Hantavirus Pulmonary Syndrome

Back

Background

In May 1993, an unusual cluster of deaths occurred in the southwestern United States. The deaths were characterized by a febrile prodrome that preceded acute respiratory failure and shock. Physicians from the Indian Health Service and the Centers for Disease Control and Prevention (CDC) determined that a rodent vector was responsible for the infection and identified the responsible virus as a member of the Hantavirus family.

Sin Nombre virus (SNV), as it is now known, is the primary agent responsible for Hantavirus pulmonary syndrome (HPS) and the deadliest member of the Hantavirus family. However, there are numerous other pathogenic hantaviruses. The New York virus has been identified as the cause of HPS in New York and Rhode Island, and the Bayou and Black Creek Canal viruses, found in the southeastern United States, produce a variant of the syndrome that includes a greater degree of renal failure. The more distantly related Hantaan, Seoul, Dobrava/Belgrade, and Puumala hantaviruses produce a distinct syndrome of hemorrhagic fever and renal failure (HFRS).

The hantaviruses are RNA zoonotic viruses that are generally spherical in shape, measuring 70-100 nm in diameter, and can be identified by inclusion bodies and distinctive gridlike patterns on electron microscopy. They are transmitted to humans from rodent hosts, including possibly from pet rats,[1] but, except for the Andes hantavirus, have not been shown to be capable of human-to-human transmission.

Retrospective analyses indicate that HPS has been present in North America since as early as 1959, and Hantavirus infections have now been reported in at least 32 states in the United States, as well as in Canada and South America.

Pathophysiology

The basic pathophysiological lesion of HPS, and indeed of all Hantavirus infections, is a generalized increase in capillary permeability that results from endothelial damage. This injury appears to be a consequence of the host's immunological response to viral antigens that have penetrated the endothelium by means of the cells' own integrins. The onset of clinical symptoms is correlated with the development of specific antibodies to the virus. The increased capillary permeability gives rise to widespread protein-rich edema. The particular organs affected are related to the specific species of Hantavirus. In HFRS, a large outpouring of edema fluid flows into the retroperitoneum and is associated with hemorrhage and necrosis. Individuals with HPS have edema concentrated in the pleura and lungs.

The endothelial cells appear swollen. Lung examination findings reveal an interstitial pneumonitis made up of edema fluid, mononuclear cells, and lymphocytes with polymorphonuclear leukocytes. Hyaline membranes appear along with a proliferation of type 2 alveolar lining cells. As the disease progresses, the alveolar septa become increasingly fibrotic. The spleen in patients with HPS shows infiltration of immunocompetent cells within the red pulp and the periarteriolar sheaths.

HPS can present clinically as noncardiogenic pulmonary edema. The pathophysiology of the pulmonary findings is that of a pulmonary capillary leak syndrome. The heart is not directly affected. The pulmonary capillary leak syndrome is the primary underlying pathophysiological defect responsible for both cardiopulmonary and renal dysfunction. Prerenal azotemia is due to the inadequate intravascular volume of the hypotensive patient and not to direct infection. Hantavirus particles are not found within the renal tubular cells of patients with HPS. Hypoxia also contributes to the state of shock.

Epidemiology

Frequency

United States

HPS occurs primarily in the fall, when small rodents (eg, field mice) inhabit human dwellings to protect themselves from the cold weather. In the wild, many small rodents (eg, voles, white-footed deer mice) also transmit the virus. Inhalation of infected aerosolized rodent urine or dried excreta can lead to infection with HPS. Human-to-human transmission of HPS has not been reported in the United States, nor have nosocomial infections been reported. HPS is a zoonosis and parallels the distribution of the associated rodent vectors. The climactic conditions of El Niño promote the transmission of the causative virus.

International

Hantavirus infections occur in eastern Asia, Latin America, and North America, including Canada. However, HPS seems to be restricted to North and South America. While human-to-human transmission has not been reported in the United States, outbreaks of HPS reported from Argentina were possibly associated with human-to-human transmission.[2, 3, 4]

One report suggests clinical and pathological findings in 3 cases of severe European Puumala hantavirus infection were similar to those found in American hantavirus patients and met the case definition of HPS.[5]

Mortality/Morbidity

Initially, HPS was thought to be uniformly lethal. Current experience indicates that HPS represents a wide spectrum of clinical disease, from mild infection in ambulatory patients to severe infection requiring mechanical ventilation. The fatality rate for the complete syndrome is approximately 50%.

Recent studies have suggested that asymptomatic Hantavirus infection may be quite common, with some populations showing up to 4% seropositivity for anti-Hantavirus antibodies.[6]

Race

HPS has no racial predilection.

Sex

HPS has no sexual predilection; however, because of cultural sex roles, males are more likely than females to encounter small rodents in hunting and/or field exposures.

Age

HPS is conspicuously absent among very young persons and very elderly persons. This absence may reflect their relative lack of contact with rodents in the outdoor setting. However, infections in these age groups appear to be more deadly.[7]

Breed

The small rodent vectors of Hantavirus are thought to be lifelong carriers of the virus and are not subject to symptomatic infection by the virus. The deer mouse (Peromyscus maniculatus) is the primary reservoir for SNV in the western United States. Some attention has also been given to the cactus mouse (Peromyscus eremicus) in this region. The white-footed mouse (Peromyscus leucopus) serves that role for SNV and the New York virus in the northeastern United States.[8]

Prognosis

The prognosis of HPS varies, although it appears to correlate with the severity of disease. It does not appear to correlate with viral load.

Mild cases of HPS are typically nonfatal, and patients can be expected to make a full recovery. Most patients who recover from near-fatal HPS do not have any residual cardiopulmonary disease, although recovery time may be substantially longer. Superinfection has been observed in more severe cases.

Patient Education

The CDC has provided patient education materials for the prevention of Hantavirus pulmonary syndrome in hikers and campers.

History

The incubation period of Hantavirus pulmonary syndrome (HPS) ranges from 1-4 weeks. HPS has been divided into 3 clinical phases: (1) the prodromal phase, (2) the cardiopulmonary phase, and (3) the convalescent phase.

Prodromal symptoms resemble those of many viral illnesses, including fever, headache, and myalgias. Vomiting, diarrhea, and abdominal pain are common. Because symptoms initially referable to the respiratory tract are minimal or absent, the physician may incorrectly conclude that the patient has viral gastroenteritis. Neurologic symptoms, except dizziness, are uncommon. This phase lasts 3-5 days.

The cardiopulmonary phase is initiated by dyspnea, nonproductive cough, and circulatory collapse. This stage typically lasts only 24-48 hours, although has been observed for up to 7 days. Seventy-five percent of patients with pulmonary edema require mechanical ventilation. Oliguric renal failure is uncommon. When it does occur, it is due to acute tubular necrosis (ATN), as compared to the renal tubular cell damage observed in hemorrhagic fever with renal failure syndrome (HFRS).

Resolution of the cardiopulmonary stage of HPS is heralded by the onset of significant diuresis. After this occurs, the patient improves quite rapidly (ie, convalescent phase). The chronic sequelae of HPS are minimal.

Physical Examination

Physical examination findings of Hantavirus pulmonary syndrome are typically consistent with those of sepsis, as follows:

Causes

Sin Nombre virus (SNV) is the primary agent responsible for Hantavirus pulmonary syndrome (HPS) and is the deadliest member of the Hantavirus family. However, there are numerous other pathogenic hantaviruses. The New York virus has been identified as the cause of HPS in New York and Rhode Island, and the Bayou and Black Creek Canal viruses, found in the southeastern United States, produce a variant of the syndrome that includes a greater degree of renal failure. The more distantly related Hantaan, Seoul, Dobrava/Belgrade, and Puumala hantaviruses produce a distinct syndrome of hemorrhagic fever and renal failure (HFRS).

Complications

Renal failure due to ATN may occur.

Severe capillary pulmonary leakage may result in intractable noncardiogenic pulmonary edema and cardiorespiratory collapse and/or shock.

Laboratory Studies

Specific diagnosis of Hantavirus pulmonary syndrome (HPS) may be achieved by serological techniques, polymerase chain reaction (PCR), and immunohistochemistry (IHC) studies, as follows:

The following are other laboratory results that may aid in diagnosis:

The serum albumin level is decreased in almost all patients with Hantavirus pulmonary syndrome (HPS). Although this depression represents an acute-phase reactant that may be observed in many types of infections, the presence of severe hypoalbuminemia in a previously healthy patient with an acute onset of respiratory distress should suggest HPS.

Isolation of Hantavirus in tissue culture is not clinically available because of the technical difficulty of achieving this and because of issues related to biosafety.

Imaging Studies

Chest Radiography

The chest radiograph typically shows a pattern of noncardiac pulmonary edema. Perihilar haziness ("shaggy heart sign") is characteristic of HPS. Almost all patients with HPS have interstitial edema due to pulmonary capillary leak, which manifests radiologically as peribronchial cuffing or Kerley B lines. Pleural effusions are also common.

The chest radiograph typically does not show new cardiomegaly or mediastinal widening.

Other Tests

Patients with HPS often have a normal pulmonary wedge pressure, decreased cardiac index, and elevated systemic vascular resistance. However, these studies are not necessary for the diagnosis.

Histologic Findings

The histologic findings of HPS are nonspecific and correlate with the pathophysiology of the disease. Histology of lung tissue reveals capillaritis, pulmonary capillary leak syndrome, or both. Hemorrhage is typically not observed. In patients with severe and/or prolonged hypotension, the kidneys may develop histological findings suggestive of ATN.

Approach Considerations

Currently, treatment for Hantavirus pulmonary syndrome (HPS) is primarily supportive in nature. The attending physician must pay careful attention to acid-base disturbances and fluid balance, as well as respiratory status. HPS is a nationally reportable condition, and the state health department should be contacted immediately for instructions on reporting and submitting samples.

Medical Care

The nucleoside analogue ribavirin has been shown to be effective in a related disease, hemorrhagic fever with renal failure syndrome (HFRS), which is also caused by the Hantaviruses. Ribavirin has also been shown to be effective against HPS in animal studies. However, a meta-analysis of only two small trials showed no mortality benefit for HPS in humans. Additional studies are underway.[10]

Extracorporeal membrane oxygenation (ECMO) has been used successfully in several patients.[11] ECMO was most effective when initiated prior to the development of hemodynamic instability and major coagulopathy.[12]

Some experts have suggested that VEGF antagonists may be effective for hantaviral infections based on the observed up-regulation of VEGF during infection. However, this has not been studied clinically.[13]

Treatment with corticosteroids has not been shown to affect mortality.[14]

Consultations

An infectious disease specialist should be consulted for every patient considered to have HPS or a zoonotic infectious disease, and a pulmonologist and critical care specialist should be involved intubation and mechanical ventilation may be required. 

Activity

 Some suggestion has also been made to reduce physical activity.

Prevention

Caution patients against having contact with rodents or aerosolized rodent urine or excreta. Dead rodents should not be handled without taking proper precautions and wearing protection. Make dwellings rodent-proof; follow cleanliness and maintenance procedures such that dwellings do not attract small rodents.

Currently, there are no widely available vaccines against Hantavirus infection, although a controversial inactivated Hantavirus vaccine has been used in Korea with some effect.[15]

Long-Term Monitoring

Continue monitoring patients with mild Hantavirus pulmonary syndrome (HPS) in an outpatient setting until they are completely well.

Patients with mild HPS often complain of substernal discomfort. In patients with such symptoms, perform an ECG and/or cardiac enzyme test to help exclude myocardial infarction. Substernal discomfort that is oppressive in character is common in patients recovering from HPS. Although a cardiac explanation for the chest pain is suggested by its sternal location, myocardial infarction is not a complication of HPS.

Author

David J Cennimo, MD, FAAP, FACP, AAHIVS, Assistant Professor of Medicine and Pediatrics, Adult and Pediatric Infectious Diseases, Rutgers New Jersey Medical School; Hospital Epidemiologist and Co-Director of Antimicrobial Stewardship, University Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Zachariah E Hale, MD, Resident Physician, Departments of Internal Medicine and Pediatrics, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Kenneth C Earhart, MD Deputy Head, Disease Surveillance Program, United States Naval Medical Research Unit #3

Kenneth C Earhart, MD is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and Undersea and Hyperbaric Medical Society

Disclosure: Nothing to disclose.

References

  1. Rubin R. Pet Rats Infect Daughter, Mother With Hantavirus. JAMA. 2017 Nov 28. 318 (20):1969. [View Abstract]
  2. Enria D, Padula P, Segura EL, et al. Hantavirus pulmonary syndrome in Argentina. Possibility of person to person transmission. Medicina (B Aires). 1996. 56(6):709-11. [View Abstract]
  3. Padula PJ, Edelstein A, Miguel SD, et al. Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology. 1998 Feb 15. 241(2):323-30. [View Abstract]
  4. Martinez VP, Bellomo CM, Cacace ML, Suarez P, Bogni L, Padula PJ. Hantavirus pulmonary syndrome in Argentina, 1995-2008. Emerg Infect Dis. 2010 Dec. 16(12):1853-60. [View Abstract]
  5. Rasmuson J, Andersson C, Norrman E, Haney M, Evander M, Ahlm C. Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus. Eur J Clin Microbiol Infect Dis. 2011 May. 30(5):685-90. [View Abstract]
  6. Rozental T, Silva ASVD, Oliveira RC, Favacho ARM, Oliveira MLA, Bastos FI, et al. Seroprevalence of Bartonella spp., Coxiella burnetii, and Hantavirus among people who inject drugs in Rio de Janeiro, Brazil: a retrospective assessment of a biobank. Rev Inst Med Trop Sao Paulo. 2018 Jul 19. 60:e31. [View Abstract]
  7. Fonseca LX, Oliveira SV, Duarte EC. Magnitude and distribution of deaths due to hantavirus in Brazil, 2007-2015. Epidemiol Serv Saude. 2018 Jun 28. 27 (2):e2017221. [View Abstract]
  8. Burns JE, Metzger ME, Messenger S, Fritz CL, Vilcins IE, Enge B, et al. Novel Focus of Sin Nombre Virus in Peromyscus eremicus Mice, Death Valley National Park, California, USA. Emerg Infect Dis. 2018 Jun. 24 (6):1112-1115. [View Abstract]
  9. Kuenzli AB, Marschall J, Schefold JC, Schafer M, Engler OB, Ackermann-Gäumann R, et al. Hantavirus Cardiopulmonary Syndrome Due to Imported Andes Hantavirus Infection in Switzerland: A Multidisciplinary Challenge, Two Cases and a Literature Review. Clin Infect Dis. 2018 May 22. [View Abstract]
  10. Moreli ML, Marques-Silva AC, Pimentel VA, da Costa VG. Effectiveness of the ribavirin in treatment of hantavirus infections in the Americas and Eurasia: a meta-analysis. Virusdisease. 2014. 25 (3):385-9. [View Abstract]
  11. Crowley MR, Katz RW, Kessler R, et al. Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation. Crit Care Med. 1998 Feb. 26(2):409-14. [View Abstract]
  12. Wernly JA, Dietl CA, Tabe CE, Pett SB, Crandall C, Milligan K, et al. Extracorporeal membrane oxygenation support improves survival of patients with Hantavirus cardiopulmonary syndrome refractory to medical treatment. Eur J Cardiothorac Surg. 2011 Dec. 40 (6):1334-40. [View Abstract]
  13. Alkharsah KR. VEGF Upregulation in Viral Infections and Its Possible Therapeutic Implications. Int J Mol Sci. 2018 Jun 1. 19 (6):[View Abstract]
  14. Vial PA, Valdivieso F, Ferres M, Riquelme R, Rioseco ML, Calvo M, et al. High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial. Clin Infect Dis. 2013 Oct. 57 (7):943-51. [View Abstract]
  15. Jung J, Ko SJ, Oh HS, Moon SM, Song JW, Huh K. Protective Effectiveness of Inactivated Hantavirus Vaccine Against Hemorrhagic Fever With Renal Syndrome. J Infect Dis. 2018 Apr 11. 217 (9):1417-1420. [View Abstract]
  16. Boroja M, Barrie JR, Raymond GS. Radiographic findings in 20 patients with Hantavirus pulmonary syndrome correlated with clinical outcome. AJR Am J Roentgenol. 2002 Jan. 178(1):159-63. [View Abstract]
  17. Butler JC, Peters CJ. Hantaviruses and hantavirus pulmonary syndrome. Clin Infect Dis. 1994 Sep. 19(3):387-94; quiz 395. [View Abstract]
  18. Carneiro M, Koch BE, Krummenauer EC, Machado JA. Hantavirus pulmonary syndrome: when should you consider this diagnosis?. Braz J Infect Dis. 2011 May-Jun. 15(3):298-9. [View Abstract]
  19. Castillo C, Naranjo J, Sepúlveda A, et al. Hantavirus pulmonary syndrome due to Andes virus in Temuco, Chile: clinical experience with 16 adults. Chest. 2001 Aug. 120(2):548-54. [View Abstract]
  20. Castillo C, Nicklas C, Mardones J, et al. Andes Hantavirus as possible cause of disease in travellers to South America. Travel Med Infect Dis. 2007 Jan. 5(1):30-4. [View Abstract]
  21. Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome--Northeastern United States, 1994. MMWR Morb Mortal Wkly Rep. 1994 Aug 5. 43(30):548-9, 555-6. [View Abstract]
  22. Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome--Vermont, 2000. JAMA. 2001 Aug 22-29. 286(8):912-3. [View Abstract]
  23. Chang B, Crowley M, Campen M, et al. Hantavirus cardiopulmonary syndrome. Semin Respir Crit Care Med. 2007 Apr. 28(2):193-200. [View Abstract]
  24. Chaparro J, Vega J, Terry W, et al. Assessment of person-to-person transmission of hantavirus pulmonary syndrome in a Chilean hospital setting. J Hosp Infect. 1998 Dec. 40(4):281-5. [View Abstract]
  25. Chapman LE, Khabbaz RF. Etiology and epidemiology of the Four Corners hantavirus outbreak. Infect Agents Dis. 1994 Oct. 3(5):234-44. [View Abstract]
  26. Christensen PJ, Armstrong LR, Fak JJ, et al. Regulation of rat pulmonary dendritic cell immunostimulatory activity by alveolar epithelial cell-derived granulocyte macrophage colony-stimulating factor. Am J Respir Cell Mol Biol. 1995 Oct. 13(4):426-33. [View Abstract]
  27. da Rosa Elkhoury M, da Silva Mendes W, Waldman EA, et al. Hantavirus pulmonary syndrome: prognostic factors for death in reported cases in Brazil. Trans R Soc Trop Med Hyg. 2012 May. 106(5):298-302. [View Abstract]
  28. da Silva MV, Vasconcelos MJ, Hidalgo NT, et al. Hantavirus pulmonary syndrome. Report of the first three cases in São Paulo, Brazil. Rev Inst Med Trop Sao Paulo. 1997 Jul-Aug. 39(4):231-4. [View Abstract]
  29. 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. 1994 Apr 7. 330(14):949-55. [View Abstract]
  30. Engelthaler DM, Mosley DG, Cheek JE, et al. Climatic and environmental patterns associated with hantavirus pulmonary syndrome, Four Corners region, United States. Emerg Infect Dis. 1999 Jan-Feb. 5(1):87-94. [View Abstract]
  31. Fulhorst CF, Milazzo ML, Armstrong LR, et al. Hantavirus and arenavirus antibodies in persons with occupational rodent exposure. Emerg Infect Dis. 2007 Apr. 13(4):532-8. [View Abstract]
  32. Hallin GW, Simpson SQ, Crowell RE, et al. Cardiopulmonary manifestations of hantavirus pulmonary syndrome. Crit Care Med. 1996 Feb. 24(2):252-8. [View Abstract]
  33. Jenison S, Hjelle B, Simpson S, et al. Hantavirus pulmonary syndrome: clinical, diagnostic, and virologic aspects. Semin Respir Infect. 1995 Dec. 10(4):259-269. [View Abstract]
  34. Ketai LH, Kelsey CA, Jordan K, et al. Distinguishing hantavirus pulmonary syndrome from acute respiratory distress syndrome by chest radiography: are there different radiographic manifestations of increased alveolar permeability?. J Thorac Imaging. 1998 Jul. 13(3):172-7. [View Abstract]
  35. Ketai LH, Williamson MR, Telepak RJ, et al. Hantavirus pulmonary syndrome: radiographic findings in 16 patients. Radiology. 1994 Jun. 191(3):665-8. [View Abstract]
  36. Khan AS, Khabbaz RF, Armstrong LR, et al. Hantavirus pulmonary syndrome: the first 100 US cases. J Infect Dis. 1996 Jun. 173(6):1297-303. [View Abstract]
  37. Khan AS, Kitsutani PT, Corneli AL. Hantavirus pulmonary syndrome in the Americas: the early years. Semin Respir Crit Care Med. 2000. 21(4):313-22. [View Abstract]
  38. Klein SL, Calisher CH. Emergence and persistence of hantaviruses. Curr Top Microbiol Immunol. 2007. 315:217-52. [View Abstract]
  39. Koch J, Brockmann SO, Winter C, et al. Significant increase of hantavirus infections in Germany since the beginning of 2007. Euro Surveill. 2007 May 3. 12(5):E070503.1. [View Abstract]
  40. Koster F, Foucar K, Hjelle B, et al. Rapid presumptive diagnosis of hantavirus cardiopulmonary syndrome by peripheral blood smear review. Am J Clin Pathol. 2001 Nov. 116(5):665-72. [View Abstract]
  41. Ksiazek TG, Peters CJ, Rollin PE, et al. Identification of a new North American hantavirus that causes acute pulmonary insufficiency. Am J Trop Med Hyg. 1995 Feb. 52(2):117-23. [View Abstract]
  42. Lazaro ME, Cantoni GE, Calanni LM, et al. Clusters of hantavirus infection, southern Argentina. Emerg Infect Dis. 2007 Jan. 13(1):104-10. [View Abstract]
  43. Levy H, Simpson SQ. Hantavirus pulmonary syndrome. Am J Respir Crit Care Med. 1994 Jun. 149(6):1710-3. [View Abstract]
  44. Macneil A, Nichol ST, Spiropoulou CF. Hantavirus pulmonary syndrome. Virus Res. 2011 Dec. 162(1-2):138-47. [View Abstract]
  45. Mehta S, Jiandani P. Ocular features of hantavirus infection. Indian J Ophthalmol. 2007 Sep-Oct. 55(5):378-80. [View Abstract]
  46. Mertz GJ, Hjelle BL, Bryan RT. Hantavirus infection. Adv Intern Med. 1997. 42:369-421. [View Abstract]
  47. Miedzinski L. Community-acquired pneumonia: new facets of an old disease--Hantavirus pulmonary syndrome. Respir Care Clin N Am. 2005 Mar. 11(1):45-58. [View Abstract]
  48. 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. 2002 Jul 26. 51:1-12. [View Abstract]
  49. Montgomery JM, Ksiazek TG, Khan AS. Hantavirus pulmonary syndrome: the sound of a mouse roaring. J Infect Dis. 2007 Jun 1. 195(11):1553-5. [View Abstract]
  50. Moolenaar RL, Dalton C, Lipman HB, et al. Clinical features that differentiate hantavirus pulmonary syndrome from three other acute respiratory illnesses. Clin Infect Dis. 1995 Sep. 21(3):643-9. [View Abstract]
  51. Murgue B, Domart Y, Coudrier D, et al. First reported case of imported hantavirus pulmonary syndrome in europe. Emerg Infect Dis. 2002 Jan. 8(1):106-7. [View Abstract]
  52. Outbreak news. Hantavirus pulmonary syndrome, Yosemite National Park, United States of America. Wkly Epidemiol Rec. 2012 Sep 14. 87(37):345-6. [View Abstract]
  53. Padula P, Martinez VP, Bellomo C, et al. Pathogenic hantaviruses, northeastern Argentina and eastern Paraguay. Emerg Infect Dis. 2007 Aug. 13(8):1211-4. [View Abstract]
  54. Passaro DJ, Shieh WJ, Hacker JK, et al. Predominant kidney involvement in a fatal case of hantavirus pulmonary syndrome caused by Sin Nombre virus. Clin Infect Dis. 2001 Jul 15. 33(2):263-4. [View Abstract]
  55. Peters CJ, Khan AS. Hantavirus pulmonary syndrome: the new American hemorrhagic fever. Clin Infect Dis. 2002 May 1. 34(9):1224-31. [View Abstract]
  56. Pini NC, Resa A, del Jesús Laime G, et al. Hantavirus infection in children in Argentina. Emerg Infect Dis. 1998 Jan-Mar. 4(1):85-7. [View Abstract]
  57. Ramos MM, Overturf GD, Crowley MR, et al. Infection with Sin Nombre hantavirus: clinical presentation and outcome in children and adolescents. Pediatrics. 2001 Aug. 108(2):E27. [View Abstract]
  58. Rasmuson J, Andersson C, Norrman E, et al. Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus. Eur J Clin Microbiol Infect Dis. 2011 May. 30(5):685-90. [View Abstract]
  59. Rosenberg RB, Waagner DC, Romano MJ, et al. Hantavirus pulmonary syndrome treated with inhaled nitric oxide. Pediatr Infect Dis J. 1998 Aug. 17(8):749-52. [View Abstract]
  60. 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. 2007 May 15. 195(10):1541-9. [View Abstract]
  61. Shefer AM, Tappero JW, Bresee JS, et al. Hantavirus pulmonary syndrome in California: report of two cases and investigation. Clin Infect Dis. 1994 Dec. 19(6):1105-9. [View Abstract]
  62. Simpson SQ, Spikes L, Patel S, Faruqi I. Hantavirus pulmonary syndrome. Infect Dis Clin North Am. 2010 Mar. 24(1):159-73. [View Abstract]
  63. Slama TG, Zon R. Fatal hantavirus pulmonary syndrome in Indiana. N Engl J Med. 1994 Apr 7. 330(14):1010. [View Abstract]
  64. Smithee L, Bos J, Mallonee S, et al. Update on hantavirus in Oklahoma: are we missing cases?. J Okla State Med Assoc. 2007 May. 100(5):145-8. [View Abstract]
  65. Tahirkheli NK, Greipp PR. Treatment of the systemic capillary leak syndrome with terbutaline and theophylline. A case series. Ann Intern Med. 1999 Jun 1. 130(11):905-9. [View Abstract]
  66. Verity R, Prasad E, Grimsrud K, et al. Hantavirus pulmonary syndrome in northern Alberta, Canada: clinical and laboratory findings for 19 cases. Clin Infect Dis. 2000 Oct. 31(4):942-6. [View Abstract]
  67. Vinh DC, Embil JM. Hantavirus pulmonary syndrome: a concise clinical review. South Med J. 2009 Jun. 102(6):620-5. [View Abstract]
  68. Werker DH, Artsob H. Of mice and mostly men--hantavirus pulmonary syndrome. CMAJ. 1998 Apr 7. 158(7):912-5. [View Abstract]
  69. Young JC, Hansen GR, Graves TK, et al. The incubation period of hantavirus pulmonary syndrome. Am J Trop Med Hyg. 2000 Jun. 62(6):714-7. [View Abstract]
  70. Zaki SR, Greer PW, Coffield LM, et al. Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol. 1995 Mar. 146(3):552-79. [View Abstract]
  71. Zavasky DM, Hjelle B, Peterson MC, et al. Acute infection with Sin Nombre hantavirus without pulmonary edema. Clin Infect Dis. 1999 Sep. 29(3):664-6. [View Abstract]