Background

The Hantavirus causes a devastating cardiopulmonary syndrome where patients may die from severe pulmonary edema. Most investigation has centered upon rapid diagnosis by serologic studies as well as therapeutic intervention. In spite of progress, the case fatality rate is still very high.

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE
Seroprevalence study of Hantavirus infection in the community based population. Diglisic G, Rossi CA, Doti A, Walshe DK. St. Agnes Hospital, Baltimore, MD, USA.	Md Med J 1999 Nov-Dec;48(6):303-6 Abstract quote The genus Hantavirus, family Bunyaviridae, comprise at least 20 distinct viruses. Ten of these have been linked to specific human diseases. Hemorrhagic fever with renal syndrome has been recognized since the 1950s. Hantavirus pulmonary syndrome was recognized in the United States in 1993. Epizootiologic studies of Norway rats in the Baltimore area have shown that rodent infections with hantaviruses are common and geographically widespread with prevalence reaching 44% in tested rat populations. These viruses are antigenically related to the Seoul virus. Hantavirus infections in humans occur through transmission from a rodent reservoir, primarily by inhalation of virus laden rodent excreta. There is no evidence to support person-to-person transmission of any known Hantavirus. To establish the prevalence of Hantavirus infections in humans in the Baltimore area we collected sera from 1,212 persons attending a community based health care system. These were tested for antibodies against three reference Hantavirus strains: Hantaan (HTN), Seoul (SEO), and Convict Creek (HN017). HN017 was chosen to represent the SinNombre (SN-like) strains of Hantavirus. Sera from nine patients were positive to Hantavirus specific antibodies, HTN, and SEO by Enzyme Linked Imuno Sorbent Assay (ELISA). No sera were positive for HN017 antigen. All sera that were positive for HTN and SEO were tested by western blot for HTN. All nine sera were confirmed positive by western blot. This suggests that unrecognized infections with Hantaan or Seoul-like viruses occur in the Baltimore area in humans, although the prevalence rate in humans is low (0.74%). Epidemiologic monitoring may be warranted to establish the health implications of these infections.
GEOGRAPHY	Highest incidence of this rodent-borne zoonosis is observed in rural areas of the southwestern and northwestern United States and western Canada, and in the eastern United States

 

EPIDEMIOLOGIC ASSOCIATIONS

CHARACTERIZATION

Ecology and demographics of hantavirus infections in rodent populations in the Walker River Basin of Nevada and California. Boone JD, Otteson EW, McGwire KC, Villard P, Rowe JE, St Jeor SC. Department of Biology, University of Nevada, Reno 89557, USA.

Am J Trop Med Hyg 1998 Sep;59(3):445-51 Abstract quote To study the ecologic correlates of hantavirus in deer mice (Peromyscus maniculatus), we sampled 114 sites in the Walker River Basin of Nevada and California in 1995-1996. Blood samples were tested for antibody to hantavirus, and a subset of samples was also tested for virus RNA by reverse transcription-polymerase chain reaction. Average prevalence of antibody-positive mice was 17%, with heavier males the most likely to be infected. Antibody prevalence varied within repeatedly sampled sites from 0% to 50% over the course of several months, suggesting possible infection cycles. Although there was no linear correlation between deer mouse density and antibody prevalence on sample sites, more complex relationships between density and prevalence appeared likely. Specifically, infections were less likely where rodent densities were lower than a critical threshold value. However, above this value, density had no effect on prevalence.

 

PATHOGENESIS	CHARACTERIZATION
New York 1 and Sin Nombre viruses are serotypically distinct viruses associated with hantavirus pulmonary syndrome. Gavrilovskaya I, LaMonica R, Fay ME, Hjelle B, Schmaljohn C, Shaw R, Mackow ER. The Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA.	J Clin Microbiol 1999 Jan;37(1):122-6 Abstract quote New York 1 virus (NY-1) and Sin Nombre virus (SN) are associated with hantavirus pulmonary syndrome (HPS). NY-1 and SN are derived from unique mammalian hosts and geographic locations but have similar G1 and G2 surface proteins (93 and 97% identical, respectively). Focus reduction neutralization assays were used to define the serotypic relationship between NY-1 and SN. Sera from NY-1-positive Peromyscus leucopus neutralized NY-1 and SN at titers of >/=1/3,200 and 16-fold-lower neutralizing titers to NY-1 than to SN. Reference sera to Hantaan, Seoul, and Prospect Hill viruses also failed to neutralize NY-1. These results indicate that SN and NY-1 define unique hantavirus serotypes and implicate the presence of additional HPS-associated hantavirus serotypes in the Americas.
Sin Nombre virus pathogenesis in Peromyscus maniculatus. Netski D, Thran BH, St Jeor SC. Cell and Molecular Biology Program and Department of Microbiology, Reno School of Medicine, University of Nevada, Reno, Nevada, USA.	J Virol 1999 Jan;73(1):585-91 Abstract quote Sin Nombre virus (SNV), a member of the Hantavirus genus, causes acute viral pneumonia in humans and is thought to persistently infect mice. The deer mouse, Peromyscus maniculatus, has been identified as the primary reservoir host for SNV. To understand SNV infection of P. maniculatus, we examined wild deer mice for localization of viral antigens and nucleic acid. Morphologic examination consistently revealed septal edema within lung tissue and mononuclear cell infiltrates in portal areas of the liver. Immunohistochemical analysis of SNV-infected deer mice identified viral antigens within lung, liver, kidney, and spleen. The lungs consistently presented with the highest levels of viral antigen by immunohistochemistry and with the highest levels of nucleic acid by reverse transcriptase (RT) PCR. The mononuclear cell infiltrates surrounding liver portal triads were positive for SNV antigens in addition to resident macrophages in liver sinuses. Spleen tissue contained antigens in both the red pulp and the periartereolar region of the white pulp. The kidney presented with no gross pathology, although antigens could be localized to glomeruli. Virus antigen levels within the kidney were highest in deer mice that did not have antibodies to SNV but contained viral nucleic acid detectable by RT PCR. Since transmission is thought to occur via urine, our results suggest that virus transmission may be highest in the early stages of infection. In addition, these results indicate that SNV does cause some pathology within its reservoir host.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Distinguishing hantavirus pulmonary syndrome from acute respiratory distress syndrome by chest radiography: are there different radiographic manifestations of increased alveolar permeability? Ketai LH, Kelsey CA, Jordan K, Levin DL, Sullivan LM, Williamson MR, Wiest PW, Sell JJ. Department of Radiology, University of New Mexico, Albuquerque, USA.	J Thorac Imaging 1998 Jul;13(3):172-7 Abstract quote Hantavirus infection may cause diffuse air space disease, termed hantavirus pulmonary syndrome (HPS). The authors sought to determine if chest radiographs could differentiate HPS from typical acute respiratory distress syndrome (ARDS). The authors identified patients with either HPS (n = 11) or acute ARDS (n = 32) and selected the earliest chest radiograph showing diffuse airspace disease, and a chest radiograph taken 24 to 48 hours previously. Thoracic and general radiologists first viewed the chest radiograph showing diffuse air space disease, and ranked the likelihood that each case represented HPS versus ARDS. Afterward, readers viewed earlier chest radiographs and rescored each case. Receiver operating characteristic (ROC) curves from both scoring sessions were generated. The mean areas under the ROC curves for the entire group was 0.83 +/- 0.12 initially, and improved to 0.87 +/- 0.09 (p < 0.05) after viewing prior chest radiographs. Receiver operating characteristic curves of thoracic radiologists described greater areas than those of general radiologists both before and after viewing prior chest radiographs; 0.95 +/- 0.01 versus 0.78 +/- 0.08 (p < 0.05) and 96 +/- 0.02 versus 0.80 +/- 0.05 (p < 0.05). The mean sensitivity and specificity of chest radiograph interpretation for HPS was 86 +/- 13% and 74 +/- 11%, respectively. Chest radiographs can differentiate HPS from ARDS. Accuracy is improved by the use of serial radiographs and more highly trained readers. The chest radiograph findings may represent differences in the extent of alveolar epithelial damage seen in HPS and ARDS.
LABORATORY MARKERS	Definitive diagnosis of SNV infection is made by serologic detection of specific IgM and IgG antibodies to the SNV N antigen in combination with IgG antibodies to the viral G1 glycoprotein.
Enzyme immuno assay for the detection of virus specific IgG and IgM antibody in patients with haemorrhagic fever with renal syndrome. Ivanov AP, Tkachenko EA, Petrov VA, Pashkov AJ, Dzagurova TK, Vladimirova TP, Voronkova GM, van der Groen G. Institute of Poliomyelitis and Virus Encephalitides of the U.S.S.R. Academy of Medical Sciences, Moscow.	Arch Virol 1988;100(1-2):1-7 Abstract quote Consecutive serum samples collected from 235 patients with Haemorrhagic Fever with Renal Syndrome (HFRS), between two days and two years after onset of disease, have been analysed for the presence of IgG and IgM type of antibodies specific for Hanta-viruses. The sera were screened in parallel by a newly developed indirect Immuno Enzyme Assay (EIA) in parallel with Indirect Immunofluorescent Antibody Assay (IFA). In both tests the Hantaan virus strain 76-118 was used as the antigen. The EIA was much more sensitive than the IFA test for the detection of IgM type antibodies. With the indirect EIA IgM type antibodies against Hantaan virus 76-118 have been detected in HFRS patient's sera from the second day of illness indicating the usefulness of this test for the early serological diagnosis of this disease.
Detection of Hantaan and Seoul viruses by reverse transcriptase-polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP) in renal syndrome patients with hemorrhagic fever. Ahn C, Cho JT, Lee JG, Lim CS, Kim YY, Han JS, Kim S, Lee JS. Department of Internal Medicine, Seoul National University Hospital, Korea.	Clin Nephrol 2000 Feb;53(2):79-89 Abstract quote BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS), also called Korean hemorrhagic fever (KHF), is the most common cause of acute renal failure in the Far East. Two serotypes of hantavirus, Hantaan and Seoul viruses are known pathogens for HFRS in Korea. PURPOSE: To elucidate the diagnostic applicability for the serotype diagnosis in HFRS patients, we used nested reverse transcriptase-PCR and restriction fragment length polymorphism (nRT-PCR/RFLP) to screen 2 prototype viruses, 11 virus isolates from HFRS patients, and 69 specimens obtained from 31 HFRS patients. METHODS: The nRT-PCR was performed using primers specific for the G1 segments of the Hantaan (HF3 1140-1163, HB14 1363-1342) and Seoul (SF2 809-832, SB3 1200-1177) viruses. The initial PCR products were then further amplified using nested primers for the Hantaan (HF4 1141-1164, HB13 1360-1339) and Seoul (SF7 863-884, SB1 1165-1142 ) viruses. Amplified segments were then digested with restriction enzymes specific for either Hantaan (C1a I) or Seoul (Sac I) virus sequences. RESULTS: In all cultured viruses, the serotypes identified by nRT-PCR/RFLP were consistent with those of PRNT. nRT-PCR/RFLP results indicated the presence of Hantaan virus in 10 patients and of Seoul virus in 15 patients. In 3 patients, both Hantaan- and Seoul-specific amplified bands were visualized in serially collected samples, and in 4 patients no amplicon was detected. Among 69 specimens, 55 were positive; these positive specimens were obtained between days 3 and days 33 of illness. The positive rate was not affected by the clinical phase, day of illness, or severity of HFRS. CONCLUSIONS: nRT-PCR/RFLP is a rapid and convenient method for serotype diagnosis in most HFRS patients. It could also allow detection of genetic variation of hantavirus within the same serotype.
Sin nombre virus (SNV) Ig isotype antibody response during acute and convalescent phases of hantavirus pulmonary syndrome. Bostik P, Winter J, Ksiazek TG, Rollin PE, Villinger F, Zaki SR, Peters CJ, Ansari AA. Emory University School of Medicine, Atlanta, GA 30322, USA.	Emerg Infect Dis 2000 Mar-Apr;6(2):184-7 Abstract quote Serum samples from 22 hantavirus pulmonary syndrome (HPS) patients were tested for Sin Nombre virus (SNV)-reactive antibodies. In the acute phase of HPS, 100% and 67% of the samples tested positive for SNV-specific immunoglobulin (Ig) M and IgA, respectively. Among the virus-specific IgG antibodies, the most prevalent were IgG3 (in 97% of samples), followed by IgG1 (70%), IgG2 (30%), and IgG4 (3%).
Rapid Presumptive Diagnosis of Hantavirus Cardiopulmonary Syndrome by Peripheral Blood Smear Review Frederick Koster, MD Kathryn Foucar, MD Brian Hjelle, MD Amy Scott, MD Yap-Yee Chong, MD Richard Larson, MD and Melvina McCabe, MD	Am J Clin Pathol 2001;116:665-672 Abstract quote Hantavirus cardiopulmonary syndrome (HCPS) is a rare but frequently lethal acute zoonotic viral infection in rural North America. The rapidity of progression from febrile prodrome to cardiogenic shock and noncardiogenic pulmonary edema requiring intensive care creates high diagnostic urgency and a need for a rapid screening tool. In this retrospective cohort study, 2 pathologists scored blinded peripheral blood smears from 52 patients with HCPS and 128 seronegative patients referred for diagnosis of suspected hantavirus infection. During the prodromal phase, thrombocytopenia was the only consistent abnormality and could be used to indicate hantavirus serologic testing. After the onset of pulmonary edema detected radiographically, the presence of 4 of 5 findings (thrombocytopenia, myelocytosis, hemoconcentration, lack of significant toxic granulation in neutrophils, and more than 10% of lymphocytes with immunoblastic morphologic features) has a sensitivity for HCPS of 96% and a specificity of 99% and missed no patients with HCPS who required intensive care. While each abnormality is commonly seen, the combination of at least 4 of these CBC count data and peripheral blood smear findings can guide early treatment and patient transport decisions until rapid, specific, serologic testing becomes widely available.
Highly sensitive Taqman PCR detection of Puumala hantavirus. Garin D, Peyrefitte C, Crance JM, Le Faou A, Jouan A, Bouloy M. Unite de virologie, CRSSA Emile Parde, 38702 Grenoble, France.	Microbes Infect 2001 Jul;3(9):739-45 Abstract quote An increasing number of clinical cases of Hantavirus infections have been reported from various regions in Asia, Europe and North America. Hantaviruses (family Bunyaviridae, genus Hantavirus) are enveloped and possess a single-stranded trisegmented RNA genome of negative polarity. Rodents or insectivores are natural hosts of hantaviruses and transmit the virus to humans chiefly by aerosolisation. These viruses are the causative agents of haemorrhagic fever with renal and pulmonary syndromes. In the northeast of France, Puumala hantavirus causes, every year, more than 150 mild forms of haemorrhagic fever with a renal syndrome known as nephropathia epidemica. Serological tests may lack sensitivity for diagnosing early stages of infection and virus isolation is limited because it grows poorly in cell culture. Since reverse transcription (RT)-PCR amplification is an efficient method for detecting viral genomes in patient specimens, we developed an assay using a Taqman probe and compared it with the classical RT-PCR amplification. To achieve this goal, a Puumala strain was grown in Vero E6 cells and RNA extracted from the culture supernatant. We found that the semi-nested RT-PCR detected a minimal amount of 300 TCID(50) mL(-1), while the Taqman PCR allowed detection of less than 10 TCID(50) mL(-1 )and provided a quantitative analysis.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Cardiopulmonary Syndrome
Prodromal stage	Thrombocytopenia 2-10 days
Cardiopulmonary stage	Coincides with radiographic infiltrates of pulmonary edema Presence of 4 of 5 hematologic criteria, thrombocytopenia, myelocytosis, lack of severe toxic granulation, immunoblastosis, and hemoconcentration Neutrophils lack the striking toxic granulation and Döhle bodies that typify bacterial infections Circulating immunoblasts decrease or disappear 3 to 5 days after the onset of pulmonary edema
Diuresis and convalescnece
Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, Feddersen RM, Zumwalt RE, Miller GL, Khan AS, et al. Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333.	Am J Pathol 1995 Mar;146(3):552-79 Abstract quote A recent outbreak of a severe pulmonary disease in the southwestern United States was etiologically linked to a previously unrecognized hantavirus. The virus has been isolated from its major reservoir, the deer mouse, Peromyscus maniculatus, and recently named Sin Nombre virus. Clinically, the disease has become known as the hantavirus pulmonary syndrome (HPS). Since May 1993, 44 fatal cases of HPS have been identified through clinicopathological review and immunohistochemical (IHC) testing of tissues from 273 patients who died of an unexplained noncardiogenic pulmonary edema. In 158 cases for which suitable specimens were available, serological testing and/or reverse transcription-polymerase chain reaction (RT-PCR) amplification of extracted RNA was also performed. IHC, serological, and PCR results were concordant for virtually all HPS and non-HPS patients when more than one assay was performed. The prodromal illness of HPS is similar to that of many other viral diseases. Consistent hematological features include thrombocytopenia, hemoconcentration, neutrophilic leukocytosis with a left shift, and reactive lymphocytes. Pulmonary histopathological features were similar in most of the fatal HPS cases (40/44) and consisted of an interstitial pneumonitis with a variable mononuclear cell infiltrate, edema, and focal hyaline membranes. In four cases, however, pulmonary features were significantly different and included diffuse alveolar damage and variable degrees of severe air space disorganization. IHC analysis showed widespread presence of hantaviral antigens in endothelial cells of the microvasculature, particularly in the lung. Hantaviral antigens were also observed within follicular dendritic cells, macrophages, and lymphocytes. Hantaviral inclusions were observed in endothelial cells of lungs by thinsection electron microscopy, and their identity was verified by immunogold labeling. Virus-like particles were seen in pulmonary endothelial cells and macrophages. HPS is a newly recognized, often fatal disease, with a spectrum of microscopic morphological changes, which may be an important cause of severe and fatal illness presenting as adult respiratory distress syndrome.
Retrospective diagnosis of hantavirus pulmonary syndrome, 1978-1993: implications for emerging infectious diseases. Zaki SR, Khan AS, Goodman RA, Armstrong LR, Greer PW, Coffield LM, Ksiazek TG, Rollin PE, Peters CJ, Khabbaz RF. Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.	Arch Pathol Lab Med 1996 Feb;120(2):134-9 Abstract quote OBJECTIVE: To investigate the occurrence of unrecognized cases of hantavirus pulmonary syndrome preceding the detection of the 1993 outbreak in the southwestern United States and the initial description of the syndrome. DESIGN: Retrospective clinicopathologic and immunohistologic study. PATIENTS: Eighty-two patients who died prior to April 1993 with histologically unexplained noncardiogenic pulmonary edema. METHODS: Clinicopathologic review and immunohistochemical evaluation of autopsy tissues for evidence of hantaviral infection. RESULTS: Twelve retrospective fatal cases of hantavirus pulmonary syndrome were identified through clinicopathologic review and immunohistochemical testing of tissues. Patients' ages ranged from 16 to 49 years. The earliest identified case occurred in 1978, 15 years prior to the outbreak of hantavirus pulmonary syndrome in the southwestern United States. Immunohistochemical testing showed widespread deposition of hantaviral antigens, primarily within endothelial cells, similar to the pattern observed with current hantavirus pulmonary syndrome cases. CONCLUSIONS: Although hantavirus pulmonary syndrome was first recognized in 1993, the findings from this study document the earlier existence of this disease. These findings underscore the need for systematic archiving and analysis of clinical information and specimens from patients with diseases of unknown etiology to facilitate the study of new clinical entities and their associated etiologic agents.
VARIANTS
CNS
Central nervous system and ophthalmic involvement in nephropathia epidemica (European type of haemorrhagic fever with renal syndrome). Ahlm C, Linden C, Linderholm M, Alexeyev OA, Billheden J, Elgh F, Fagerlund M, Zetterlund B, Settergren B. Department of Infectious Diseases, University Hospital of Northern Sweden, Umea.	J Infect 1998 Mar;36(2):149-55 Abstract quote Central nervous system (CNS) - related symptoms occur in haemorrhagic fever with renal syndrome (HFRS). To study the CNS and ophthalmic involvement in nephropathia epidemica (NE), the European type of HFRS, we included 26 patients in a prospective study. Most common CNS-related symptoms were headache (96%), insomnia (83%), vertigo (79%), nausea (79%), and vomiting (71%). Ophthalmic symptoms were reported by 82% of patients; 41% had photophobia and 50% had impaired vision. A transient loss of vision was recorded in one patient, who also had a generalized seizure. Minor white matter lesions were found in about half of the patients investigated with brain magnetic resonance imaging (MRI). Electroencephalography (EEG) showed severe alterations in only one patient, and slight and reversible patterns in another two patients. Neopterin, interleukin-6 and interferon-gamma levels in the cerebrospinal fluid (CSF) were elevated, which may indicate immune activation. However, we found no evidence of intrathecal NE virus replication. We conclude that CNS-related symptoms are common in NE, and transient ophthalmic involvement can be demonstrated in about half of the patients.

 

HISTOPATHOLOGY	CHARACTERIZATION
Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent. Nolte KB, Feddersen RM, Foucar K, Zaki SR, Koster FT, Madar D, Merlin TL, McFeeley PJ, Umland ET, Zumwalt RE. Department of Pathology, University of New Mexico School of Medicine, Albuquerque 87131-5091.	Hum Pathol 1995 Jan;26(1):110-20 Abstract quote3 An outbreak of an acute respiratory disease in the southwestern United States has led to the recognition of a new hantaviral illness. This report describes a unique spectrum of antemortem and postmortem pathological findings seen in a case series of nine surviving patients and 13 who died. Clinical, laboratory, and autopsy findings were derived from a consecutive series of individuals confirmed to have hantavirus pulmonary syndrome. Laboratory studies included chemical, hematological, and bone marrow analyses as well as flow cytometric and immunohistochemical phenotyping. Autopsy tissues were examined by routine histological stains, immunohistochemical methods, and transmission electron microscopy. The lung is the primary target organ in this illness. Pulmonary abnormalities include pleural effusions, alveolar edema and fibrin, and an interstitial mononuclear cell infiltrate. Large immunoblast type cells are seen in the lungs, blood, bone marrow, lymph nodes, liver, and spleen. A tetrad of hematological findings includes left-shifted neutrophilic leukocytosis, thrombocytopenia, hemoconcentration in severe cases, and circulating immunoblasts. In contrast to previously described nephropathic hantaviral syndromes, hantavirus pulmonary syndrome is characterized by a unique constellation of pulmonary, hematological, and reticuloendothelial pathological findings. The pulmonary findings are distinguishable from fatal adult respiratory distress syndrome. The data suggest a capillary leak syndrome restricted to the pulmonary circulation. Likewise, the hematological picture is unique and may be valuable in the rapid identification of cases for further diagnostic studies.
Histopathology of Peromyscus leucopus naturally infected with pathogenic NY-1 hantaviruses: pathologic markers of HPS viral infection in mice. Lyubsky S, Gavrilovskaya I, Luft B, Mackow E. Department of Pathology, State University of New York at Stony Brook, USA.	Lab Invest 1996 Mar;74(3):627-33 Abstract quote Hantavirus research is impeded by the absence of animal models of viral pathogenesis. We have studied the histopathology of mice (P. leucopus) naturally infected with the NY-1 hantavirus on Shelter Island, New York. Five mice were determined to be seropositive in Western blotting to Four Corners Virus nucleocapsid protein and had serum antibodies to Seoul and Puumala hantavirus antigens by immunofluorescence assay. Hantavirus gene segments of the NY-1 hantavirus were identified in these mice and shown to be 99% identical to hantavirus genes isolated from the Rhode Island patient with hantavirus pulmonary syndrome. In ultrastructural examinations, we identified hantavirus particles in pulmonary endothelial cells. Morphologically, these mice demonstrate lymphohistocytic infiltrates in hepatic portal zones and slightly increased numbers of immunoblasts in splenic red pulp. Additionally, the alveolar septa in the lungs of infected mice are edematous with hyperplasia of type 1 pneumocytes. Naturally infected P. leucopus may serve as potentially useful animal models of hantavirus pulmonary syndrome disease.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Cardiopulmonary syndrome	Case fatality rate of 45%
TREATMENT
Intravenous ribavirin for hantavirus pulmonary syndrome: safety and tolerance during 1 year of open-label experience. Ribavirin Study Group. Chapman LE, Mertz GJ, Peters CJ, Jolson HM, Khan AS, Ksiazek TG, Koster FT, Baum KF, Rollin PE, Pavia AT, Holman RC, Christenson JC, Rubin PJ, Behrman RE, Bell LJ, Simpson GL, Sadek RF. Division of Viral and Rickettsial Diseases (DVRD), National Center for Infectious Diseases (NCID), Atlanta, Ga., USA.	Antivir Ther 1999;4(4):211-9 Abstract quote Intravenous ribavirin was provided non-selectively for investigational open-label use among persons with suspected hantavirus pulmonary syndrome (HPS) in the United States between 4 June 1993 and 1 September 1994. Therapy was initiated prior to laboratory confirmation of hantavirus infection because most deaths from HPS occur within 48 h of hospitalization. Thirty patients with confirmed HPS, 105 patients without HPS and 5 patients without adequate diagnostic testing for HPS were enrolled. This observational study arguably provides the most complete information available on ribavirin-associated adverse effects. Although ribavirin was generally well tolerated, 71% of recipients became anaemic and 19% underwent transfusion. An apparent excess of hyperamylasaemia/pancreatitis was either therapy-associated or due to enrollment bias. The 30 enrolled HPS patients had a case-fatality rate of 47% (14/30). It is not possible to assess efficacy with this study design. However, comparison of survival curves for the 30 enrolled HPS patients and 34 patients who developed HPS during the same time period but were not enrolled did not suggest an appreciable drug effect. A randomized, placebo-controlled trial that enrolls patients during the prodrome phase would be necessary to assess the efficacy and further define the safety of intravenous ribavirin for HPS.
DNA vaccination with the Hantaan virus M gene protects Hamsters against three of four HFRS hantaviruses and elicits a high-titer neutralizing antibody response in Rhesus monkeys. Hooper JW, Custer DM, Thompson E, Schmaljohn CS. Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702, USA.	J Virol 2001 Sep;75(18):8469-77 Abstract quote Four hantaviruses-Hantaan virus (HTNV), Seoul virus (SEOV), Dobrava virus (DOBV) and Puumala virus-are known to cause hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. HTNV causes the most severe form of HFRS (5 to 15% case-fatality rate) and afflicts tens of thousands of people annually. Previously, we demonstrated that DNA vaccination with a plasmid expressing the SEOV M gene elicited neutralizing antibodies and protected hamsters against infection with SEOV and HTNV. Here, we report the construction and evaluation of a DNA vaccine that expresses the HTNV M gene products, G1 and G2. DNA vaccination of hamsters with the HTNV M gene conferred sterile protection against infection with HTNV, SEOV, and DOBV. DNA vaccination of rhesus monkeys with either the SEOV or HTNV M gene elicited high levels of neutralizing antibodies. These are the first immunogenicity data for hantavirus DNA vaccines in nonhuman primates. Because a neutralizing antibody response is considered a surrogate marker for protective immunity in humans, our protection data in hamsters combined with the immunogenicity data in monkeys suggest that hantavirus M gene-based DNA vaccines could protect humans against the most severe forms of HFRS.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.

Viruses

Last Updated 10/3/2002

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