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HANTAVIRUS
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Abstract
In May, 1993, a cluster of unexplained deaths occurred among young Native Americans living in a semi-arid region of the southwestern United States known as the Four Corners. The illness was characterized by a febrile prodrome and acute pulmonary edema simulating acute respiratory distress syndrome (ARDS). Caused by a hitherto unknown hantavirus, subsequently isolated, a six-month investigation of this cluster of cases concluded with the recognition of hantavirus pulmonary syndrome (HPS) named Sin Nombre Virus (SNV).
HPS is now recognized as a pan-American zoonosis, with an expanding clinical spectrum, caused by many novel New World hantaviruses with distinct rodent hosts. Humans become infected by contact with infected rodents or their excretions. Infection is strongly associated with disturbing rodent urine, droppings or nests in closed-up spaces; once disturbed, viral particles become airborne and are inhaled. In North America there is no evidence of secondary, person-to-person transmission. In South America person-to-person transmission may be a factor in disease spread.
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Clinical Disease
Manifestations of HPS
Discusses the symptoms and development of the HPS syndrome and how clinicians may diagnose
the disease.
CLINICAL DISEASE MANIFESTATIONS
Presentation and First Evaluation
Patients with HPS typically present in a very nonspecific way with a relatively short febrile prodrome lasting 3-5 days. In addition to fever and myalgias, early symptoms include headache, chills, dizziness, non-productive cough, nausea, vomiting, and other gastrointestinal symptoms. Malaise, diarrhea, and lightheadedness are reported by approximately half of all patients, with less frequent reports of arthralgias, back pain, and abdominal pain. Patients may report shortness of breath, (respiratory rate usually 26 - 30 times per minute). Typical findings on initial presentation include fever, tachypnea and tachycardia. The physical examination is usually otherwise normal.
HPS Clinical Presentation
| Most Frequent | Frequent | Other |
| fever | headaches | shortness of breath |
| chills | nausea, vomiting | dizziness |
| myalgias | abdominal pain | arthralgia |
| diarrhea | back or chest pain | |
| cough | sweats | |
| malaise |
The diagnosis is seldom made at this stage, as cough and tachypnea generally do not develop until approximately day seven. Once the cardiopulmonary phase begins, however, the disease progresses rapidly, necessitating hospitalization and often ventilation within 24 hours.
Signs that make a diagnosis of HPS unlikely include rashes, conjunctival or other hemorrhages, throat or conjunctival erythema, petechiae, and peripheral or periorbital edema.
Clinical Assessment
If a hantavirus infection is suspected, a CBC and blood chemistry should be repeated every 8 to 12 hours.
A fall in the serum albumin and a rise in the hematocrit may indicate a fluid shift from the patient's circulation into the lungs. The white blood cell count tends to be raised with a marked left shift. The percentage of white blood cells precursors may be as high as 50% and atypical lymphocytes are frequently present, usually at the time of onset of pulmonary edema.
In about 80% of individuals with HPS, the platelet count is below 150,000 units. A dramatic fall in the platelet count may herald a transition from the prodrome to the pulmonary edema phase of the illness.
The most severe cases of HPS develop disseminated intravenous coagulation (DIC), but, unlike the hantavirus-related hemorrhagic fevers (HFRS) seen in Asia, this is uncommon.
Coagulation Abnormalities in HPS
A Fatal Case
| Day 1 | Day 3 | |
| PT | 13.5 (NL) | 29.8 (up) |
| PTT | 32.8 (NL) | >240 (up) |
| Fibrinogen | 144 (down) | |
| Fibrin Split Products | >4000 (up) |
Proteinuria, and mild elevations of transaminases, CPK, amylase, and creatinine have also been reported.
When metabolic acidosis, prolongation of PT and PPT times and rising serum lactate levels develop, the prognosis is poor. Marked renal insufficiency has mainly been noted among cases from the southeastern United States although some degree of renal insufficiency, assessed by elevated serum creatinine levels, has been noted in 15% of all patients.
The combination of atypical lymphocytes, a significant bandemia, and thrombocytopenia in the setting of pulmonary edema is strongly suggestive of a hantavirus infection.
Disease Development
Within 24 hours of initial evaluation, most patients develop some degree of hypotension and progressive evidence of pulmonary edema and hypoxia, usually requiring mechanical ventilation. The patients with fatal infections appear to have severe myocardial depression which can progress to sinus bradycardia with subsequent electromechanical dissociation, ventricular tachycardia or fibrillation.
Hemodynamic compromise occurs a median of 5 days after symptom onset--usually dramatically within the first day of hospitalization. In contrast to HFRS, overt hemorrhage occurs rarely in HPS, although hemorrhage is occasionally seen in association with disseminated intravascular coagulation. In contrast to septic shock, HPS patients have a low cardiac output with a raised systemic vascular resistance. Poor prognostic indicators include a plasma lactate of greater than 4.0 mmol/L or a cardiac index of less than 2.2 L/min/m2 Whilst pulmonary edema and pleural effusions are common, multiorgan dysfunction syndrome is rarely seen. However, HPS patients sometimes have mildly impaired renal function. Survivors frequently become polyuric during convalescence and improve almost as rapidly as they decompensated.
Differential Diagnosis
The prodromal phase of HPS is indistinguishable clinically from numerous other viral infections. Often the only guide to the etiology of the patient's illness is the blood picture, which may show circulating immunoblasts, which appear as large atypical lymphocytes, and thrombocytopenia. However, unlike other viral infections, HPS patients usually have concurrent left-shifted neutrophilia with circulating myelocytes.
In the cardiopulmonary stage of the disease, the patients have a diffuse pulmonary edema. The most frequent cause for such a picture is silent myocardial infarction so it is important to obtain an ECG and echocardiogram early to aid in the assessment. Intensivists at the University of New Mexico, where many of the patients have been managed, have found that a echocardiogram also helps to distinguish these patients from patients with ARDS as cardiac function is depressed to a much greater degree in the HPS patients and cardiac output does not respond to fluid challenge as it tends to with ARDS.
Infections in the immunocompetent which might present with a non-specific prodrome leading to acute cardiopulmonary deterioration as in HPS include leptospirosis, Legionnaire's disease, mycoplasma, Q fever, chlamydia, and in regions where the organisms are present, septicemic plague, tularemia, coccidioidomycosis and histoplasmosis. Non-infectious conditions such as Goodpasture's syndrome should also be considered. Lack of coryza aids the clinical distinction between HPS and Influenza A infection.
It must be remembered that HPS is relatively uncommon and in the immunocompromised PCP, CMV, cryptococcus, aspergillus and graft vs. host disease are far more likely to be the cause of diffuse pulmonary infiltrates than a hantaviral infection.
Atypical Presentations
Atypical clinical presentations with prominent renal insufficiency have also been reported; therefore, HPS and infection due to Seoul virus, one of the Old World hantaviruses that cause HFRS, should be considered for patients with unexplained febrile nephropathies and appropriate laboratory findings. Asymptomatic illness is rare. However, an increasing number of acutely infected patients who develop either no cardiopulmonary disease or extremely mild pulmonary disease with minimal hypotension have been identified; one such patient was managed successfully as an outpatient.
Radiologic Findings
HPS has a characteristic radiological evolution, beginning with minimal changes of interstitial pulmonary edema, progressing to alveolar edema with severe bilateral involvement. Pleural effusions are common and are often large enough to be evident radiographically. Heart size is usually normal. Cardiac silhouette size on chest radiographs is usually normal.
Approximately one-third of patients show evidence of pulmonary edema in the initial radiograph. Forty-eight hours after the initial radiograph, virtually all patients demonstrate interstitial edema and two-thirds have developed extensive bibasilar or perihilar airspace disease.
This radiograph shows the interstitial changes of early HPS. At the lung bases are Kerley B lines, short linear opacities which are perpendicular to the pleural surfaces. The longer linear opacities radiating from the lung hilum are known as Kerley A lines. Together these findings are classically seen in heart failure, but are also seen in HPS. Peribronchial cuffing is also seen well on this film. The bronchi viewed end on are surrounded by a "cuff" of edema. This makes the bronchi appear as prominent circular opacities, appearing as "ring-like" shapes next to pulmonary blood vessels.
The lack of peripheral distribution of the initial airspace disease, the prominence of interstitial edema and the presence of pleural effusions early in the disease process help distinguish HPS from ARDS. There is, however, overlap in the radiographic appearance of the two diseases. Atypical pneumonias such as that caused by mycoplasm pneumonia can produce radiographic findings similar to early HPS, although the clinical illness tends to be much less severe.
Hyperacute hypersensitivity reactions, mitral stenosis, acute myocardial infarctions, all can cause interstitial edema with a normal heart size, and are also in the radiologic differential diagnosis of early HPS.
Treatment of patients with HPS remains supportive in nature. All patients should receive broad spectrum antibiotic coverage until HPS is proven. Early intensive care management is important, with prompt correction of electrolyte, pulmonary, and hemodynamic abnormalities.
Flow-directed catheterization of the pulmonary artery is helpful not only in intensively monitoring and clinically managing the patient but also in verifying the normal-to-low pulmonary wedge pressure, decreased cardiac index, and increased systemic vascular resistance in patients who progress to shock.
The UNM approach is to administer fluids (usually crystalloid) to reach a PAOP of 12-15 mm, and then to rely on inotropic agents to augment myocardial contractility. PAOP levels higher than this have resulted in pulmonary edema that responded poorly to mechanical ventilation, and in some cases, was refractory. As systemic vascular resistance is actually high, vasopressors such as norepinephrine have poor efficacy but tend to be added as a last resort in the critically ill.
Vasopressor Dosage
| Dopamine | 4 - 8 micrograms/kg/min |
| Dobutamine | 5 - 20 micrograms/kg/min |
Given that patients who recover from this syndrome do so rapidly, cardiovascular support with extracorporeal membrane oxygenation (ECMO), has been tried. ECMO successfully provided cardiopulmonary support in two of three patients with HPS. From their clinical appearance, prior to instituting ECMO, and by criteria developed from previous experience with HPS patients, none of the three patients had been expected to survive.
Intravenous Ribavirin has reduced case fatality in a controlled trial for hemorrhagic fever with renal syndrome (HFRS), another disease syndrome caused by Old World hantaviruses. However, despite its in vitro activity against Sin Nombre virus, an open-label trial during the initial 1993 outbreak failed to document a dramatic reduction in case fatality. This may due to the fact that patients were enrolled too late in their disease course or that the symptoms may relate more to the immunological response to the virus rather than direct viral invasion. Either condition would render direct antiviral therapy ineffective.
There is an NIH-sponsored double-blinded placebo-controlled trial of intravenous ribavirin for presumed HPS. Information about the trial and active enrollment sites may be obtained by calling 1-888-866-7257.
Take-home Message for Care Providers
No single pathognomonic lesion is found that would permit certain histopathologic diagnosis of HPS. In fact, the incipient stages of ARDS can create a picture of pulmonary edema similar to HPS. However, the total picture is rather distinctive. Pathology in HPS patients is characterized mainly by pulmonary findings, as well as findings in the spleen, liver, and lymph nodes.
Grossly, the lungs are dense, rubbery and heavy, usually weighing twice as much as the average lung. They are often found floating in a pool of yellow serous fluid within the pleural cavity.
A.The pathologic lesions are primarily vascular with variable degrees of generalized capillary dilation and edema. Morphologic changes of the endothelium are uncommon and, when present, consist of prominent and swollen endothelial cells. Histopathologic lesions are mainly seen in the lung and spleen. In most cases, the lungs reveal a mild to moderate interstitial pneumonitis with variable degrees of congestion, edema, and mononuclear cell infiltration. The cellular infiltrate is composed of small and enlarged mononuclear cells with the appearance of immunoblasts. Focal hyalin membranes are observed, as well as extensive intraalveolar edema and fibrin. Neutrophils are scanty, and the respiratory epithelium is intact in typical cases, with no evidence of cellular debris, nuclear fragmentation, or type II pneumocyte hyperplasia.
Among patients who die after a longer-than-average course of the disease, and in lung biopsy specimens from survivors, the histopathologic changes are more characteristic of exudative and proliferative stages of diffuse alveolar damage. In these cases, proliferation of reparative type II pneumocytes, severe edematous and fibroblastic thickening of the alveolar septa with severe airspace disorganization, and distortion of lung architecture can be seen.
Other typical histopathologic findings are seen in lymphoid tissues of HPS patients. These include the presence of immunoblasts within the red pulp and periarteriolar sheaths of the spleen and paracortex, within sinuses of lymph nodes, and in the peripheral blood.
Functional impairment of vascular endothelium is central to the pathogenesis of HPS. However, the pathogenesis of HPS is complex, and a myocardial depressant may contribute significantly to the mortality of this disease. It is unclear how the shock syndrome relates to factors such as viral distribution and immunologic and pharmacological mediators of capillary permeability. There appears to be compartmentalization of a selective immune response in the lungs of HPS patients in combination with extremely high levels of viral antigens in the pulmonary vasculature. This feature suggests that the mechanism of inflammatory cell recruitment in the lungs of HPS patients may result from specific attraction and adherence of a selective population of inflammatory cells to an activated pulmonary microvascular endothelium.
Immunohistochemistry analysis has shown that viral antigens are distributed primarily within the endothelium of capillaries throughout various tissues from patients with HPS. Marked accumulations of hantaviral antigens are seen in the pulmonary microvasculature and in follicular dendritic cells within the lymphoid follicles of spleen and lymph nodes. Hantaviral nucleic acids can also be localized to endothelial and inflammatory cells in tissues from HPS cases by using in situ hybridization. Electron micrographic studies confirm the infection of endothelial cells and macrophages in the lungs of HPS patients. Typical hantaviral inclusions are seen frequently in pulmonary endothelial cells, and their identity can be confirmed by immunolabeling. In the heart, endothelial staining is mainly in the capillaries of the myocardium and varies from focal immunostaining in some cases to diffuse and extensive staining in others. Occasionally, staining of endothelial cells lining the endocardium is observed.
A positive serological test result, evidence of viral antigen in tissue by
immunohistochemistry, or the presence of amplifiable viral RNA sequences in blood or
tissue, with compatible history of HPS, is considered diagnostic for HPS.
Serologic assays
At the time of the 1993 outbreak in the Four Corners area, cross-reactive antibodies to the previously known hantaviruses (e.g., Hantaan, Seoul, Puumala, and Prospect Hill viruses) were found in the acute- and convalescent-phase sera of some of the initial HPS patients. Tests based on specific viral antigens from SNV have since been developed and are now widely used for the routine diagnosis of HPS. CDC uses an enzyme-linked immunosorbent assay (ELISA) to detect IgM antibodies to SNV and to diagnose acute infections with other hantaviruses. This assay is also available in some state health laboratories.
An IgG test is used in conjunction with the IgM-capture test. Acute- and convalescent-phase sera should reflect a four-fold rise in IgG antibody titer or the presence of IgM in acute-phase sera to be diagnostic for hantaviral disease. Note that acute-phase serum sent as an initial diagnostic specimen may not yet have IgG. IgG antibody is long lasting, and sera of patients retrospectively identified appear to have retained antibody for many years. The SNV IgG ELISA has therefore been used in serologic investigations of the epidemiology of the disease and appears to be appropriate for this purpose. Investigations of selected populations using this assay have confirmed that infections with the virus are not common and that mild or inapparent infections are rare.
A Western blot assay using recombinant antigens and isotype-specific conjugates for IgM-IgG differentiation has also been developed and its results are generally in agreement with those of the IgM-capture format.
Epitope mapping of SNV antibodies has been used to identify immunodominant epitopes of 43 and 31 amino acids in the nucleocapsid protein and G1 glycoprotein, respectively. The immunodominant epitope of G1 is conserved among SNV strains from a broad geographical area, despite extensive nucleotide sequence heterogeneity, and this feature constitutes the basis of a type-specific assay for SNV-like antibodies. Antibodies from HPS patients separated by more than 3000 km have been shown to react with the dominant G1 epitope.
Also in use is a rapid immunoblot strip assay (RIBA), an investigational prototype assay to identify serum antibody to recombinant proteins and peptides specific for SNV and other hantaviruses.
Serologic confirmation of hantaviral infections has traditionally been done with neutralizing plaque assays, which have been recently described for SNV. However, these specific assays are also not commercially available.
Isolation
Isolation of hantaviruses (see below) from human sources is difficult, and the viruses
causing HPS seem to be no exception to this rule. To date, no isolates of SNV-like viruses
have been recovered from humans, and therefore virus isolation is not a consideration for
diagnostic purposes.
Immunohistochemistry (IHC)
IHC testing of formalin-fixed tissues with specific monoclonal and polyclonal antibodies can be used to detect hantavirus antigens and has proven to be a sensitive method for laboratory confirmation of hantaviral infections. IHC has an important role in the diagnosis of HPS in patients from whom serum samples and frozen tissues are unavailable for diagnostic testing and in the retrospective assessment of disease prevalence in a defined geographic region.
Polymerase Chain Reaction (PCR)
Reverse transcriptase-PCR (RT-PCR) can be used to detect hantaviral RNA in fresh frozen lung tissue, blood clots, or nucleated blood cells. However, RT-PCR is very prone to cross-contamination and should be considered an experimental technique. Differences in viruses in the United States complicate the use and sensitivity of RT-PCR for the routine diagnosis of hantaviral infections.
Case Characteristics
For the latest counts and descriptive statistics on confirmed cases of HPS in the United States, please see the HPS Case Information page. Information on this page is updated as the case count changes.
HPS an Old Disease, Newly Recognized
Although the high-profile investigation of the HPS syndrome emphasized public health authorities' warnings about new and emerging infectious diseases, HPS has turned out to be a newly identified, but not a "new," disease (see Tracking a Mystery Disease). In fact, the earliest case of a serologically confirmed SNV infection was in a person who developed an HPS-compatible illness in July 1959 and was found to have IgG antibodies in September 1994. The earliest case of HPS to be confirmed by IHC with direct visualization of hantaviral antigens in postmortem tissue involved a patient who died in 1978.
Risk Factors for Disease
Little is known about activities that lead to a greater risk of infection. However, an early case-control study suggests that increased numbers of rodents in the household is the strongest risk factor for infection. Entering rarely opened or seasonally closed buildings may also contribute to infection. Among the confirmed cases of HPS for which exposure information is available, 70% of the patients in the case control study had exposures closely associated with peridomestic activities, such as cleaning, in homes that showed signs of rodent infestation. Four clusters of HPS cases involving 2-4 persons have been documented; for each cluster, exposure probably occurred within a shared, enclosed structure. Taken together, these observations suggest that disturbing or inhabiting closed, actively rodent-infested structures may constitute an important risk factor for contracting HPS
Potentially occupationally acquired SNV infections have been recognized but are infrequent. Among documented U.S. cases of HPS, patients with potential occupational exposures have included grain farmers, an extension livestock specialist, field biologists, and agricultural, mill, construction, utility and feedlot workers. Many of these individuals had concurrent peridomestic exposures. Among U.S. mammalogists and rodent workers with varying degrees of rodent exposure, the seroprevalence of SNV antibodies was 1.14%. In contrast, a recent HPS seroprevalence study focused on selected occupational groups with frequent contact with rodents and their excreta (e.g., farm workers, laborers, professionals, home repairers, service industry and park service workers, heating and plumbing contractors, utility workers, and technicians) found no evidence of SNV infection.
Travel to and within all areas where hantavirus infection has been reported is not considered a risk factor for infection with HPS. The possibility of exposure to hantavirus for campers, hikers, and tourists is very small and is reduced further if steps are taken to reduce rodent contact.
The identification of the etiology of HPS has added another group of hantaviruses and their associated sigmodontine rodent hosts to the annals of hantavirus vector relationships.
Reservoir and Reservoir Distribution: United States
The investigation of the original HPS outbreak in the Four Corners region implicated the deer mouse, Peromyscus maniculatus, (subfamily Sigmodontine, family: Murideae) as the primary rodent reservoir. However, cases of HPS have been identified in people who have not visited the regions populated by P. maniculatus, and three additional hantaviruses with different rodent hosts have now been identified.
The first of these three viruses, Black Creek Canal virus (BCCV), is associated with the cotton rat (Sigmodon hispidus); a single case of infection with this virus has been described in Dade County, Florida. Investigations of cases of HPS in Louisiana and Texas have yielded the unique viral sequence of a second, Bayou virus. This virus sequence has now been associated with the rice rat (Oryzomys palustris). Finally, cases of HPS in the northeastern United States have been caused by a virus (New York-1) that is similar to SNV, but distinct enough to suggest that it is a variant found in the eastern third of the United States. This virus is associated with both P. maniculatus and the white footed mouse, P. leucopus . To date, most of the human cases of HPS have been associated with the SNV.
Recent studies have confirmed that infected rodents are present in every habitat type--from desert to alpine tundra--but that the prevalence of infection is higher among certain species of Peromyscus and in certain middle-altitude habitats. Surveys of rodents throughout the United States suggest that SNV is distributed in all locations where P. maniculatus occurs and that related viruses are found in P. leucopus throughout its range. Thus cases of HPS can be expected to occur throughout the range of rodent distribution. This probably reflects the fact that P. maniculatus and P. leucopus are found in a wider range of habitats, are more commonly found in the peridomestic setting; and typically have much higher population densities than other rodents. Other implicated species, such as S. hispidus and O. palustris, generally do not live in such close proximity to human habitats, and this factor may decrease the probability of human exposure to viruses shed by these rodents.
Lower population density, a lesser propensity for peridomestic encroachment and a narrower geographic and ecologic distribution (and perhaps differing virulence) may explain the lack of human disease associated with hantaviruses (or genetic sequences thought to represent additional hantaviruses) from meadow and California voles (Microtus pennsylvanicus and californicus, respectively) and the western harvest mouse (Reithrodontomys megalotis).
Reservoir Distribution Outside the United States
HPS clearly occurs in South America and these cases are caused by viruses distinct from those described in the United States. A genetically distinct hantavirus (provisionally named Juquitaba virus) has been detected in autopsy tissues from a fatal case of HPS in Brazil. The virus is probably carried by a distinct rodent vector and efforts to identify the host species are in progress. Cases of HPS-like disease have also been described in Argentina and Paraguay and similar efforts to determine the rodent vector are proceeding in these countries. The hosts will also likely be sigmodontine rodents. A number of New World rodent species from which distinct hantaviral sequences or viral isolates have been derived exist in Central and South America, but these viruses remain unassociated with human disease.
It is likely that HPS does not occur in the Old World. All of the rodent hosts identified thus far belong to a New World subfamily of the family Muridae and order Rodentia.
Among rodents trapped as part of the initial investigation of the Four Corners outbreak in 1993, the overall prevalence rate of hantavirus antibody in P. Maniculatus was 30.4%. Almost ninety-seven percent of the mice with detectable antibodies had amplifiable genetic sequences in their tissues, suggesting viral persistence in this host species. Body mass studies of the infected rodents show that there is a direct correlation between weight and antibody reactivity, indicating that the virus is transmitted horizontally among rodents. Transmission from rodent to rodent is believed to occur primarily after weaning and through contact, perhaps aggressive contact with accompanying combat wounds. Although hantaviruses infect their rodent hosts, there is minimal evidence to suggest that they cause illness in the rodents. Studies of the genomic sequences indicate that the virus is not the result of genomic rearrangement, but has probably evolved over a long period of time concurrently with its rodent host.
Transmission
Aerosols are most likely to be the major route of transmission from rodents to humans. Humans, who are dead-end hosts, may contract the virus when saliva or excreta from infected rodents are inhaled as aerosols produced directly from the animal. Transmission may also occur when fresh or dried materials contaminated by rodent excreta are disturbed, directly introduced into broken skin, introduced into the eyes, or, possibly, ingested in contaminated food or water. Persons have also become infected after being bitten by rodents.
Ticks, fleas, mosquitoes and other biting insects have not been implicated in the transmission of HPS. In fact, aside from the rodent vectors described above, no other animals are known to have a direct role in the transmission of the previously identified hantaviruses or with any case of HPS. However, domestic cats and dogs may bring infected rodents into contact with humans.
Person-to-person transmission of HFRS in Asia and HPS in the United States has not been reported. In addition, a study of 396 health care workers in the southwestern United States failed to show nosocomial transmission. Therefore, CDC guidelines for management of HPS patients in the U.S. recommend standard precautions. Information collected recently in Argentina, however, suggests that person-to-person transmission may have ocurred during a 1996 outbreak centered in the towns of El Bolson and Bariloche. For more information on this subject, please visit "Hantavirus In South America".
Nosocomial transmission of HFRS has also never been reported, which is consistent with the difficulty of culturing virus from infected persons. Analogously, nosocomial transmission of HPS has not been reported. Furthermore, a serosurvey among health care workers who took care of the initial cluster of HPS patients failed to show any seropositive results. Therefore, no additional precaution besides universal precautions is indicated for HPS patients.
Hantaviruses
Hantaviruses belong to the bunyavirus family of viruses. There are 5 genera within the family: bunyavirus, phlebovirus, nairovirus, tospovirus, and hantavirus. Each is made up of negative-sensed, single-stranded RNA viruses. All these genera include arthropod-borne viruses, with the exception of hantavirus, which is rodent-borne.
Like other members of the bunyavirus family, hantaviruses are enveloped viruses with a genome that consists of three single-stranded RNA segments designated S (small), M (medium), and L (large). All hantaviral genes are encoded in the negative (genome complementary) sense. The S RNA encodes the nucleocapsid (N) protein. The M RNA encodes a polyprotein that is cotranslationally cleaved to yield the envelope glycoproteins G1 and G2. The L RNA encodes the L protein, which functions as the viral transcriptase/replicase. Within virions, the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, which circularize due to sequence complementarity between the 5' and 3' terminal sequences of each genomic segment.
Hantaviruses replicate exclusively in the host cell cytoplasm. Entry into host cells is thought to occur by attachment of virions to cellular receptors and subsequent endocytosis. Nucleocapsids are introduced into the cytoplasm by pH-dependent fusion of the virion with the endosomal membrane. Transcription of viral genes is initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this "cap snatching," the mRNAs of hantaviruses are believed to be capped and contain nontemplated 5' terminal extensions. The viral N and L mRNAs are thought to undergo translation at free ribosomes, whereas the M mRNA is translated in the endoplasmic reticulum. G1 and G2 glycoproteins form heterodimers and are then transported from the endoplasmic reticulum to the Golgi complex, where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirions are believed to form by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae. Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis.
Hantaviruses Causing HPS
Sin Nombre virus (SNV) was first isolated from rodents collected on the premises of one of the initial HPS patients in the Four Corners region. Isolation was achieved through blind passage in Peromyscus maniculatus and subsequent adaptation to growth in Vero E6 cells. Additional viral strains have also been isolated from P. maniculatus associated with a fatal case in California and P. leucopus from the vicinity of probable infection of a New York case. Black Creek Canal virus was isolated from S. hispidus collected near the residence of a human case in Dade County, Florida.
Other Hantaviruses
Several members of the hantavirus genus cause different forms of hemorrhagic fever with renal syndrome (HFRS), an ancient disease first described in Russia in 1913. The four viruses that are associated with HFRS, each named for the region from where they were first isolated, have different primary rodent hosts: Apodemus agrarius (the striped field mouse) for Hantaan virus, Rattus norvegicus (the Norway rat) and Rattus rattus (the black rat) for Seoul virus, Clethrionomys glareolus (the bank vole) for Puumala virus, and Apodemus flavicollis (the yellow-necked field mouse) for Dobrava virus. Hantaan virus from Korea and Dobrava virus from Slovenia are associated with a severe form of HFRS characterized by renal failure that can precede pulmonary edema and disseminated intravascular coagulation (DIC), with estimated mortality rates of 5% to 15%. A moderate form of HFRS caused by Seoul virus (which, along with its host, is distributed worldwide) is responsible for thousands of Eurasian cases annually. Serologic evidence for infection with Seoul-like hantaviruses has been found in rodents in major cities of the United States, and this virus was recently implicated in human cases of HFRS in Baltimore. One report has also associated Seoul virus with chronic renal disease. A mild form of HFRS, caused by Puumala virus, is responsible for nephropathia epidemica in Scandinavia, with an estimated mortality rate of 1% to 3%.
Characteristics of Some Known Hantaviruses
| Hantaan | Seoul | Puumala | Prospect Hill | Sin Nombre | |
| Geographic Region | Asia | Worldwide | Northern Europe | U.S. | North America |
| Reservoir | Field Mouse | Domestic Rat | Bank Vole | Meadow Vole | Deer Mouse |
| Pathology | Renal | Renal | Renal | No known human disease | Pulmonary |
| Mortality | 5 - 15% | 1% | 1% | N/A | 50% |
Another hantavirus, Prospect Hill, has been previously isolated in the United States, but has not been implicated as a cause of human disease. Prospect Hill virus was originally isolated from Microtus pennsylvanicus (meadow vole) in Frederick, MD.
Comparison of HFRS and HPS
| HFRS | HPS | |
| Major Target Organ | kidney | lung |
| First Phase | febrile | febrile "prodrome" |
| Second Phase | shock | shock, pulmonary edema |
| Evolution | oliguria, diureses, convalescence | diureses, convalescence |
| Mortality | 1 - 15% | 50% |
Epidemiology in the Virology Laboratory
During the outbreak in 1993, definitive proof that the agent causing HPS was a novel hantavirus was obtained using a genetic detection assay. Oligonucleotide primers were designed on the basis of regions of the M segment (G2 coding region) conserved among hantaviruses and were used in a nested RT-PCR assay to amplify hantavirus-specific DNA fragments from RNA extracted from the tissues of patients. The amplified DNA fragments were then sequenced. Comparative and phylogenetic analyses of derived sequence data demonstrated that the hantavirus associated with the HPS outbreak (SNV) was a novel virus most closely related to Prospect Hill virus (PHV). In addition, a direct genetic link was made between the human HPS cases and the virus harbored by peridomestic P. maniculatus rodents. Characterization of hantaviral genetic sequences recovered from human tissues demonstrated that these sequences were identical to those from rodents captured at the site of the patient's presumed infection. This characterization has continued to facilitate identification of the site of infection when more than one such site exists and therefore focus the public health response. These techniques also allow implication of a specific rodent host in areas of overlapping hosts.
Sin Nombre Virus Sequencing
The entire genomic sequence of SNV has subsequently been determined by using RNA extracted from autopsy material as well as RNA extracted from cell culture-adapted virus. The L RNA is 6562 nucleotides (nt) in length; the M RNA is 3696 nt long; and the S RNA is 2059 to 2060 nt long. Interestingly, when the prototype sequence (NMH10) of SNV detected in tissues from an HPS case was compared with the sequence of the SNV isolate (NMR11; isolated in Vero E6 cells from P. maniculatus trapped in the residence of the same case), only 16 nucleotide changes were found, and none of these changes resulted in alterations in amino acid sequences of viral proteins. It had been assumed that in the process of adaptation to cell culture, selection of SNV variants which grow optimally in cell culture would occur, and selected variants would differ genetically from the parental virus. Though NMH10 and NMR11 are identical in protein sequence, nucleotide substitutions in nontranslated regions of the genome could be responsible for altered viral phenotypes, as could changes in protein glycosylation or virus membrane components.
The nested RT-PCR assay developed during the initial HPS outbreak provided a rapid method for the genetic characterization of novel hantaviruses that did not require a virus isolate. Numerous new hantaviruses have been detected by RT-PCR in rodent tissues but have yet to be associated with human disease. These include El Moro Canyon virus associated with the western harvest mouse (Reithrodontomys megalotis), Tula virus with Microtus arvalis and M. rossiaemeridionalis, Rio Segundo virus with the Mexican harvest mouse (R. mexicanus), Isla Vista virus with the California vole (M. californicus), and Prospect Hill-like viruses in Microtus species.
Phylogenetic Analysis
Phylogenetic analysis of Old World and American hantaviruses indicates that the relationship among hantaviruses corresponds with the phylogeny of their rodent hosts. Viruses of rodents belonging to the subfamily Murinae are monophyletic as are hantaviruses of arvicoline and sigmodontine rodents, suggesting that long-term virus-rodent coevolution is taking place. Hantavirus evolution is best understood as co-evolution within specific lineages in the rodent family Muridae. The apparent coupling between hantaviruses and their rodent hosts suggests that viruses of sigmodontine rodents share a common ancestor, as do viruses of the subfamily Arvicolinae and Murinae. This coupling also has a geographic and clinical correlate: viruses found in Old World murine rodents, including Hantaan virus (HTNV), Seoul virus (SEOV) and Dobrava virus, are associated with HFRS in Eurasia. By contrast, viruses carried by New World sigmodontine rodents, including SNV Black Creek Canal virus (BCCV) and Bayou virus (BAYV), are associated with HPS in the Americas. This distinction can narrow the search for a rodent host for newly discovered HPS-like diseases and suggest disease implications for the various new viruses being genetically amplified from rodents.
Sequence Divergence
Detection and characterization of Sin Nombre-like viruses in P. maniculatus and P. leucopus populations have shown that multiple phylogenetic lineages of SNV exist in North America, and in some cases similar viruses are detected in both Peromyscus species. Sequence divergence among SNV genes has been shown to be as high as 23% nucleotide dissimilarity and 7% amino acid dissimilarity. Comparison of SNV sequences with those of other hantaviruses provides no obvious explanation as to why SNV and related viruses cause HPS while other hantaviruses are associated with HFRS. The development of a reverse genetics system for manipulation of virus genomes and an animal model for studying pathogenesis will be necessary to define the molecular mechanism(s) of SNV pathogenicity.
Genomic reassortment by RNA viruses with segmented genomes is well documented and has the potential to produce viruses with altered biological activity, host range, and disease potential. For example, segment reassortment among influenza virus strains (antigenic shift) is thought to be responsible for influenza pandemics. Genomic reassortment among SNV variants is known to occur in nature, but the precise role of genomic reassortment in the epidemiology of HPS and HFRS is unknown.
Special Pathogens Branch has several sources of information on HPS prevention issues.
Prevention of HPS in the Laboratory
For information on handling rodents in the laboratory, see "Guidelines for Removing Organs or Obtaining Blood from Rodents Potentially Infected with Hantavirus".
See "Laboratory Management of Agents Associated with Hantavirus Pulmonary Syndrome: Interim Biosafety Guidelines" for information on this subject.
Controlling Rodent Infestations
Handling small-scale rodent infestations, and the prevention of rodent infestations, is covered in "How Do I Prevent HPS?", (this is the text-only link) designed for general readers in this web site. Guidelines for dealing with particularly heavy rodent infestations may be found there.
Handling Frequent Exposures to Rodents
Please see "Precautions for Workers in Affected Areas Who are Regularly Exposed to Rodents" in the text-only version of "How Do I Prevent HPS?" (this is the text-only version).
Updated Information on Respirators
Read the "Update On the Nomenclature and Use of Respirators as a Precaution for Hantavirus Infection, February, 1999" in the text-only version of "How Do I Prevent HPS?".
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1999, Special Pathogens Branch
Division of Viral and Rickettsial Diseases
National Center for Infectious Diseases
The Centers for Disease Control and Prevention (CDC)
U.S. Department of Health and Human Services