhagic disease takes hold and when death occurs due to shock and multiorgan hypoperfusion. The oliguric phase starts with the return of blood pressure to normal and lasts for 3 to 7 days. Oliguric renal failure develops in up to 60 to 70% of patients and patients may die due to pulmonary edema, neurological complications, uremia and bleeding. Dialysis may be required. The diuretic phase may be brief in patients with mild disease or may gradually resolve over weeks in those with more severe disease. Convalescence is usually prolonged lasting weeks or months. The mortality rate is 5 to 10%.
Nephropathia epidemica by Puumala virus is a mild form of hemorrhagic fever with renal syndrome without clear phases of the disease, the mortality is low 0 to 0.2%. Many cases are recognized and managed as outpatients without hospitalization.
Seoul infection represents the moderate form of hemorrhagic fever with renal syndrome and is recognized in South East Asia, and has also been recognized in urban areas all over the world where the reservoir lives (Rattus norvegicus and Rattus rattus). This virus infection is associated with hepatitis in a proportion of patients, in these cases leptospirosis has to be included in the differential diagnosis. Mortality is 1 to 2 % (25, 40).
Hemorrhagic cardiopulmonary syndrome has three well characterized stages. The first is the prodromic phase during which the patient has fever, myalgias, headache, backache and gastrointestinal symptoms like abdominal pain or diarrhea (31, 46). After 2-8 days, the patient enters the cardiopulmonary stage, with cough and dyspnea. The pulmonary edema rapidly progresses to respiratory failure, although that problem can generally be corrected through artificial ventilation. In severe cases, the cardiac index is depressed and the systemic vascular resistance increased. Most fatalities occur during this stage and result from cardiogenic shock and arrhythmias rather than from respiratory failure. Lastly, the diuretic phase starts after 2 to 4 days of cardiopulmonary symptoms and coincides with the resolution of the cardiopulmonary phase (26). After the diuretic phase some patients complain of weakness, fatigue, impaired exercise tolerance and abnormal pulmonary function.
Laboratory Diagnosis
Both for hantavirus infection with renal compromise as well for the cardiopulmonary form, several diagnostic techniques have been used with the aim of having an early and confident diagnosis. During the prodromic or initial phase of both forms of the disease the finding of thrombocytopenia is a very good sign to request hantavirus serology.
For the presumptive diagnosis of hemorrhagic cardiopulmonary syndrome, and after the onset of pulmonary edema the presence of at least four of five findings, (thrombocytopenia, myelocytosis, hemoconcentration, and absence of granulations in neutrophils with more than 10% of lymphocytes with immunoblastic morphology) has sensitivity for hemorrhagic cardiopulmonary syndrome diagnosis of 96% and a specificity of 99%. The combination of four of these elements can guide early treatment and patient transport decisions until a definitive diagnosis is available (20).
The standard diagnostic technique for hantavirus infection today is serology. When the patient is already showing symptoms, it is almost always possible to detect a specific IgM for hantavirus, while at the same time IgG is undetectable in some patients in whom seroconversion will be possible to see at the end of the first week of disease. The amount of IgM antibodies declines to an undetectable level in a few months and IgG persists for decades (18, 28).
The best antigen for the detection of hantavirus antibodies is the viral nucleocapsid (N) protein, which is uniformly recognized in all the patients with hantavirus infection.
Serological cross-reactivity between different hantaviruses has been reported. The most common is Hantaan virus and Dobrava virus, Puumala virus and Sin Nombre Virus, Andes and Laguna Negra virus. This antigen can be expressed as a recombinant protein, in bacteria, yeast or insect cells. The binding of the patient’s antibodies to N antigen can be visualized using Enzyme Immunosorbent Assay (EIA), Western Blot, Strip Immune Blot (SIA) or Immunofluorescence (IFA). EIA and Strip blot are the most commonly used in America. For the diagnosis of acute-phase hemorrhagic fever with renal syndrome, especially in areas where multiple hantaviruses are endemic, the combination test, which contains N antigens from Puumala virus, Dobrava virus, Hantaan virus and even Seoul virus, in prevalent zones it would be a good approach to have rapid diagnosis tests. Even though the serological cross reactivity between viral strains is not total, the use of individual antigen improves the serological diagnosis of infection (17).
For the diagnosis of the Panamerican viruses the current development of novel and sensitive assays, where cross reactivity between antibodies to different viruses has been appreciated should facilitate early diagnosis of Andes virus infections and might contribute to a successful treatment of hemorrhagic cardiopulmonary syndrome among these patients (37).
Cross neutralization antibodies and specific immunoglobulin for glycoprotein 1 (G1) are two serological resources for differentiation between different hantavirus strains. This option might be particularly useful when causality with a particular viral strain needs to be documented, and only serum is available for making the diagnosis.
The use of molecular biology techniques such polymerase-chain reaction (PCR) has been evaluated for diagnosis, however, since the viremia in the acute phase of the disease is relatively short, it does not represent a technique widely used and does not yet replace serology for diagnosis. For the Panamerican strains such Andes virus, Sin Nombre Virus and Choclo virus, there has been, under research circumstances, wide use of qualitative heminested RT-PCR and a quantitative RT-PCR assay using real time techniques, using primers for the S segment (N). The first is a good diagnostic resource for tissues or fluids recovered from very sick or dead patients in whom a final diagnosis is unknown. Use of quantitative assays has been of great help in understanding the pathogenesis of viremia during the first week of disease for Sin Nombre Virus and Andes virus infection (42).
Furthermore, in a prospective study of household contacts of index patients with hemorrhagic cardiopulmonary syndrome in Chile, we have found that Andes virus RNA can be detected in peripheral blood cells by RT-PCR for up to 2 weeks prior to the onset of symptoms or development of anti-hantavirus antibodies (M Ferres, unpublished data).
Immunohistochemistry, in autopsy material has been of great help not only in diagnosis but also in the understanding of the immune pathological phenomena described in the lungs, kidneys, and vascular endothelial cells.
Pathogenesis
The clinical presentation of hemorrhagic fever with renal syndrome and hemorrhagic cardiopulmonary syndrome strongly suggests pathologic immunologic response of the patient, particularly T cell response instead of the cytopathic damage secondary to the viral infection. The capillary leak is one of the most important findings, represented clinically in kidney failure, for the European and Asian infections, and in the cardiopulmonary phase for the Panamerican syndromes. In autopsy studies viral antigens have been found in many different organs, like lungs, kidney, spleen, liver, lymph nodes, pancreas, brain and adrenal glands. Interestingly, the viral antigens are deposited along the small vessels of these organs, without disrupting the anatomy and are almost absent from the larger vessels like veins or arteries (2, 25).
Hemorrhagic cardiopulmonary syndrome pathogenic hantaviruses use beta 3 integrins to enter endothelial cells, where the virus predominantly replicates; beta 3 integrins interact and may regulate endothelial cell function and contribute to viral pathogenesis modifying vascular permeability or vascular integrity (12). The main histopathological findings in fatal cases of hemorrhagic fever with renal syndrome are hemorrhagic necrosis of the renal medulla with tubular degeneration. In hemorrhagic cardiopulmonary syndrome there are interstitial pneumonitis with congestion, edema, and some hyaline membranes with integrity of the respiratory epithelium, but it is cardiogenic shock and not respiratory failure, due to severe tissue hypoperfusion, metabolic acidosis and development of severe arrhythmias, that is the final cause of death in these patients.
Elevation of cytokines mediators in hantavirus infection has been documented in humans and animals. Increase in TNF alfa, transforming growth factor beta, platelet derived growth factor, soluble TNF alfa mediators, interleukin (IL)-6 and IL-10 have seen in patients with nephropathie epidemica and other forms of hemorrhagic fever with renal syndrome. In hemorrhagic cardiopulmonary syndrome, infected endothelial cells may be injured by T cells, cytokines or other immune mediated factors, creating gaps between endothelial cells. Elevated levels of IL-2 and its receptors, gammainterferon, IL-6 and soluble receptors for TNF in plasma suggest marked cytokine activation in hemorrhagic cardiopulmonary syndrome (2,13).
The role of viral load during the infection has been studied mostly in hemorrhagic cardiopulmonary syndrome patients. The viral RNA- Sin Nombre Virus in plasma is high during acute infection and then decreases to undetectable levels within the first week of disease. The levels of viremia correlated with the lowest platelet counts and highest hematocrit levels (42). In 66 Chilean patients with hemorrhagic cardiopulmonary syndrome due to Andes virus, viral RNA was measured in different fluids such as plasma, urine and tracheal aspirate during the first 5 days of hospitalization. In 58% of them viral RNA was detectable in plasma with levels of viremia in decline around the first 5 days of observation. In one third of the patients viral RNA was detected in urine but at a lower viral load than in plasma and respiratory secretions. The highest amount of viral RNA was seen in 68% of the tracheal aspirates. This last finding helps to understand the mechanism for person to person transmission, unique observation in Andes virus infection in Argentina and Chile. (Vial P. unpublished data).
Recent experimental studies have been trying to better define the role of respiratory secretion or saliva in interpersonal transmission. A primary hamster tracheal epithelial cell (TEC) culture system was used to characterize Andes virus infection of the respiratory epithelium. Primary hamster TEC cultures were selected as representative model to study Hantavirus interactions with the respiratory epithelium. Andes virus was capable of replicating in the hamster TECs, releasing virus into both the apical and basolateral supernatants. Infection resulted in no obvious cell damage, and basolaterally secreted virus was not due to a breakdown in tight junction integrity as trans-epithelial resistance. These experiments with Andes virus, suggests that respiratory epithelium may play a role in the early or prodrome phase of disease as well as serving as a source of virus involved in transmission (34). Another study, Andes virus in saliva was studied in Chilean wild sigmodontine rodents. The study was designed to understand the conditions under which the transmission of Andes virus in Oligoryzomys longicaudatus reservoir populations took place. Seronegative mice were exposed to seropositive rodents either sharing a cage, in different cages separated by a wire mesh and other group of mice exposed to excrement from seropositive rodents contaminating bedding in the cages. The Andes virus transmitted efficiently in the 17% of those rodents exposed to direct contact with the infectious rodents. Transmission was not observed between wire mesh-separated animals, and mice were not infected from excrement-tainted bedding. Bites seemed not to be a requisite for oral transmission. Genomic viral RNA was amplified in two out of three saliva samples from seropositive rodents, but it was not detected in urine samples obtained by bladder puncture from two other infected rodents. Through immuno histochemistry techniques using antibodies against Andes virus proteins, they found strong reactions in the lung and salivary glands, supporting the possibility of Andes virus via saliva or saliva aerosols rather than via feces and urine (27).
SUSCEPTIBILITY IN VITRO AND IN VIVO
Ribavirin’s carboxamide group can resemble adenine or guanosine so when it is incorporated into RNA, it pairs equally well with either cytosine or uridine, inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses. In addition, Ribavirin 5' mono- di- and tri-phosphates are all inhibitors of certain viral RNA-dependent RNA polymerases. Finally, ribavirin is known to enhance host T-cell-mediated immunity against viral infection through helping to switch the host T-cell phenotype from type 2 to type 1. Its main serious adverse effect is hemolytic anemia, which may worsen pre-existing cardiac disease. The mechanism for this side effect is unknown. It is dose-dependent and may sometimes be compensated by decreasing the dose. Ribavirin does have a dose-dependent inhibiting effect on DNA synthesis, as well as having other effects on gene-expression. Possibly for these reasons, significant teratogenic effects have been noted in all non-primate animal species on which ribavirin has been tested. It should not be used on pregnant women. Ribavirin is active in vitro against all hantaviruses (38).
ANTIVIRAL THERAPY
Ribavirin
Ribavirin is currently the only antiviral that has shown activity against hantaviruses, nevertheless this has only been proved effective for old world hantaviruses. Intravenous ribavirin has been reported to be effective to treat hemorrhagic fever with renal syndrome which is caused by Hantaan virus in a study performed in China. When this drug was started before the end of the first week of illness the risk of dying was reduced by seven-fold (16). However, for the treatment of hemorrhagic cardiopulmonary syndrome currently none antivirals, including ribavirin, have shown effectiveness. An open-label trial conducted in the United States where patients were treated during the cardiopulmonary phase and nonrandomized, untreated patients were used as controls did not show differences between the two groups (6).
The only placebo-controlled, double-blind trial to asses the effectiveness and safety of intravenous ribavirin to treat hemorrhagic cardiopulmonary syndrome had to be stopped prematurely because of slow rate of accrual of subjects and the findings of a futility analysis (24). In this study that was conducted in the United States there were not differences in the survival for 28 days without ECMO and in any of the secondary outcome measurements after using intravenous (IV) ribavirin. The utilized doses were 33 mg/kg as a loading dose and then 16 mg/kg every 6 hours for 4 days or 8 mg/kg every 8 hours for three days. No significant differences in the frequency of adverse event between treatment and control groups were observed. These findings are different from those obtained to treat hemorrhagic fever with renal syndrome. These results were not due to differences in susceptibility to the antiviral drug between Sin Nombre Virus and HTV viruses because the ID50 of ribavirin is similar for both viruses. The differences in the efficacy are probably better explained because of the rate of disease progression. Once the second phase of infection begins the time for progression to death is shorter for hemorrhagic cardiopulmonary syndrome compared to hemorrhagic fever with renal syndrome, so if treatment can be started early after the symptoms start, we would have a better efficacy in the treatment of HPCS. The efficacy of this drug when started during the prodromic phase could not be assessed in this trial due to the lack of patients enrolled during this period. Even intravenous ribavirin is well tolerated and probably is not effective after the onset of the cardiopulmonary phase. When this phase begins the rate of disease progression and the time to death are too fast for ribavirin to show any benefits. No other antiviral drug has been tried for the treatment of hemorrhagic fever with renal syndrome or hemorrhagic cardiopulmonary syndrome.
ADJUNCTIVE THERAPY
Patients with severe forms of hemorrhagic fever with renal syndrome and hemorrhagic cardiopulmonary syndrome should ideally be transferred to an intensive care unit. The more critical patients will be those who are at risk of developing shock and lung and cardiac assistance like those affected by hemorrhagic cardiopulmonary syndrome. For these patients monitoring should focus on oxygenation, blood pressure and continuous cardiac output measuring. Indicators of poor outcome include shock, cardiac arrhythmias (including ventricular tachycardia or fibrillation), serum lactate concentration over 4.0 mmol/L, cardiac index lower that 2.5 L/min/m2. Intubation, mechanical ventilation, fluid resuscitation and vasoactive medications should be provided as required.
Non Antiviral Drugs
Based on the concept that hantaviruses use the beta 3 integrin receptor to enter to cells, researchers are working in finding peptide antagonists that block such receptors inhibiting the viral entry through them. Four peptides have been identified that bind αvβ3 receptors and inhibit Sin Nombre Virus entry measured by their ability the number of foci of Sin Nombre Virus and Hantaan virus in a focus reduction assay (21). Hantaviruses interaction with αvβ3 integrins provide a potentially contributory mechanism for the observed alterations in vascular permeability during infection and also provide potential target for therapeutic interventions.
Neutralizing Antibodies
Evidence that neutralizing antibodies might be useful to treat hemorrhagic cardiopulmonary syndrome comes from different studies. First, some studies performed on animals using passive immunization protects against disease (9). Second, the efficacy has been proved of the administration of convalescent plasma with high titers of antibodies to treat patients with Argentinean Hemorrhagic Fever due to Junin virus, another rodent borne virus which belongs to the Arenaviridae family (10,19). Third, there is evidence that patients with mild hemorrhagic cardiopulmonary syndrome have higher titres of neutralizing antibodies early in the disease than those with severe disease (1). Fourth, studies of the kinetics of neutralizing antibodies from patients with HPCS caused by Sin Nombre Virus have demonstrated that these antibodies persist for substantial period after recovery from the disease, however not all recovered patients are equally rich sources of neutralizing antibodies. In a recent publication, no differences where found between antibody titres and severity of the disease (7). The authors believe that convalescent-phase plasma therapy may represent a practical intervention that is feasible with current resources and finding levels for potential anti-hantavirus therapy. Another study has tested homotopic and heterotopic neutralizing activity using plasma from a patient who recovered from Sin Nombre Virus and Andes virus infection. The results show that plasma from patients infected with Sin Nombre Virus is able to neutralize Andes virus and vice versa. They conclude that neutralizing antibodies could be used as a therapeutic alternative for patients with acute disease or as a post exposure prophylaxis. Because of the absence of cross-neutralizing activity between viruses from different geographic regions, plasma from patients infected with the one virus should be used only where the same virus is the endemic strain. They also suggest that a monovalent vaccine would not elicit protection against different hantavirus even if they are phylogenetically related like Sin Nombre Virus and Andes virus (44).
Steroids
The use of steroids in the acute phase of the hemorrhagic cardiopulmonary syndrome, particularly in Chile where Andes virus is endemic, has the goal to avoid early on the pathologic immunologic response of the patient that evolves into a severe and lethal disease. Initial use in non-comparative studies showed a decrease in lethality among those who receive steroids in high doses, from 53.8% to 18% (41). Currently a randomized placebo-controlled trial to study the efficacy of methylprednisolone is being performed in Chile. No evidence exists so far proving that steroid administration has a benefit in hemorrhagic cardiopulmonary syndrome.
ECMO
Evidence has shown that ECMO successfully provided cardiopulmonary support in patients with severe hemorrhagic cardiopulmonary syndrome who survived with a good outcome (8). Current experience from the group of New Mexico and Chile suggests that ECMO is a beneficial therapy for patients that are critically ill with hemorrhagic cardiopulmonary syndrome but it should be reserved for patients with very severe hemorrhagic cardiopulmonary syndrome and it should be initiated as soon as advanced shock and respiratory failure has developed (43).
VACCINES
Currently, only one vaccine has been licensed for human use. This is Hantavax®, a hantaan formaline-inactivated vaccine. This vaccine is commercially available in South Korea since 1990, however no efficacy trial has been ever done. A good efficacy has been estimated based in immunogenicity trials. It is indicated for risk population but also for children as national program. The recommended schedule is two doses 1 month apart and a booster after 12 months. Different studies have shown a variable seroconversion rate. One study measured the seroconversion of neutralizing antibodies after one and two doses. The seroconversion was 33.3% after two doses (39) so the efficacy of the vaccine is doubtful. Recently a case control trial to asses the protective effectiveness of a hantavirus vaccine has been published. The effectiveness was evaluated after one, two and three doses and they were 25%, 46% and 75% respectively compared with controls. However all the confidence intervals passed through zero so the difference could be just by chance (30).
Trials using a DNA based vaccine against old world hantaviruses (pWRG/HTN-M) which contains the full length M genome of Haantan virus have been attempted. This vaccine protects against many viruses producing hemorrhagic fever with renal syndrome (15) but failed in give complete protection when a test with Andes virus was done, only a low level of neutralizing antibodies were detected. Vaccine for hemorrhagic cardiopulmonary syndrome is in early development and being tested in animals. No human trials are currently in progress. No vaccines, antiviral or immunotherapy have proved to be effective to prevent or treat hemorrhagic cardiopulmonary syndrome.
One DNA based vaccine against Andes virus (pWRG/AND-M) has been able to induce neutralizing antibodies and protect hemorrhagic cardiopulmonary syndrome in rhesus macaques. The antibodies cross-neutralized at least two other viruses associated with hemorrhagic cardiopulmonary syndrome, the Sin Nombre Virus and Black Creek Canal virus. This vaccine does not generate antibodies nor protect from disease after being challenged with Andes virus in Syrian hamsters, but when this rodents are previously inoculated with plasma from rhesus macaques after they have been vaccinated, they were protected from disease (9). These combined findings, the use of DNA vaccines and passive immunization could be proposed as a treatment or immune prophylaxis tool in situations where a clear accidental exposure occurred.
One of the latest vaccines on research is a vaccine containing plasmids of full-length M segment genome (pWRG/HA-M) from Hantaan virus and Andes viruses. The level of the elicited neutralizing antibodies is lower and the duration of them is shorter than the single immunogenic vaccines. However, a high level of neutralizing antibodies are observed after a booster one or two years after initial vaccination and last more than 1.5 years. The cross neutralization with other hantavirus from the old and new world is also improved after the booster (14).
In conclusion no effective vaccine is available today to prevent hemorrhagic cardiopulmonary syndrome although DNA based vaccine are in progress, it is going to be some time before they will be available for human use.
PREVENTION OF INFECTION CONTROL MEASURES
Since the main source of infection for hantavirus are infected rodents and their droppings, saliva, urine and finally rodent bite, all the activities oriented to avoid contact and inhalation of aerosolized virus will be enforced, particularly among the people who may work in risk activities like forestry and agricultural workers. Infection has also been transmitted via rodent bites, so laboratory personnel who work with rats, have to be advised about their work risks.
The general precautions are periodically updated and related to the general population and are available in the center For Disease Control and Prevention web site at www.cdc.gov (4). There is no evidence of person-to-person transmission of other hantaviruses, with the exception of the Andes virus (29). One serological study of health care workers who care for patients infected with Sin Nombre Virus and the other two where patients were infected with AND virus failed to detect evidence of nosocomial acquisition (3,5,47).
However, investigation of the outbreak of Andes virus infection in Argentina in 1996–1997 strongly suggested person-to-person and nosocomial transmission. The Pan American Health Organization recommends that, in South America, if health care workers believe they might have encountered patients with hantavirus infection characterized by respiratory distress, standard precautions should be used along with the use of surgical masks and the placement of the patient into a private room. In addition, goggles and a high-efficiency particulate air (HEPA) mask should be used when procedures that may generate a high concentration of droplets and small particle aerosols, such as tracheostomy and intubation, are performed (48).
Although pre-exposure or post-exposure prophylaxis for hantavirus infection is not available, in the epidemiological environment where Andes is the etiology of hemorrhagic cardiopulmonary syndrome a diagnosis of Andes virus infection should be considered for health care personnel who develop clinical illness compatible with Andes virus infection within 4 weeks of exposure to infected persons.
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Table 1. Hemorrhagic Fever with Renal Syndrome and Hantavirus Syndrome
| Disease | Virus Serotypes | Location | Rodent host |
|---|---|---|---|
Hemorrhagic fever with renal syndrome (HFRS) |
Hantaan Seoul Dobrava/Belgrade Puumala |
Korea Korea Slovenia Finland |
Striped field mouse Norway rat Yellow-necked mouse Bank vole |
| Hantavirus syndrome | Sin Nombre Black Creek Canal New York Bayou Andes
Laguna Negra Choclo |
Southwest US Southern US New York Louisiana Patagonia Argentina Paraguay Panama |
Deer mouse Cotton rat White footed mouse Rice rat Long-tailed pygmy rice rat
Vesper mouse Fulvous pygmy rice rat |
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