Special Article

Hantaviruses A Short Review John A. Lednicky, PhD

● Objective.—Hantaviruses are rodent viruses that have been identified as etiologic agents of 2 diseases of humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). This article presents a concise review of hantavirus biology, the medical features of HFRS and HPS, and tests for the detection of hantavirus infections in humans. Data Synthesis.—Hemorrhagic fever with renal syndrome is a disease found outside the Americas and denotes a group of clinically similar illnesses that vary in severity relative to the causative agent. Hantavirus pulmonary syndrome is associated with higher mortality than HFRS, was first recognized as a hantavirus disease in 1993, and occurs within the American continents. Recent genetic studies show that both Old and New World hantavirus species coevolved with specific rodent hosts. The list of distinct hantaviruses associated with HPS is growing. The burgeoning

human population is causing disruption of natural habitats as more and more land is cleared for commercial and residential purposes. Many rodents readily adapt to life in human settlements, where they generally benefit from reduced predation and where they sometimes proliferate to high numbers. Conclusions.—Although often referred to as emerging pathogens, HPS-associated hantaviruses emerge through increased exposure of humans to rodents and their excreta, not through genetic drift or reassortment of the viral genome. Based on current human population growth and development trends, hantavirus diseases will become more common in the near future unless public health measures are taken to curtail or eliminate rodents from human communities. (Arch Pathol Lab Med. 2003;127:30–35)

H

that are seen less frequently in other bunyaviruses (Figure 2). A distinctive chessboard-like (ordered mosaic) pattern composed of square (approximately 8 3 8 nm) surface morphologic subunits is seen when negatively stained hantaviruses are viewed by electron microscopy.2–4 The list of distinct (separate species) hantaviruses is growing, and most of the currently recognized members and their natural rodent hosts are given in the Table. The taxonomy of hantaviruses is complex, and it is presently being refined by the International Committee on Taxonomy of Viruses (ICTV). As an example, one criterion set by the ICTV for hantavirus species recognition is a 7% cutoff level for protein diversity. Whereas other bunyaviruses infect arthropod hosts, such as mosquitoes and ticks (which also serve as the vectors of viral transmission), and require alternating viral replication cycles in vertebrates to maintain the viral life cycle, hantaviruses appear to be borne primarily by rodents of the family Muridae, subfamilies Arvicolinae (voles), Murinae (Old World mice and rats), and Sigmodontinae (New World mice and rats). For this reason, bunyaviruses are sometimes distinguished according to those that are arthropod-borne (arboviruses) and those that are rodent-borne (roboviruses). At least 1 insectivore (a shrew) might serve as a hantavirus reservoir (see Thottapalayam virus, Table). Transmission of hantaviruses to humans does not require direct human-rodent contact. Instead, human hantavirus infections are acquired by the respiratory route, most commonly through inhalation of

antaviruses (family Bunyaviridae, genus Hantavirus) are serologically and phylogenetically related, enveloped RNA viruses of rodents that have been detected in the Americas, Asia, and Europe, but to date, not in Africa, Antarctica, or Australia.1–3 In Europe and Asia, hantaviruses have long caused human diseases whose syndromes were recognized by medical authorities, whereas many American hantaviruses have been documented as important emerging zoonotic pathogens of humans only within the last decade. As with other bunyaviruses, the genomes of hantaviruses are tripartite, consisting of 3 different single-stranded RNA segments that are predominantly negative stranded. The 3 genomic segments are termed L, M, and S, and they encode the viral RNA polymerase (transcriptase), a precursor glycoprotein that is processed into 2 separate envelope glycoproteins (termed G1 and G2), and a nucleocapsid protein, respectively.3 A schematic representation of a hantavirus particle is shown in Figure 1. Electron microscopic studies of hantavirus-infected cells reveal that hantavirus particles generally have morphologies typical of other members of the Bunyaviridae family (spherical or ovoid particles, 80–120 nm in diameter), although they can also form elongated particles (170 nm) Accepted for publication August 15, 2002. From the Department of Pathology, Loyola University Medical Center, Maywood, Ill. Reprints: John A. Lednicky, PhD, Department of Pathology, Loyola University Medical Center, Room 0177, Bldg 103, 2160 S First Ave, Maywood, IL 60153 (e-mail: [email protected]). 30 Arch Pathol Lab Med—Vol 127, January 2003

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virus-contaminated aerosols of rodent excreta (feces, saliva, or urine).5–7 Hantaviruses have the potential to cause 1 of 2 different types of diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), each with varying degrees of severity.2–10

Figure 1. Schematic representation of a hantavirus particle. The letters L, M, and S identify the viral large, medium, and small single-stranded RNA genomes, respectively. Hydrogen bonding occurs between inverted repeat sequences at the 59 and 39 ends of the genomes, giving a closed-loop appearance. Figure 2. Thin section electron micrograph of Sin Nombre virus (original magnification approximately 345 000). Photograph courtesy of the Centers for Disease Control and Prevention. Figure 3. Immunofluorescence assay of Vero E6 cells infected with Chilean hantavirus isolate CHI-7913. A, Immunofluorescence assay with seropositive human sera from a Chilean patient with hantavirus pulmonary syndrome; arrow shows infected Vero E6 cells expressing hantavirus antigens. B, Immunofluorescence assay with seronegative human sera from uninfected control; arrow shows negative results obtained in Vero E6 cells infected with the CHI-7913 isolate. Photograph courtesy of the Centers for Disease Control and Prevention, reprinted from Galeno et al.30 Arch Pathol Lab Med—Vol 127, January 2003

CLINICAL FEATURES OF HFRS Hemorrhagic fever with renal syndrome is a disease found outside the Americas. Descriptions of syndromes now recognized as those of HFRS are found in 20th century European and older Chinese and Korean medical literature. Hemorrhagic fever with renal syndrome came to the attention of US military physicians as a disease with significant mortality during the Korean war, when about 3000 United Nations soldiers were afflicted with it and about 7% died. The viruses currently recognized as agents of HFRS are Dobrava-Belgrade (usually referred to as Dobrava), Hantaan, Puumala, and Seoul viruses; other hantaviruses causing HFRS are presently considered subspecies of these 4 viruses. Depending in part on the causative virus, HFRS manifests as mild, moderate, or severe disease. Severe HFRS is usually attributed to Dobrava and Hantaan viruses, moderate HFRS to Seoul virus, and mild HFRS to Puumala virus. In general, HFRS is characterized by the development of an acute influenza-like febrile illness that may lead to hemorrhagic manifestations and renal failure. In severe HFRS caused by Dobrava and Hantaan viruses, there is a 2- to 3-week incubation phase, which is followed by a febrile phase (prodrome) characterized by the sudden onset of influenza-like symptoms that last for 3 to 5 days. Hemorrhage can occur during the febrile phase and is manifested as a flushing of the face or injection of the conjunctiva and mucous membranes. Sudden and extreme albuminuria occurring on day 4 of the febrile phase is also characteristic of severe HFRS. This sign is followed by a hypotensive phase lasting hours to days that is marked by thrombocytopenia (often with petechial rash), during which nausea and vomiting are common. Shock occurs in about 15% of the patients. About one half of the fatalities occur during the subsequent oliguric phase, with fatalities primarily due to renal failure. Surviving patients transition to a diuretic phase, which may last months, then to a final (convalescent) phase, which can last weeks to months. The mortality rate is about 7%.* The defined stages of severe HFRS described herein are not observed in all patients, and the reasons remain elusive, but are certainly the focus of intense investigations. Dobrava-Belgrade virus is found in the Balkans and possibly elsewhere in southern Europe,11–13 whereas Hantaan virus is found in China, Far Eastern Russia, and Korea (Table).† Hemorrhagic fever with renal syndrome is usually milder if Seoul virus is the causative agent, with a mortality rate up to 2%, although more prominent liver involvement often occurs than is found in cases of severe HFRS.2,14 Seoul virus is associated with domestic rats and has a global distribution due to the spread of domestic rats by international shipping.‡ The mildest form of HFRS (nephropathia epidemica) is * References 2, 10, and references therein. † References 2, 10, and references therein. ‡ Reference 2 and references therein.

Hantavirus Review—Lednicky 31

Old and New World Hantaviruses* Species

Andes

Disease

HPS

Bermejo

HPS

Hu39694 Lechiguanas Oran

HPS HPS HPS

Araraquara Bayou Black Creek Canal Calabazo

HPS HPS HPS ND

Can˜o Delgadito Castelo dos Sonhos Choclo

ND HPS HPS

Dobrava-Belgrade

HFRS

Saaremaa

HFRS

El Moro Canyon

ND

Hantaan

HFRS

Isla Vista

ND

Juquitiba Khabarovsk Laguna Negra Limestone Canyon Maciel Muleshoe

HPS ND HPS ND ND ND

Pergamino Prospect Hill

ND ND

Bloodland Lake

ND

Puumala

HFRS

Rio Mamore

ND

Rio Segundo

ND

Seoul

HFRS

Sin Nombre

HPS

Blue River

ND

Monongahela

HPS

New York

HPS

Thailand Thottapalayam Tobetsu Topografov Tula

ND ND ND ND ND

Principal Rodent Reservoir†

Known Distribution

References

Oligoryzomys longicaudatus (longtailed pygmy rice rat) Oligoryzomys chacoensis (Chacoan pygmy rice rat) Unknown Oligoryzomys flavescens (rice rat) Oligoryzomys longicaudatus

Argentina and Chile

34

Northwest Argentina

35, 36

Central Argentina Central Argentina Northwest Argentina

37 37 37

Bolomys lasiurus Oryzomys palustris (rice rat) Sigmodon hispidus Zygodontomys brevicauda (sugarcane mouse) Sigmodon alstoni Unknown Oligoryzomys fulvescens (pygmy rice rat) Apodemus flavicollis (yellow-necked field mouse) Apodemus agrarius (striped field mouse)

Brazil Southeastern United States United States, especially Florida Panama

38 39, 40 41 42

Venezuela Brazil Panama

43 38 42

Balkans

11

Europe

44

United States, Mexico

45

China, Korea, Russia

46

California, Oregon, Baja (Mexico)

47

Brazil Russia Bolivia and Paraguay Western United States Central Argentina Southern United States

38 48 49 50 37 51

Central Argentina North America

37 52

North America

Unpublished‡

Europe

53, 54

Bolivia

55

Costa Rica

56

Worldwide

57

Western and Central United States, Mexico Central United States

58, 59

Eastern United States and Canada

61

Eastern United States

62

Reithrodontomys megalotis (Western harvest mouse) Apodemus agrarius (striped field mouse) Microtus californicus (California meadow vole) Unknown Microtus fortis (reed vole) Calomys laucha (vesper mouse) Peromyscus boylii (brush mouse) Necromys benefactus Sigmodon hispidus (cotton rat, western form) Akodon azarae (grass field mouse) Microtus pennsylvanus (meadow mole) Microtus ochrogaster (prairie vole) Clethrionomys glareolus (red bank vole) Oligoryzomys microtis (small-eared pygmy rice rat) Reithrodontomys mexicanus (Mexican harvest mouse) Rattus norvegicus (Norway [brown] rat); Rattus rattus (black rat) Peomyscus maniculatus (deer mouse) Peromyscus leucopus (white-footed mouse, southwest/northwest haplotypes) Peromyscus maniculatus nubiterrae (Cloudland deer mouse) Peromyscus leucopus (white-footed mouse, eastern haplotype)

60

Bandicota indica (bandicoot rat) Thailand 63, 64 Suncus murinus (musk [tree] shrew) India 65 Clethrionomys glareolus Japan 66 Lemmus sibiricus (Siberian lemmings) Northern Europe 67 Microtus arvalis (European common Europe 26 vole) * This table adapted from Nichol,2 Monroe et al,8 Peters and Khan,9 Schmaljohn and Hjelle,10 and from the International Committe on Taxonomy of Viruses (ICTV) database. Official virus species names recognized by the ICTV are italicized. Related distinct virus lineages that may represent additional species, strains, or subspecies are not italicized and are indented below virus species. HPS indicates hantavirus pulmonary syndrome; ND, none documented; and HFRS, hemorrhagic fever with renal syndrome. † Some rodent hosts are suspected (not verified experimentally). Rodent common names (United States) are given when cited in reference(s) indicated. ‡ See GenBank U19301, U19303, U19305–7.

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caused by Puumala virus in Scandinavia and Europe west of the Ural Mountains (mortality less than 1%). In general, the symptoms of nephropathia epidemica are milder, the phases of the illness are less pronounced, and there is relatively mild renal involvement.§ CLINICAL FEATURES OF HPS Hantavirus pulmonary syndrome was first recognized as a hantavirus disease in 1993 and is a disease of the Americas. Sin Nombre virus (SNV) (Table) has been the cause of most HPS cases in North America, and HPS due to this virus is a more severe disease than HFRS, with a mortality rate of about 40%. In general, HPS is characterized by a distinctive febrile phase (prodrome) and pulmonary infection, cardiac depression, and hematologic manifestations.2,9 Among the hantaviruses causing HPS, SNV presents the clearest syndrome, with minimal clinical manifestations outside the thoracic cavity. This restriction is not true for other American hantavirus infections, in which extrathoracic findings are seen more often than is observed for SNV infections. In HPS caused by SNV, there is a 14- to 17-day incubation period after exposure.15 Renal involvement during SNV infection is often present, but is rarely a major consideration.9,16 During the febrile phase (usually lasting 3– 5 days), headache, malaise, myalgia, and a fever of abrupt onset occur in the absence of cough and coryza. Thrombocytopenia occurs and anorexia, abdominal pain, nausea, and vomiting may begin.2,9 Following the febrile phase of disease, SNV-induced HPS is characterized by cardiopulmonary involvement, which also coincides with the time patients are hospitalized. Cough is usually present, although gastrointestinal manifestations may dominate the clinical presentation. Tachypnea, tachycardia, and postural hypotension are typical, whereas chest examination is not contributory (with few rales). Laboratory test results during this period become abnormal, starting with a decreasing or low platelet count.2,9,17,18 Other laboratory findings are elevated hematocrit and circulating immunoblasts (often interpreted as atypical lymphocytes).9,19 Pulmonary evaluation will be distinctly abnormal, with low PAO2 level or low pulse oximetry findings and often low PACO2. By 48 hours after the onset of cardiopulmonary involvement, severe interstitial edema is almost always found, and extensive air-space disease occurs in two thirds of the cases.2,9 Symptoms of HPS vary somewhat relative to the causative agent. For example, renal disease and myositis appear to be more common in cases of Bayou virus and Black Creek virus infection.9 PATHOGENESIS The early events that occur during human hantavirus infection are not fully understood. Viremia is thought to occur subsequent to infection of alveolar macrophages or other primary targets, leading to infection of kidney and lung endothelial cells (hantaviruses appear to target endothelial cells). Infection of endothelial cells of the microvasculature (especially in human lungs) in HPS probably accounts for the severe edema associated with HPS.2,9,17,18 Cellular entry of some hantaviruses is thought to be mediated by b3-integrins.2,9 Cytopathic ef§ Reference 2 and references therein. Arch Pathol Lab Med—Vol 127, January 2003

fects are not evident in hantavirus-infected human cells, and both HFRS and HPS are currently thought to be immunopathologic.20,21 Acute tubulointerstitial nephritis is seen in biopsies of HFRS patients, although the exact causes of kidney failure are unclear.2,9 The main pulmonary histopathologic findings of SNV infection are interstitial pneumonitis, hyaline membrane formation, and mononuclear cell infiltrates.17,18 Hantavirus infections of rodents are typically persistent\ and were previously thought to be asymptomatic in their natural rodent hosts, as stated in numerous reviews of hantavirus biology. However, newer studies indicate that at least 2 New World hantaviruses are capable of causing some pathology in their reservoir hosts. Immune infiltrates in portal zones of the liver and edema of alveolar septa of the lungs were seen in Peromyscus leucopus infected with New York virus22; similar findings were seen in Peromyscus maniculatus infected with SNV.23 Unfortunately, neither situation mimics HPS, ruling these hosts out as models for the study of HPS. Fortuitously, it was recently discovered that Andes virus induces a disease with pathology like that of typical HPS in hamsters,24 providing the first animal model for the study of HPS. SEROLOGICAL AND MOLECULAR TESTS Various serological tests are currently used for the detection of antibodies formed against Old World hantaviruses by infected individuals. One common approach is to perform standard immunofluorescence assays using serum drawn from a patient, in conjunction with fluorescein-labeled goat anti-human antibodies, and slides containing hantavirus-infected cells (see Antoniadis et al12 for an example). Immunoglobulin (Ig) M and IgG enzymelinked immunosorbent assays are also available and often used.13,25 Because cross-neutralizing primary antibody against several Old World hantavirus genotypes is formed during HFRS, it is usually not possible to distinguish the causative virus species by serology without additional testing by other methods.25 Currently, molecular tests based on nested reverse transcriptase–polymerase chain reaction (RT-PCR) procedures that have been optimized for the detection of Old World hantaviruses are favored for this purpose.2,26,27 RNA for these assays is typically purified from whole blood or serum during the acute phase of infection, or from autopsy tissue samples. A number of different laboratory tests are required to make a final diagnosis for HPS, even in the case of SNVinduced HPS, which presents with characteristic features. (It is likely that characteristic features will also be determined for other types of hantavirus-induced HPS as clinical observations accumulate.) Because of the low prevalence of hantavirus antibodies in the general population of the United States, the most effective and widely used test for screening American patients is the IgM capture enzyme-linked immunosorbent assay, which detects IgM in all acute cases. Specific IgG levels can also be measured by a similar test; IgG levels peak during the first week of illness and remain detectable for a relatively long period of time afterward.9,28 These tests are less meaningful in other countries, such as Paraguay, where the general population has a high seroprevalence of hantavirus antibodies without a history of HPS.9,20 For HPS, RT-PCR can be per\ Reference 2 and references therein.

Hantavirus Review—Lednicky 33

formed on acute-phase serum specimens during the first 10 days of illness.29 The success of the procedure depends on the choice of primers (optimized for New World hantaviruses) and whether a nested reaction is used to improve detection efficiency.9 Reverse transcriptase–PCR tests are useful for both HFRS and HPS because the viral genotype can be identified if the PCR product is sequenced, and the resulting data may be of epidemiological value. Owing to the hazardous nature of hantaviruses and the dangers posed by aerosols formed during various laboratory procedures, tissues and serum specimens for serological or molecular tests are handled in biosafety cabinets in biosafety level 3 (BSL-3)-rated (or BSL-4) laboratories. Virus isolation is also performed in BSL-3 or BSL-4 facilities, but it is difficult and usually inefficient and not routinely performed by clinical laboratories.2,9,29 Primary isolation of hantaviruses is most often attempted using VERO E6 cells (an African green monkey kidney cell line), in which the viruses usually grow without forming cytopathic effects; the success of virus isolation is commonly determined by isolating RNA from the infected cells after about 2 weeks of incubation and performing RT-PCR to detect hantavirus RNA. Except for a single recent isolation of Andes virus isolate CHI-7913 from a 10-year-old Chilean boy, hantaviruses associated with HPS have only been isolated from infected animals.30 It is likely that previous failures to recover virus were due to specimen choice, as Andes virus isolate CHI-7913 was isolated from serum taken prior to the onset of HPS symptoms. A useful diagnostic tool in future attempts at virus isolation from humans is to use serum taken from seropositive HPS patients to screen for virus production in VERO E6 cells (prior to confirmation by RT-PCR) using an immunofluorescence assay, as was done in the study by Galeno et al (Figure 3).30 EPIDEMIOLOGY Hantavirus pulmonary syndrome and HFRS are principally rural diseases2,20 that occur with obvious exposure to rodents. Disruption of natural habitats due to farming or land development are often cited, as are hunting and camping, all of which are activities that bring humans to areas populated by rodents. Disruption of predator-prey relationships is also important, since conditions can be created that allow for unchecked proliferation of rodents when predators are eliminated. It is likely that cases of HPS will increase as the human population continues to encroach on undeveloped land in the Americas. Unfortunately, rodents such as P maniculatus are considered attractive (‘‘cute’’), and there is a temptation to maintain them as pets or to feed free-ranging animals, activities that should always be discouraged. Since they are potential carriers of hantaviruses (and other pathogens), wild mice and rats should be handled only by trained professionals wearing protective apparel, including respirator masks equipped with N-100 filters (N-100 filters are the new designation for high-efficiency particulate-arresting [HEPA] filters). For the prevention of hantavirus diseases, human habitations showing signs of rodent activity should be decontaminated, and steps should be taken to rid the premises of the offending animals. Decontamination in many cases can be accomplished by soaking the affected area with a 10% (v/v) solution of household bleach. The realization that Andes virus can be transmitted person to person30,31 raises the possibility that future 34 Arch Pathol Lab Med—Vol 127, January 2003

outbreaks of HPS might occur without rodent-human contact, the worrisome implication being that hantaviruses might emerge into common pathogens of humans. COMMENT Clearly, rodent control is crucial for the prevention of HFRS and HPS. There are no specific therapies currently available for hantavirus diseases, although supporting therapy during early hospitalization is important and helpful. The ability to recognize HFRS and HPS symptoms is a skill that is likely to be of importance to physicians, since it is anticipated that the number of HFRS and HPS cases will increase significantly in the near future. It is noteworthy also that the nonspecific prodrome leading to acute cardiopulmonary deterioration in HPS can be confused for those of mycoplasmal and chlamydophilial infections (J.A.L., unpublished data),32 as well as those of leptospirosis, Legionnaire disease, Q fever, septicemic plague, tularemia, coccidiomycosis, and histoplasmosis.33 References 1. Elliot RM, Schmaljohn CS, Collett MS. Bunyaviridae genome structure and gene expression. In: Kolkofsky D, ed. Current Topics in Microbiology and Immunology. New York, NY: Springer-Verlag; 1991:91–141. 2. Nichol ST. Bunyaviruses. In: Knipe DM, Howley PM, eds. Field’s Virology. Vol 2, 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:1603–1633. 3. Schmaljohn CS, Hooper JW. Bunyaviridae: the viruses and their replication. In: Knipe DM, Howley PM, eds. Field’s Virology. Vol 2, 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:1581–1602. 4. Martin ML, Lindsey-Regenery H, Sasso DR, McCormick JB, Palmer E. Distinction between Bunyaviridae genera by surface structure and comparison with Hantaan virus using negative stain electron microscopy. Arch Virol. 1985;86:17– 28. 5. Zu Z-Y, Guo C-S, Wu Y-L, Zhang X-W, Liu K. Epidemiological studies of hemorrhagic fever with renal syndrome: analysis of risk factors and mode of transmission. J Infect Dis. 1985;152:137–143. 6. Tsai TF. Hemorrhagic fever with renal syndrome: mode of transmission to humans. Lab Animal Sci. 1987;37:428–430. 7. Lee H, van der Groen G. Hemorrhagic fever with renal syndrome. Prog Med Virol. 1989;36:62–102. 8. Monroe MC, Morzunov SP, Johnson AM, et al. Genetic diversity and distribution of Peromyscus-borne hantaviruses in North America. Emerg Infect Dis. 1999;5:75–86. 9. Peters CJ, Khan AS. Hantavirus pulmonary syndrome: the new American hemorrhagic fever. Clin Infect Dis. 2002;34:1224–1231. 10. Schmaljohn C, Hjelle B. Hantaviruses: a global disease problem. Emerg Infect Dis. 1997;3:95–104. 11. Avsic-Zupanc T, Xiao SY, Stojanovic R, Gligic A, van der Groen G, LeDuc JW. Characterization of Dobrava virus: a hantavirus from Slovenia, Yugoslavia. J Med Virol. 1992;38:132–137. 12. Antoniadis A, Stylianakis A, Papa A, et al. Direct genetic detection of Dobrava virus in Greek and Albanian patients with hemorrhagic fever with renal syndrome. J Infect Dis. 1996;174:407–410. 13. Papa A, Johnson AM, Stockton PC, et al. Retrospective serological and genetic study of the distribution of hantaviruses in Greece. J Med Virol. 1998;55: 321–327. 14. Kim YS, Ahn C, Han JS, Kim S, Lee JS, Lee PW. Hemorrhagic fever with renal syndrome caused by the Seoul virus. Nephron. 1995;71:419–427. 15. Young JC, Hansen GR, Graves TK, et al. The incubation period of hantavirus pulmonary syndrome. Am J Trop Med Hyg. 2000;62:714–717. 16. Peters CJ, Simpson GL, Levy H. Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med. 1999;50:531–545. 17. Nolte KB, Feddersen RM, Foucar K, et al. Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent. Hum Pathol. 1995;26:110–120. 18. Zaki SR, Greer PW, Coffield LM, et al. Hantavirus pulmonary syndrome: pathogenesis of an emerging infectious disease. Am J Pathol. 1995;146:552–579. 19. Chapman LE, Ellis BA, Koster FT, et al, for the Ribavirin Study Group. Discriminators between hantavirus-infected and -uninfected persons enrolled in a trial of intravenous ribavirin for presumptive hantavirus pulmonary syndrome. Clin Infect Dis. 2002;43:293–294. 20. Peters CJ, Mills JN, Spiropoulou C, Zaki SR, Rollin PE. Hantaviruses. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles, Pathogens, and Practice. New York, NY: WB Saunders; 1998. 21. Peters CJ. Hantavirus pulmonary syndrome in the Americas. In: Scheld WM, Craig WA, Hughes JM, eds. Emerging Infections 2. Washington, DC: American Society for Microbiology Press; 1998:17–64.

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