AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Hantavirus pulmonary syndrome (HPS) is a rodent-borne viral infection caused by Hantaviruses and characterized by severe pulmonary illness with a high mortality rate. The Hantaviruses comprise 1 of the 5 genera of the family Bunyaviridae, with more than 250 animal viruses. Hantaviruses derive their name from the Hantaan River in South Korea near which the prototypic virus was first isolated in 1978 from a striped field mouse. Hantaviruses have been previously described to cause hemorrhagic fever with renal syndrome (HFRS) in countries of the eastern hemisphere and worldwide, as listed in the table below.

Table 1. Hantaviruses That Cause HFRS, Rodent Hosts and Geographic Distribution

Hantavirus pulmonary syndrome was first recognized in the United States in 1993 during an investigation of a cluster of sudden and unexplained deaths that occurred in rural New Mexico.¹ Investigation by the local health officials and researchers at the Centers for Disease Control and Prevention (CDC) discovered an outbreak of Hantavirus pulmonary syndrome in the Four Corners region of the United States (ie, New Mexico, Arizona, Colorado, Utah). The outbreak was quickly linked to a Hantavirus that is now called Sin Nombre (nameless) virus. A reservoir of this virus was found in the regional deer mouse, Peromyscus maniculatus (see Media file 1).

In the autumn of 1992, the weather phenomenon known as El Niño caused heavy precipitation in the Four Corners region of the United States, hypothetically resulting in the increased growth of berries, seeds, and nuts. A rapid rise in the rodent population resulted in this area. Aerosols contaminated by the infectious rodent urine and feces are thought to represent the principal vehicle for the transmission of Hantaviruses. The disease has also followed the bite of infected rodents and the consumption of food contaminated with infected rodent urine, droppings, or saliva.

Unlike viruses in the other genera of the family Bunyaviridae that are transmitted to humans by the arthropod vector, Hantaviruses have a rodent host. Each Hantavirus is adapted to a single host rodent species. Spillover of a Hantavirus to another rodent host may occur in endemic areas; however, adaptation and long-term propagation of the Hantavirus in the new host does not occur.

Hantaviruses are lipid-enveloped, negative-sense, single-stranded RNA viruses, 90-100 nm in diameter (see Media file 2). The viral genome is trisegmented and composed of 3 fragments, with sedimentation coefficients of approximately 32S, 26S, and 16S, respectively. Each fragment has its own encoding function as follows:

• The small fragment encodes the viral nucleocapsid protein.
• The large fragment encodes the viral polymerase.
• The medium fragment encodes the envelope glycoproteins G1 and G2, regions of which are conserved among Hantaviruses, allowing the identification of new strains by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry.

Pathophysiology

The basic lesion in Hantavirus pulmonary syndrome is increased pulmonary capillary permeability that leads to severe pulmonary edema. The pathogenesis of pulmonary edema in Hantavirus pulmonary syndrome is not well understood, although an immunologic mechanism is considered to play an important role. The lymphoblasts and the macrophages recruited to pulmonary tissue by the high viral burden may provoke a lymphokine-mediated activation of vascular endothelium, thereby increasing pulmonary capillary permeability.

In 1999, Mori and colleagues used immunohistochemical staining to enumerate cytokine-producing cells (ie, monokines, such as interleukin [IL]-1α [IL-1α], IL-1β, IL-6, and tumor necrosis factor [TNF]-α [TNF-α], and lymphokines, such as interferon-γ, IL-2, IL-4, and TNF-beta) in tissues obtained at autopsy from subjects with Hantavirus pulmonary syndrome.² High numbers of cytokine-producing cells were observed in the lung and spleen tissues of patients with Hantavirus pulmonary syndrome. These results suggest that local cytokine production may play an important role in the pathogenesis of Hantavirus pulmonary syndrome.

Patients with Hantavirus pulmonary syndrome have very high levels of viremia at the onset of pulmonary edema and then rapidly clear the virus from plasma; however, pulmonary damage persists. These data suggest that the endothelial cells are not directly injured by the cytopathic effect of viral infection.

In Hantavirus pulmonary syndrome, the patient's lung CD8+T cells are present in infiltrated alveolar walls. In 2004, Kilpatrick et al found significantly higher frequencies of viral-specific CD8+T cells in peripheral blood mononuclear cell (PBMC) samples from patients with severe disease than in those with moderate disease (44 [2%] and 9 [8%], respectively).³ These results support the hypothesis that virus-specific CD8+T cells contribute to Hantavirus pulmonary syndrome disease outcome. Impairment of endothelial cell's defense mechanisms against cytotoxic CD8+ T cells may be the mechanism of capillary leakage in Hantavirus pulmonary syndrome. Active suppression of immune T regulatory cells is probably involved in Hantavirus pulmonary syndrome pathogenesis.

Hantaviral antigen and particles have been noted in the cardiac endothelium and interstitial macrophages in association with atypical myocarditis in Hantavirus pulmonary syndrome. These findings support the opinion that structural changes could also be responsible for myocardial depression and shock in Hantavirus pulmonary syndrome. Hantavirus pulmonary syndrome shock is probably related to an exacerbated immune response of CD8+ T cells producing cytotoxicity on infected endothelial cells; the presence of myocarditis and myocardial depression is induced by nitric oxide.

Frequency

United States

Through March 26, 2007, a total of 465 cases of Hantavirus pulmonary syndrome have been reported in the United States. The case count started when the disease was first recognized in May 1993. The vast majority of cases have occurred sporadically, although outbreaks of Hantavirus pulmonary syndrome have been periodically reported in the United States. The first outbreak in the Four Corners region of the southwestern United States occurred in 1993 following an El Niño year. A second strong El Niño phenomenon occurred in 1997-1998, resulting in an increased prevalence of Hantavirus pulmonary syndrome 5-fold above the baseline in the Four Corners region. The disease has been reported from 33 of 50 states in the United States, including most of the western half of the country and some eastern states as well (see Media file 3). Over half of the confirmed cases have been reported from areas outside the Four Corners area. About three fourths of patients with Hantavirus pulmonary syndrome have been residents of rural areas.

Since the original description of Hantavirus pulmonary syndrome due to Sin Nombre virus, cases of Hantavirus pulmonary syndrome–like disease outside the range of P maniculatus have led to the isolation of additional distinct Hantaviruses in the United States, as summarized in Table 2 below.

Table 2. Hantavirus Pulmonary Syndrome Virus Types, Rodent Hosts, and Distribution in the United States

Hantavirus pulmonary syndrome in the United States is largely due to infection with the Sin Nombre virus. Other Hantaviruses have been implicated in only a handful of cases in isolated locations (see Media file 4).

International

Since the description of Hantavirus pulmonary syndrome in 1993, awareness and heightened surveillance has led to the discovery of several new Hantaviruses in other countries of the western hemisphere. Hantaviruses that cause HPS have their reservoir in the sigmodontine rodents that are asymptomatically infected. In 1997, Mills et al studied the prevalence of antibody to Sin Nombre virus among 3,069 small mammals of 69 species in 9 communities from the lower Sonoran desert to the Alpine tundra.⁴ An overall prevalence of 6.3% was noted in the animals captured. Seropositivity was more common in the male animals. Individual seropositivity was as follows:

• Deer mice (928) - 11%
• Brush mice (355) - 20%
• Western harvest mice (35) - 23%
• Mexican voles (24) - 12%

In 2000, Kuenzi et al found that 7 of 35 (20%) deer mice captured from 28% of the urban and suburban homes of southwestern Montana were seropositive for antibody to Sin Nombre virus.⁵ The infected mice were mostly adult males captured in the spring and fall.

Hantaviruses linked to sporadic cases or limited outbreaks of Hantavirus pulmonary syndrome in other regions of the western hemisphere are listed below with their rodent host.

Table 3. Hantavirus Types, Rodent Hosts, and Geographic Distribution in the Western Hemisphere (other than the United States)

Mortality/Morbidity

Through March 26, 2007, 35% of the 465 cases of Hantavirus pulmonary syndrome reported in the United States have resulted in death.

Race

All races are susceptible to Hantavirus pulmonary syndrome. However, 77% of all cases reported to the CDC occurred in whites, 19% in American Indians, 2% in African Americans, and 1% in Asians. Thirteen percent of cases were reported in Hispanic persons, independent of race.

Sex

To date, 63% of reported cases were in males, and 37% were in females.

Age

The age of confirmed cases ranges from 10-83 years, with a mean of 38 years.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

• Hantavirus pulmonary syndrome (HPS) begins after an incubation period averaging 2 weeks. Rodent exposure is most commonly noted to have occurred peridomestically. In a 1995 report of 70 confirmed cases of Hantavirus pulmonary syndrome, Armstrong et al reports rodent exposure to have occurred as follows:⁶
• • Peridomestic exposure - 69%
  • Peridomestic and occupational exposure -19%
  • Peridomestic and recreational exposure - 9%
  • Occupational exposure - 4%
  • Entering and/or cleaning rodent-infested structures - 9%
• Illness starts with a prodrome of fever and severe myalgia involving the large muscles, particularly in the thigh and the lower back.
• Abdominal discomfort and GI disturbances may be noted.
• Although cough is not necessarily an early symptom, dizziness is frequently reported. Signs of viral upper respiratory tract infections, such as rhinorrhea and pharyngitis, are generally absent.
• About 4-5 days later (range of 1-10 d), the patient develops respiratory symptoms that usually consist of modest cough and dyspnea. Rapid deterioration leads to hospitalization.

Physical

• Examination may be quite unrevealing early in the disease.
• • Fever is generally present.
  • Tachycardia may be noted.
  • Tachypnea is common.
• Patients with full-blown Hantavirus pulmonary syndrome appear ill with severe ventilatory insufficiency.

Causes

• Various Hantaviruses have been implicated in the causation of Hantavirus pulmonary syndrome. Human infection is thought to involve the inhalation of concentrated, aerosolized excreta of chronically infected rodents that shed the virus in their urine, feces, and saliva.
• Spread of Hantavirus may also occur by the following means:
• • An infected rodent bite
  • Eating food contaminated with infected rodent urine, droppings, or saliva
• Hantavirus infection for the types of Hantaviruses causing Hantavirus pulmonary syndrome in the United States is not transmitted from person to person. A person-to-person spread of Hantavirus pulmonary syndrome caused by the Andes virus has been reported in Southern Argentina.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Influenza

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Several laboratory tests are useful in the diagnosis of Hantavirus pulmonary syndrome (HPS).
• • Thrombocytopenia is noted early in the disease.
  • Leukocytosis is noted with a left shift.
  • Abnormal lymphocytes and immunoblasts are present in the peripheral smear.
  • The hematocrit level is elevated because of the ultrafiltration of fluid into the lungs.
  • Activated partial thromboplastin time (aPTT) is prolonged.
  • Aspartate aminotransferase (AST) and lactic dehydrogenase (LDH) may be mildly elevated.
  • ABG measurement reveals desaturation.
• The tetrad of thrombocytopenia, leukocytosis (often with left shift), elevated hematocrit levels, and presence of immunoblasts in peripheral blood smear is a sensitive and specific early clue to the underlying disease. These findings in a patient with rapid onset of respiratory insufficiency should suggest the diagnosis.
• Serologic methods are useful in the diagnosis of Hantavirus infection. Most patients have both immunoglobulin M (IgM) and immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) antibodies upon admission to the hospital.
• Hantavirus can be detected in the tissue by the RT-PCR.
• Immunohistochemical staining of tissue reveals Hantaviral antigen.

Imaging Studies

• Chest radiographs usually reveal marked peribronchial cuffing and Kerley B lines early in the disease.
• Rapid progression of bilateral interstitial and alveolar infiltrates is observed in patients with full-blown Hantavirus pulmonary syndrome.

Procedures

• Catheterization of the pulmonary artery in patients with profound Hantavirus pulmonary syndrome generally reveals decreased stroke volume index (SVI) and a low to low-normal cardiac index (CI).
• The pulmonary vascular resistance index is elevated.
• Increased systemic vascular resistance, along with the failure of correction of lowered CI and SVI by volume replacement, distinguishes Hantavirus pulmonary syndrome from septic shock.

Histologic Findings

• Histopathology of the lungs in patients with Hantavirus pulmonary syndrome is depicted in Media file 6. Under light microscopy, the lungs of these patients reveal interstitial and alveolar edema, alveolar hemorrhage, and a mononuclear interstitial pneumonitis composed of macrophages and T lymphocytes.
• Unlike the acute respiratory distress syndrome (ARDS) due to other causes, no marked necrosis, polymorphonuclear leukocyte infiltration, type II pneumocyte hyperplasia, or dense hyalinization is observed.
• Electron microscopy of lung tissue reveals intact and somewhat swollen vascular endothelium. Inflammatory cell infiltration of capillaries, interstitium, and alveoli is evident. The cytoplasm of endothelial cells contains viral inclusions. No evidence of necrosis or a structural cellular defect responsible for the capillary leak is observed.
• Examination of other tissues may reveal infiltration by immunoblasts, such as in lymph nodes, spleen, liver, and blood vessels of other organs.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

• Treatment of Hantavirus pulmonary syndrome (HPS) remains supportive, requiring invasive hemodynamic monitoring with an arterial line and a pulmonary artery catheter and intensive support. Prompt treatment is of critical importance. Treatment initiated after the onset of severe respiratory distress is less likely to favorably impact the outcome.
• Mechanical ventilation may be necessary for survival during the period of severe respiratory insufficiency.
• Excessive administration of fluids should be avoided despite the fact that patients may be hemoconcentrated and hypotensive. Overzealous fluid administration may aggravate respiratory insufficiency because of increased vascular leak of fluid into the lungs.
• Early use of pressors is recommended to correct hypotension.
• Extracorporeal membrane oxygenation may be considered for patients with refractory shock. In one report, almost two thirds of the patients with severe Hantavirus pulmonary syndrome, with predicted mortality of 100%, who were supported with extracorporeal circulation survived and completely recovered.⁷ However, the validity of this treatment is not well established through controlled trials.
• No specific treatment is available for Hantavirus pulmonary syndrome. Treatment with intravenous ribavirin, a guanosine analogue, conferred no survival benefit in an open-label trial. Prospective, controlled trials are underway.
• Hyperimmune serum offers a promising future therapy because survival is correlated with higher neutralizing antibody titers at admission.

Consultations

• Infectious diseases specialist
• Pulmonary medicine specialist
• Critical care specialist

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Drug therapy is not currently a component of the standard of care for this infection. No specific therapy has been found to be of benefit. Ribavirin therapy has proved inconclusive in the open-label studies. A controlled trial of ribavirin in Hantavirus pulmonary syndrome is underway.⁸

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Patients should be transferred to the ICU for close observation and aggressive management.

Deterrence/Prevention

Because Hantavirus pulmonary syndrome (HPS) is acquired through inhalation of the virus-laden rodent excreta, avoidance of rodent contact is of paramount importance in its prevention. Several strategies have been proposed in this regard, as follows:

• Elimination of rodent nesting sites can be achieved through keeping food storage areas clean, keeping food properly covered, elevating garbage containers, sealing holes and cracks in dwellings to prevent entrance by rodents, and clearing the brush from around homes and outbuildings.
• Rodent traps and rodenticides should be used to control rodent populations. Similarly, encouraging natural predators, such as nonpoisonous snakes, owls, and hawks, may reduce the rodent population.
• The following special precautions should be used while cleaning up rodent-infested areas:
• • Air out rodent-infested areas before cleaning.
  • The area should be thoroughly wet with household disinfectant or 10% bleach solution spray before sweeping, vacuuming, or stirring the dust.
  • Rubber gloves should be worn during cleaning, and hands should be properly washed afterward.
  • Workers should wear a half-face air-purifying (or negative-pressure) respirator equipped with high-efficiency particulate air (HEPA) filters when removing rodents from traps or handling rodents in the affected area.
• Outdoor rodent exposure should be avoided. Do not disturb rodent droppings or camp near rodent burrows or areas where trash is present. If sleeping outdoors, use elevated cots. Avoid feeding or handling rodents.

Vaccines are currently being studied for the prevention of Hantavirus infection in endemic areas. In a 1999 study of an inactivated Hantavirus vaccine by Cho and colleagues, 79% of the 64 human volunteers developed a significant Hantavirus antibody titer 30 days after vaccination.⁹ Seroconversion rates increased to 97% one month after the booster dose. Antibody titers declined by one year, but a vigorous anamnestic response occurred with revaccination in almost all subjects. However, only 50% of the subjects produced neutralizing antibodies following the booster dose one year later. Improved vaccination for Hantavirus pulmonary syndrome is needed.

Complications

• ARDS may rapidly occur. Hantavirus pulmonary syndrome should be suspected when an otherwise healthy adult develops an ARDS-like picture without any of the known causes of ARDS.

Prognosis

• In a report of 281 patients of Hantavirus pulmonary syndrome by the CDC, a case-fatality rate of 38% was noted.
• If hypoxia is managed and shock is not fatal, the vascular leak reverses in a few days and the recovery is apparently complete.

Patient Education

• Patients should be educated in avoidance of rodent contact through strategies outlined under Deterrence/Prevention.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to consider the diagnosis of Hantavirus pulmonary syndrome (HPS) in an appropriate epidemiologic setting
• Failure to promptly transfer patients suspected of having Hantavirus pulmonary syndrome to facilities with ICUs and ventilatory support

Special Concerns

• Diagnosis of HPS may not be considered unless an appropriate epidemiologic history of rodent exposure is solicited.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Maria A Horga, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Deer mouse, Peromyscus maniculatus. Courtesy of the Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Image

Media file 2:  Transmission electron micrograph of Sin Nombre virus. Courtesy of the Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

Media file 3:  A case map of the United States with the total 465 HPS cases differentiated by state. States not listed have not had confirmed cases. Five cases were reported with unknown state of residence.
	View Full Size Image
Media type:  Photo

Media file 4:  Distribution of Hantavirus pulmonary syndrome cases in the United States by virus type. Courtesy of the Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Image

Media file 5:  Characteristics of 465 Hantavirus pulmonary syndrome cases in the United States, March 26, 2007. Courtesy of the Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

Media file 6:  Histopathology of the lung in Hantavirus pulmonary syndrome. Courtesy of the Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

1. CDC. Update: hantavirus pulmonary syndrome--United States, 1993. MMWR Morb Mortal Wkly Rep. Oct 29 1993;42(42):816-20. [Medline].
2. Mori M, Rothman AL, Kurane I, et al. High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome. J Infect Dis. Feb 1999;179(2):295-302. [Medline].
3. Kilpatrick ED, Terajima M, Koster FT, et al. Role of specific CD8+ T cells in the severity of a fulminant zoonotic viral hemorrhagic fever, hantavirus pulmonary syndrome. J Immunol. Mar 1 2004;172(5):3297-304. [Medline]. [Full Text].
4. Mills JN, Ksiazek TG, Ellis BA, et al. Patterns of association with host and habitat: antibody reactive with Sin Nombre virus in small mammals in the major biotic communities of the southwestern United States. Am J Trop Med Hyg. Mar 1997;56(3):273-84. [Medline].
5. Kuenzi AJ, Douglass RJ, Bond CW. Sin nombre virus in deer mice captured inside homes, southwestern Montana. Emerg Infect Dis. Jul-Aug 2000;6(4):386-8. [Medline].
6. Armstrong LR, Zaki SR, Goldoft MJ, et al. Hantavirus pulmonary syndrome associated with entering or cleaning rarely used, rodent-infested structures. J Infect Dis. Oct 1995;172(4):1166. [Medline].
7. Dietl CA, Wernly JA, Pett SB, et al. Extracorporeal membrane oxygenation support improves survival of patients with severe Hantavirus cardiopulmonary syndrome. J Thorac Cardiovasc Surg. Mar 2008;135(3):579-84. [Medline].
8. Jonsson CB, Hooper J, Mertz G. Treatment of hantavirus pulmonary syndrome. Antiviral Res. Apr 2008;78(1):162-9. [Medline].
9. Cho HW, Howard CR. Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax). Vaccine. Jun 4 1999;17(20-21):2569-75. [Medline].
10. Abbott KD, Ksiazek TG, Mills JN. Long-term hantavirus persistence in rodent populations in central Arizona. Emerg Infect Dis. Jan-Feb 1999;5(1):102-12. [Medline].
11. Abel Borges A, Figueiredo LT. Mechanisms of shock in hantavirus pulmonary syndrome. Curr Opin Infect Dis. Jun 2008;21(3):293-7. [Medline].
12. Bartholomew DM, Hansen LA, Frank JJ, Farver DK. Case report of hantavirus pulmonary syndrome and review. S D Med. May 2007;60(5):189-91, 193-5. [Medline].
13. Bennett SG, Webb JP Jr, Madon MB, et al. Hantavirus (Bunyaviridae) infections in rodents from Orange and San Diego counties, California. Am J Trop Med Hyg. Jan 1999;60(1):75-84. [Medline].
14. Brillman J, Talan DA, Moran GJ, Pinner R. Update on emerging infections from the Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome--five states, 2006. Ann Emerg Med. Nov 2006;48(5):593-4; discussion 594-5. [Medline].
15. CDC. From the Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome--Panama, 1999-2000. JAMA. May 3 2000;283(17):2232-3. [Medline].
16. CDC. Update: hantavirus pulmonary syndrome--United States, 1999. MMWR Morb Mortal Wkly Rep. Jun 25 1999;48(24):521-5. [Medline].
17. Chang B, Crowley M, Campen M, Koster F. Hantavirus cardiopulmonary syndrome. Semin Respir Crit Care Med. Apr 2007;28(2):193-200. [Medline].
18. Cheney PR. Update on emerging infections from the Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome--Colorado and New Mexico, 1998. Ann Emerg Med. Jan 1999;33(1):121-3. [Medline].
19. Chin C, Chiueh TS, Yang WC, et al. Hantavirus infection in Taiwan: the experience of a geographically unique area. J Med Virol. Feb 2000;60(2):237-47. [Medline].
20. Douglass RJ, Calisher CH, Bradley KC. State-by-state incidences of hantavirus pulmonary syndrome in the United States, 1993-2004. Vector Borne Zoonotic Dis. Summer 2005;5(2):189-92. [Medline].
21. Drebot MA, Artsob H, Werker D. Hantavirus pulmonary syndrome in Canada, 1989-1999. Can Commun Dis Rep. Apr 15 2000;26(8):65-9. [Medline].
22. Duchin JS, Koster FT, Peters CJ, et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group. N Engl J Med. Apr 7 1994;330(14):949-55. [Medline].
23. Ferreira MS, Nishioka Sd, Santos TL, et al. Hantavirus pulmonary syndrome in Brazil: clinical aspects of three new cases. Rev Inst Med Trop Sao Paulo. Jan-Feb 2000;42(1):41-6. [Medline].
24. Hallin GW, Simpson SQ, Crowell RE, et al. Cardiopulmonary manifestations of hantavirus pulmonary syndrome. Crit Care Med. Feb 1996;24(2):252-8. [Medline].
25. Hantavirus pulmonary syndrome--five states, 2006. MMWR Morb Mortal Wkly Rep. Jun 9 2006;55(22):627-9. [Medline].
26. Hjelle B, Glass GE. Outbreak of hantavirus infection in the Four Corners region of the United States in the wake of the 1997-1998 El Nino-southern oscillation. J Infect Dis. May 2000;181(5):1569-73. [Medline].
27. Khan AS, Gaviria M, Rollin PE, et al. Hantavirus pulmonary syndrome in Florida: association with the newly identified Black Creek Canal virus. Am J Med. Jan 1996;100(1):46-8. [Medline].
28. Khan AS, Khabbaz RF, Armstrong LR, et al. Hantavirus pulmonary syndrome: the first 100 US cases. J Infect Dis. Jun 1996;173(6):1297-303. [Medline].
29. Klein SL, Calisher CH. Emergence and persistence of hantaviruses. Curr Top Microbiol Immunol. 2007;315:217-52. [Medline].
30. Koraka P, Avsic-Zupanc T, Osterhaus AD, Groen J. Evaluation of two commercially available immunoassays for the detection of hantavirus antibodies in serum samples. J Clin Virol. Sep 1 2000;17(3):189-96. [Medline].
31. Maeda K, West K, Toyosaki-Maeda T, et al. Identification and analysis for cross-reactivity among hantaviruses of H-2b-restricted cytotoxic T-lymphocyte epitopes in Sin Nombre virus nucleocapsid protein. J Gen Virol. Jul 2004;85(Pt 7):1909-19. [Medline].
32. Maes P, Clement J, Gavrilovskaya I, Van Ranst M. Hantaviruses: immunology, treatment, and prevention. Viral Immunol. 2004;17(4):481-97. [Medline].
33. Mertz GJ, Hjelle B, Crowley M, Iwamoto G, Tomicic V, Vial PA. Diagnosis and treatment of new world hantavirus infections. Curr Opin Infect Dis. Oct 2006;19(5):437-42. [Medline].
34. Mills JN, Corneli A, Young JC, et al. Hantavirus pulmonary syndrome--United States: updated recommendations for risk reduction. Centers for Disease Control and Prevention. MMWR Recomm Rep. Jul 26 2002;51(RR-9):1-12. [Medline].
35. Saggioro FP, Rossi MA, Duarte MI, et al. Hantavirus infection induces a typical myocarditis that may be responsible for myocardial depression and shock in hantavirus pulmonary syndrome. J Infect Dis. May 15 2007;195(10):1541-9. [Medline].
36. Seitsonen E, Hynninen M, Kolho E, et al. Corticosteroids combined with continuous veno-venous hemodiafiltration for treatment of hantavirus pulmonary syndrome caused by Puumala virus infection. Eur J Clin Microbiol Infect Dis. Mar 21 2006;[Medline].
37. Shope RE. A midcourse assessment of hantavirus pulmonary syndrome. Emerg Infect Dis. Jan-Feb 1999;5(1):172-4. [Medline].
38. Terajima M, Hayasaka D, Maeda K, Ennis FA. Immunopathogenesis of hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome: Do CD8+ T cells trigger capillary leakage in viral hemorrhagic fevers?. Immunol Lett. Nov 15 2007;113(2):117-20. [Medline].
39. Wells RM, Sosa Estani S, Yadon ZE, et al. An unusual hantavirus outbreak in southern Argentina: person-to-person transmission? Hantavirus Pulmonary Syndrome Study Group for Patagonia. Emerg Infect Dis. Apr-Jun 1997;3(2):171-4. [Medline].
40. Zaki SR, Greer PW, Coffield LM, et al. Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol. Mar 1995;146(3):552-79. [Medline].

Article Last Updated: Aug 11, 2008